Magnetic Resonance Imaging of the Brain and Spine [5 edition] 9781469873206

Table of contents :
Title Page
Copyright
Dedication
Contributing Authors
Preface
Contents
P r e f a c e
PART I: PRINCIPLES
Chapter 1: Instrumentation: Magnets, Coils, and Hardware
L u c a M a r i n e l l i , J o h n F . S c h e n c k , a n d D o
T Y P E S O F M A G N E T I C F I E L D C O I L S
M A I N F I E L D M A G N E T S
G R A D I E N T C O I L S
R A D I O F R E Q U E N C Y C O I L S
M R I A T H I G H E R F I E L D S T R E N G T H S
S A F E T Y O F M R I
M R I S Y S T E M A R C H I T E C T U R E
R F S U R F A C E C O I L A R R A Y S A N D A C C E L E R A T E D
A C K N O W L E D G M E N T S
R E F E R E N C E S
Chapter 2: From Image Formation to Image Contrast: Understanding Contrast Mechanisms, Acquisition Strategies, and Artifacts
S e a n C . L . D e o n i
P A R T I : F U N D A M E N T A L S O F I M A G E D A T A A C Q U
S P A T I A L R E S O L U T I O N , F I E L D O F V I E W , A N D
S I G N A L E V O L U T I O N A N D R E L A X A T I O N
P A R T I I : M E C H A N I S M S A N D M A N I P U L A T I O N O F
B I O P H Y S I C A L B A S I S O F R E L A X A T I O N A N D P R O
C O N V E N T I O N A L T 1 , T 2 , T 2 * , A N D P D - W E I G H T
A C H I E V I N G T 1 , T 2 , T * 2 , A N D P R O T O N D E N S I
M A G N E T I Z A T I O N T R A N S F E R I M A G I N G
M A G N E T I C S U S C E P T I B I L I T Y W E I G H T E D I M A G I N
D I F F U S I O N W E I G H T E D I M A G I N G
P A R T I I I : R A P I D I M A G E A C Q U I S I T I O N
R A P I D A C Q U I S I T I O N T E C H N I Q U E S
P A R T I A L F O U R I E R A C Q U I S I T I O N S
P A R A L L E L I M A G I N G
C O N C L U S I O N
A P P E N D I X A
R E F E R E N C E S
Chapter 3: Contrast Agents and Relaxation Effects
J o h n C . G o r e , M a t t h e w R . H i g h t , J a m e s M
R E L A X A T I O N T H E O R Y I N S O L U T I O N S
P A R A M A G N E T I C R E L A X A T I O N
E X C H A N G E E F F E C T S
D E L I V E R Y M E T H O D S
S M A R T A G E N T S
T A R G E T E D A G E N T S
C H E M I C A L E X C H A N G E A G E N T S
E N D O G E N O U S A G E N T S A N D H Y P E R P O L A R I Z A T I O N
S U S C E P T I B I L I T Y A G E N T S
C O N C L U S I O N S
R E F E R E N C E S
PART II: BRAIN AND SKULL BASE
Chapter 4: Disorders of Brain Development
T h i e r r y A . G . M . H u i s m a n a n d A n d r e a P o r e t
C E N T R A L N E R V O U S S Y S T E M E M B R Y O G E N E S I S
C L A S S I F I C A T I O N O F C N S M A L F O R M A T I O N S
A n o m a l i e s o f t h e C o r p u s C a l l o s u m a n d O t
M a l f o r m a t i o n o f C e r e b r a l C o r t i c a l D e v e l
M a l f o r m a t i o n s D u e t o A b n o r m a l N e u r o n a l
M a l f o r m a t i o n s S e c o n d a r y t o A b n o r m a l N e u
M a l f o r m a t i o n s S e c o n d a r y t o A b n o r m a l C o r
H o l o p r o s e n c e p h a l y
M i d d l e I n t e r h e m i s p h e r i c V a r i a n t o f H P E
S e p t o - O p t i c D y s p l a s i a
K a l l m a n n S y n d r o m e
N o r m a l D e v e l o p m e n t
D e v e l o p m e n t a l O r i g i n s o f t h e C e r e b e l l u m
N e u r o g e n e s i s i n t h e D e v e l o p i n g C e r e b e l l
M i g r a t i o n o f C e r e b e l l a r N e u r o n s
P r e d o m i n a n t l y C e r e b e l l a r M a l f o r m a t i o n s
C e r e b e l l a r H y p o p l a s i a
D a n d y – W a l k e r M a l f o r m a t i o n a n d O t h e r C y s
B l a k e ’ s P o u c h C y s t
P o s t e r i o r F o s s a A r a c h n o i d C y s t s
M e g a C i s t e r n a M a g n a
R h o m b e n c e p h a l o s y n a p s i s
C e r e b e l l a r D y s p l a s i a
C h u d l e y – M c C u l l o u g h S y n d r o m e
P o r e t t i – B o l t s h a u s e r S y n d r o m e
G P R 5 6 - R e l a t e d P o l y m i c r o g y r i a
C e r e b e l l a r H y p e r p l a s i a o r M a c r o c e r e b e l l
P o n t o c e r e b e l l a r H y p o p l a s i a
C e r e b e l l a r A g e n e s i s
J o u b e r t S y n d r o m e
P o n t i n e T e g m e n t a l C a p D y s p l a s i a
B r a i n s t e m D i s c o n n e c t i o n
H o r i z o n t a l G a z e P a l s y w i t h P r o g r e s s i v e
L 1 S y n d r o m e D u e t o M u t a t i o n s i n L 1 C A M
O t h e r D i s o r d e r s w i t h P r e d o m i n a n t l y B r a i
C h i a r i T y p e I M a l f o r m a t i o n
C h i a r i T y p e I I M a l f o r m a t i o n
C h i a r i T y p e I I I M a l f o r m a t i o n
C e p h a l o c e l e s
A t r e t i c C e p h a l o c e l e s
O c c i p i t a l C e p h a l o c e l e s
S p h e n o i d a l C e p h a l o c e l e s
L i p o m a s
D e r m o i d s a n d E p i d e r m o i d s
D e r m o i d s
E p i d e r m o i d s
A r a c h n o i d C y s t s
C N S V A S C U L A R M A L F O R M A T I O N S
N o r m a l A r t e r i a l D e v e l o p m e n t
C a r o t i d A g e n e s i s o r H y p o g e n e s i s
T r i g e m i n a l A r t e r y a n d O t h e r V a r i a n t s
A z y g o s A n t e r i o r C e r e b r a l A r t e r y
C e r e b r a l A n e u r y s m
N o r m a l V e n o u s D e v e l o p m e n t
A r t e r i o v e n o u s M a l f o r m a t i o n s i n c l u d i n g V
C a v e r n o u s A n g i o m a a n d D e v e l o p m e n t a l V e n
R E F E R E N C E S
Chapter 5: Central Nervous System Manifestations of the Phakomatoses
S u s a n I . B l a s e r , J a m e s G . S m i r n i o t o p o u l
G E N E R A L C O N C E P T S
T H E C O M M O N P H A K O M A T O S E S
A D D I T I O N A L V A S C U L A R P H A K O M A T O S E S
P H A C E S
C O N C L U S I O N
A C K N O W L E D G M E N T S
R E F E R E N C E S
Chapter 6: White Matter Diseases and Inherited Metabolic Disorders
M a r i a A . R o c c a , A n n e t t e O . N u s b a u m , M a r
C L A S S I F I C A T I O N O F W H I T E M A T T E R D I S E A S E S
D i f f u s i o n T e n s o r M R I
P r o t o n ( 1 H ) M R S p e c t r o s c o p y
D E M Y E L I N A T I N G D I S E A S E S
M u l t i p l e S c l e r o s i s
N e u r o m y e l i t i s O p t i c a a n d N M O S p e c t r u m D
I n f l a m m a t o r y D e m y e l i n a t i n g P s e u d o t u m o r
A c u t e D i s s e m i n a t e d E n c e p h a l o m y e l i t i s ( P
A c u t e H e m o r r h a g i c L e u k o e n c e p h a l i t i s
S u b a c u t e S c l e r o s i n g P a n e n c e p h a l i t i s
P r o g r e s s i v e R u b e l l a P a n e n c e p h a l i t i s
P r o g r e s s i v e M u l t i f o c a l L e u k o e n c e p h a l o p a
H u m a n I m m u n o d e f i c i e n c y V i r u s E n c e p h a l o p
C e n t r a l P o n t i n e a n d E x t r a p o n t i n e M y e l i n
M a r c h i a f a v a – B i g n a m i D i s e a s e
S u b a c u t e C o m b i n e d D e g e n e r a t i o n o f t h e S
H y p e r t e n s i v e E n c e p h a l o p a t h y ( R e v e r s i b l e
I s c h e m i a a n d A r t e r i t i s
S a r c o i d o s i s
L y m e D i s e a s e
I N H E R I T E D M E T A B O L I C D I S O R D E R S
C l i n i c a l F e a t u r e s
P a t h o l o g i c F i n d i n g s
M R I F i n d i n g s
C l i n i c a l F e a t u r e s
M R I F i n d i n g s
C l i n i c a l F e a t u r e s
M R I F i n d i n g s
C l i n i c a l F e a t u r e s
M R I F i n d i n g s
C l i n i c a l F e a t u r e s
M R I F i n d i n g s
C l i n i c a l F e a t u r e s
P a t h o l o g i c F i n d i n g s
M R I F i n d i n g s
C a n a v a n D i s e a s e
A l e x a n d e r D i s e a s e
V a n i s h i n g W h i t e M a t t e r D i s e a s e
P a t h o l o g i c F e a t u r e s
M R I F i n d i n g s
C l i n i c a l F e a t u r e s
P a t h o l o g i c F i n d i n g s
M R I F i n d i n g s
1 8 q - S y n d r o m e
R E F E R E N C E S
Chapter 7: Epilepsy
W i l l i a m B . Z u c c o n i , V i v e k G u p t a , a n d R i
M R I I N E P I L E P S Y A N D E P I L E P S Y S U R G E R Y
M A G N E T I C R E S O N A N C E I M A G I N G O F E P I L E P S Y
S T R A T E G I E S F O R S U C C E S S F U L I N T E R P R E T A T I O
M A G N E T I C R E S O N A N C E I N E P I L E P S Y B E Y O N D A
R E F E R E N C E S
Chapter 8: Adult Brain Tumors
B r u n o T e l l e s , F r a n c e s c o D ’ A m o r e , M a h e s h
F U N D A M E N T A L S O F L E S I O N L O C A L I Z A T I O N A N D
L E S I O N C H A R A C T E R I Z A T I O N
T U M O R E N H A N C E M E N T A N D T H E B L O O D – B R A I N B
A D V A N C E D L E S I O N C H A R A C T E R I Z A T I O N T O O L S :
D y n a m i c S u s c e p t i b i l i t y C o n t r a s t M R I a n d
D y n a m i c C o n t r a s t - E n h a n c e d M R I a n d V a s c u
A r t e r i a l S p i n - L a b e l i n g ( A S L )
P R I M A R Y B R A I N T U M O R S
F i b r i l l a r y ( D i f f u s e ) A s t r o c y t o m a
P r o t o p l a s m i c A s t r o c y t o m a
A n a p l a s t i c A s t r o c y t o m a
G l i o m a t o s i s C e r e b r i
G l i o b l a s t o m a M u l t i f o r m e ( G B M )
G l i o s a r c o m a
C h o r d o i d G l i o m a
P i l o c y t i c A s t r o c y t o m a
T e c t a l G l i o m a
S u b e p e n d y m a l G i a n t C e l l A s t r o c y t o m a
P l e o m o r p h i c X a n t h o a s t r o c y t o m a ( P X A )
G a n g l i o c y t o m a a n d G a n g l i o g l i o m a
D y s p l a s t i c C e r e b e l l a r G a n g l i o c y t o m a ( L h
C e n t r a l N e u r o c y t o m a
P I N E A L R E G I O N T U M O R S
C O L L O I D C Y S T S
P R I M A R Y C E N T R A L N E R V O U S S Y S T E M L Y M P H O M A
M E T A S T A T I C D I S E A S E
R A D I A T I O N E F F E C T S
E X T R A - A X I A L T U M O R S
M e n i n g i o m a s
L y m p h o m a
S a r c o i d o s i s
E x t r a - a x i a l M e t a s t a s e s
A r a c h n o i d C y s t s
E p i d e r m o i d C y s t s
D e r m o i d C y s t s
C O N C L U S I O N
A C K N O W L E D G M E N T
R E F E R E N C E S
Chapter 9: Pediatric Brain Tumors
R o b e r t A . Z i m m e r m a n a n d L a r i s s a T . B i l a
I M A G I N G E V A L U A T I O N F O R P E D I A T R I C C E N T R A
I N F R A T E N T O R I A L T U M O R S
C e r e b e l l a r A s t r o c y t o m a s
C o m p u t e d T o m o g r a p h y
M a g n e t i c R e s o n a n c e I m a g i n g
C o m p u t e d T o m o g r a p h y
M a g n e t i c R e s o n a n c e I m a g i n g
C o m p u t e d T o m o g r a p h y
M a g n e t i c R e s o n a n c e I m a g i n g
C o m p u t e d T o m o g r a p h y
M a g n e t i c R e s o n a n c e I m a g i n g
S U P R A T E N T O R I A L T U M O R S
G l i o m a s
P i l o c y t i c A s t r o c y t o m a s
G a n g l i o g l i o m a
D e s m o p l a s t i c I n f a n t i l e G a n g l i o g l i o m a
P l e o m o r p h i c X a n t h o a s t r o c y t o m a s
D y s e m b r y o p l a s t i c N e u r o e p i t h e l i a l T u m o r
F i b r i l l a r y A s t r o c y t o m a s
G l i o m a t o s i s C e r e b r i
G l i o b l a s t o m a M u l t i f o r m e
S u b e p e n d y m a l G i a n t C e l l T u m o r s
C o m p u t e d T o m o g r a p h y
M a g n e t i c R e s o n a n c e I m a g i n g
C o m p u t e d T o m o g r a p h y
M a g n e t i c R e s o n a n c e I m a g i n g
C o m p u t e d T o m o g r a p h y
M a g n e t i c R e s o n a n c e I m a g i n g
C o m p u t e d T o m o g r a p h y
M a g n e t i c R e s o n a n c e I m a g i n g
C o m p u t e d T o m o g r a p h y
M a g n e t i c R e s o n a n c e I m a g i n g
M e t a s t a s e s
P l e x i f o r m N e u r o f i b r o m a s
S c h w a n n o m a s a n d M e n i n g i o m a s
C O N C L U S I O N
R E F E R E N C E S
Chapter 10: Intracranial Hemorrhage
S c o t t W . A t l a s a n d K e i t h R . T h u l b o r n
D i a m a g n e t i s m
P a r a m a g n e t i s m
A n t i f e r r o m a g n e t i s m , F e r r o m a g n e t i s m , a n d
A n t i f e r r i m a g n e t i s m a n d F e r r i m a g n e t i s m
M R C O N T R A S T
R e l a x i v i t y E f f e c t s
S u s c e p t i b i l i t y E f f e c t s
E x c h a n g e P r o c e s s e s
E V O L U T I O N O F I N T R A P A R E N C H Y M A L H E M A T O M A S
M R P A T T E R N S S P E C I F I C F O R C L I N I C A L E T I O L
S u b a r a c h n o i d H e m o r r h a g e
S u b d u r a l a n d E p i d u r a l H e m a t o m a s
C O N C L U S I O N
R E F E R E N C E S
Chapter 11: Intracranial Vascular Malformations and Aneurysms
N i c h o l a s A . T e l i s c h a k a n d H u y M . D o
V A S C U L A R M A L F O R M A T I O N S
C l i n i c a l F e a t u r e s
P a t h o l o g i c F i n d i n g s
P r e t r e a t m e n t G r a d i n g o f A r t e r i o v e n o u s M
T h e r a p y
M a g n e t i c R e s o n a n c e I m a g i n g
D i f f e r e n t i a l D i a g n o s i s
P o s t t h e r a p y M R
S p e c i a l i z e d M R T e c h n i q u e s i n A r t e r i o v e n
C l i n i c a l F e a t u r e s
P a t h o l o g i c F i n d i n g s
I m a g i n g C h a r a c t e r i s t i c s
C l i n i c a l F e a t u r e s
P a t h o l o g i c F i n d i n g s
I m a g i n g C h a r a c t e r i s t i c s
C l i n i c a l F e a t u r e s
M R C h a r a c t e r i s t i c s
I N T R A C R A N I A L A N E U R Y S M S
R E F E R E N C E S
Chapter 12: Cerebral Ischemia and Infarction
J e r e m y J . H e i t a n d M i c h a e l P . M a r k s
P A T H O P H Y S I O L O G Y O F C E R E B R A L I S C H E M I A
I S C H E M I C S T R O K E S U B T Y P E S
T R E A T M E N T O F I S C H E M I C S T R O K E
M R T E C H N I Q U E S I N I N F A R C T I O N
M R A P P E A R A N C E O F I N F A R C T I O N B Y E T I O L O G Y
I S C H E M I C I N J U R Y I N C H I L D R E N
C O N C L U S I O N
R E F E R E N C E S
Chapter 13: Head Trauma
J a s o n F . T a l b o t t a n d A l i s a G e a n
E P I D E M I O L O G Y O F H E A D I N J U R Y
P A T H O P H Y S I O L O G Y O F T B I
R E L A T I V E R O L E S O F I M A G I N G S T U D I E S F O R H
M A G N E T I C R E S O N A N C E I M A G I N G S T R A T E G I E S A
I N J U R Y C L A S S I F I C A T I O N
P R I M A R Y I N T R A - A X I A L L E S I O N S
A C K N O W L E D G M E N T
R E F E R E N C E S
Chapter 14: Intracranial Infection
L . C e l s o H y g i n o d a C r u z , J r
V I R A L I N F E C T I O N
H e r p e s S i m p l e x V i r u s T y p e 1
H e r p e s S i m p l e x V i r u s T y p e 2
V a r i c e l l a Z o s t e r V i r u s
E p s t e i n – B a r r V i r u s
C y t o m e g a l o v i r u s
H u m a n h e r p e s v i r u s t y p e s 6 a n d 7
I m m u n e R e c o n s t i t u t i o n I n f l a m m a t o r y S y n d
P e d i a t r i c H u m a n I m m u n o d e f i c i e n c y V i r u s
C r e u t z f e l d t – J a k o b D i s e a s e
B A C T E R I A L I N F E C T I O N
F U N G A L I N F E C T I O N
P A R A S I T I C I N F E C T I O N
C O N C L U S I O N
R E F E R E N C E S
Chapter 15: Normal Aging, Dementia, and Neurodegenerative Disease
K e j a l K a n t a r c i , D a v i d J . I r w i n , J o h n Q .
M R I B R A I N C H A N G E S A S S O C I A T E D W I T H A G I N G
T h e P a r i e t o p o n t i n e T r a c t s o f t h e P o s t e r
T h e T r i g o n e : T e r m i n a l A r e a s o f M y e l i n a t
T h e F r o n t a l H o r n s : E p e n d y m i t i s G r a n u l a r
P e r i v a s c u l a r S p a c e s o f V i r c h o w a n d R o b i
A L Z H E I M E R D I S E A S E
S t r u c t u r a l M R I i n A D
1 H M R S p e c t r o s c o p y i n A D
D i f f u s i o n - W e i g h t e d I m a g i n g a n d D i f f u s i o
M R P e r f u s i o n
F u n c t i o n a l M R I
M o l e c u l a r I m a g i n g o f A D - R e l a t e d P a t h o l o
C E R E B R A L V A S C U L A R D I S E A S E
D E M E N T I A W I T H L E W Y B O D I E S
P A R K I N S O N I S M — D I S E A S E S O F S U B S T A N T I A N I G
M u l t i p l e S y s t e m A t r o p h y – P a r k i n s o n i s m ( S
M u l t i p l e S y s t e m A t r o p h y – S h y – D r a g e r S y n d
M u l t i p l e S y s t e m A t r o p h y – C e r e b e l l a r T y p e
F R O N T O T E M P O R A L L O B A R D E G E N E R A T I O N
N e u r o i m a g i n g a n d P a t h o l o g y
C R E U T Z F E L D T – J A K O B D I S E A S E
N O R M A L - P R E S S U R E H Y D R O C E P H A L U S
D E G E N E R A T I V E D I S E A S E S O F T H E D E E P G R A Y
N e u r o i m a g i n g a n d P a t h o l o g y
D E G E N E R A T I O N O F T H E C E R E B E L L U M , B R A I N S T
N e u r o i m a g i n g a n d P a t h o l o g y
F r i e d r e i c h A t a x i a
N e u r o i m a g i n g a n d P a t h o l o g y
M O T O R N E U R O N D I S E A S E S
N e u r o i m a g i n g a n d P a t h o l o g y
C O N C L U S I O N
A C K N O W L E D G M E N T S
R E F E R E N C E S
Chapter 16: Skull Base
H i l l a r y R . K e l l y , J a n W . C a s s e l m a n , M a r
G E N E R A L C O N C E P T S : N O R M A L V E R S U S A B N O R M A
T U M O R , M A S S E S , A N D I N F E C T I O N
D i r e c t E x t e n s i o n
P e r i n e u r a l S p r e a d
H e m a t o g e n o u s M e t a s t a s i s
P e t r o u s A p e x L e s i o n s
E n d o l y m p h a t i c S a c T u m o r s
S c h w a n n o m a s
P a r a g a n g l i o m a s
B e n i g n V e n o u s M a l f o r m a t i o n s ( O s s i f y i n g
M i d d l e E a r I n f l a m m a t o r y / O b s t r u c t i v e D i s
C o n g e n i t a l D e a f n e s s a n d t h e I n t e r n a l A u
S i d e r o s i s
C O N G E N I T A L S K U L L B A S E D E F E C T S A N D A R A C H
S P E C I A L I Z E D T O P I C S I N S K U L L B A S E M R I
A n a t o m y
F a c i a l N e r v e P a t h o l o g y
A n a t o m y
M R T e c h n i q u e s f o r t h e L a b y r i n t h
C o n g e n i t a l M a l f o r m a t i o n s o f t h e I n n e r E
L a b y r i n t h i n e H e m o r r h a g e
L a b y r i n t h i t i s
P e r i l y m p h a t i c F i s t u l a
L a b y r i n t h i n e N e o p l a s m s
C O N C L U S I O N
R E F E R E N C E S
Chapter 17: The Sella Turcica and Parasellar Region
S e a n P . S y m o n s , M i c h a e l W . C h a n , R i c h a r
N O R M A L A N A T O M Y
T E C H N I Q U E
C O N G E N I T A L A B N O R M A L I T I E S
T U M O R S
A d a m a n t i n o m a t o u s C r a n i o p h a r y n g i o m a
P a p i l l a r y C r a n i o p h a r y n g i o m a
T U M O R L I K E C O N D I T I O N S
I N F L A M M A T O R Y L E S I O N S
N O N I N F E C T I O U S I N F L A M M A T O R Y L E S I O N S
V A S C U L A R A N D I S C H E M I C L E S I O N S
M E T A B O L I C D I S O R D E R S
Chapter 18: Eye and Orbit
J . L e v i C h a z e n , C . D o u g l a s P h i l l i p s , a n
E Y E A N D O R B I T
O r b i t a l W a l l s a n d C a n a l s
O c u l a r M e l a n o m a
O c u l a r M e t a s t a s e s
R e t i n o b l a s t o m a
P e r s i s t e n t H y p e r p l a s t i c P r i m a r y V i t r e o u
C o a t s D i s e a s e
C h o r o i d a l a n d R e t i n a l V a s c u l a r T u m o r s
R e t i n a l a n d C h o r o i d a l D e t a c h m e n t
E n l a r g e m e n t o f t h e E x t r a o c u l a r M u s c l e s
T h y r o i d O r b i t o p a t h y
I d i o p a t h i c O r b i t a l I n f l a m m a t o r y P s e u d o t
C a v e r n o u s S i n u s a n d S u p e r i o r O p h t h a l m i c
D i s c r e t e O r b i t a l M a s s
I n f a n t i l e H e m a n g i o m a
V e n o u s M a l f o r m a t i o n ( V M ) I n c l u d i n g C a v e
L y m p h a t i c M a l f o r m a t i o n ( L M )
A r t e r i o v e n o u s M a l f o r m a t i o n ( A V M )
V e n o u s V a r i x
N e u r o f i b r o m a a n d S c h w a n n o m a
R h a b d o m y o s a r c o m a
H e m a t i c C y s t
O r b i t a l I n f i l t r a t i v e P r o c e s s e s
E n l a r g e m e n t o f t h e O p t i c N e r v e / S h e a t h C
L a c r i m a l G l a n d E n l a r g e m e n t
S a r c o i d o s i s
L e s i o n s o f t h e B o n y O r b i t
R E F E R E N C E S
PART III: SPINE AND SPINAL CORD
Chapter 19: Congenital Anomalies of the Spine and Spinal Cord: Embryology and Malformations
T h o m a s P . N a i d i c h , A n d r e s W . S u , B r a d l e
O V E R V I E W O F N O R M A L E M B R Y O G E N E S I S
T w o - L a y e r e d G e r m i n a l D i s c
G a s t r u l a t i o n F o r m s t h e T h r e e - L a y e r e d G e
P r i m i t i v e ( H e n s e n ’ s ) N o d e , P r e c h o r d a l P
C o n v e r g e n t E x t e n s i o n
F o r m i n g t h e N e u r a l F o l d s
F u s i o n o f t h e N e u r a l F o l d s
N e u r a l C r e s t M i g r a t i o n
P o i n t s o f C l o s u r e o f t h e N e u r a l T u b e
D i s j u n c t i o n o f N e u r a l f r o m E p i d e r m a l E c
M o l e c u l a r S i g n a l i n g
P a t t e r n i n g t h e B o d y A x e s
D E R A N G E D P R I M A R Y N E U R U L A T I O N
D e v a s c u l a r i z a t i o n o f t h e P l a c o d e
L o c a l W o u n d S i t e
L a t e x A n a p h y l a x i s
R e t e t h e r i n g b y S c a r
I n c l u s i o n C y s t s
H y d r o m y e l i a
D i a s t e m a t o m y e l i a a n d H e m i m y e l o c e l e
S p i n a l C u r v a t u r e i n M y e l o m e n i n g o c e l e
E f f e c t o f U n t e t h e r i n g o n S p i n a l C u r v a t u
C o r d R e t e t h e r i n g a n d R e l e a s e o f t h e R e t
L i p o m a C l a s s i f i c a t i o n
S u r g i c a l C o n s i d e r a t i o n s
C o m p l i c a t i o n s o f S u r g e r y
P r o p h y l a c t i c S u r g e r y v e r s u s C o n s e r v a t i v
C o n c u r r e n t M a l f o r m a t i o n s
M R S p e c t r o s c o p y o f C S F
S E C O N D A R Y N E U R U L A T I O N
C a u d a l C e l l M a s s a n d C a n a l i z a t i o n
R e t r o g r e s s i v e D i f f e r e n t i a t i o n
C o n f i g u r a t i o n a n d T e r m i n a t i o n o f t h e D u
T h i c k n e s s o f t h e N o r m a l F i l u m
D E R A N G E D S E C O N D A R Y N E U R U L A T I O N
P r e n a t a l D i a g n o s i s a n d P r o g n o s i s
N O R M A L E M B R Y O G E N E S I S O F T H E N O T O C H O R D
D E R A N G E D E M B R Y O G E N E S I S O F T H E N O T O C H O R D
S i n g l e D u r a l – A r a c h n o i d T u b e ( P a n g T y p e
D u a l D u r a l – A r a c h n o i d T u b e s ( P a n g T y p e I
V a r i a n t F o r m s
N O R M A L E M B R Y O G E N E S I S O F T H E S P I N A L C O L U
A x i s E l o n g a t i o n
D o r s o v e n t r a l P a t t e r n i n g
R o s t r o c a u d a l P a t t e r n i n g a n d t h e H o x C o d
M e m b r a n e D e v e l o p m e n t ( F i f t h W e e k )
C h o n d r i f i c a t i o n ( S i x t h W e e k )
O s s i f i c a t i o n ( E i g h t h W e e k O n w a r d )
D E R A N G E D E M B R Y O G E N E S I S O F T H E S P I N A L C O
V A T E R A s s o c i a t i o n
O E I S C o m p l e x
C u r r a r i n o T r i a d
G o l d e n h a r C o m p l e x
C o n g e n i t a l V e r t e b r a l D i s l o c a t i o n
M u l t i p l e V e r t e b r a l S e g m e n t a t i o n D i s o r d e
A C K N O W L E D G M E N T S
R E F E R E N C E S
Chapter 20: Degenerative Disease of the Spine
R i c h a r d T . K a p l a n , L e o F . C z e r v i o n k e , a
M A G N E T I C R E S O N A N C E P U L S E S E Q U E N C E C O N S I
A N A T O M Y O F T H E I N T E R V E R T E B R A L D I S C
A G E - R E L A T E D C H A N G E S I N T H E I N T E R V E R T E B R
A N A T O M Y O F T H E A R T I C U L A R F A C E T S
D E G E N E R A T I O N O F T H E I N T E R V E R T E B R A L D I S C
C L A S S I F I C A T I O N O F L U M B A R D I S C P A T H O L O G Y
L U M B A R D I S C H E R N I A T I O N
T H O R A C I C D I S C H E R N I A T I O N
C E R V I C A L D I S C H E R N I A T I O N
S P I N A L S T E N O S I S , O S T E O A R T H R I T I S , A N D S P
L U M B A R S P I N A L S T E N O S I S
C E R V I C A L S P I N A L S T E N O S I S
Chapter 21: Neoplastic Disease of the Spine and Spinal Cord
P u n e e t S . P a w h a , G e r a r d M . R e d d y , a n d G
E X T R A D U R A L T U M O R S
V e r t e b r a l H e m a n g i o m a
O s t e o c h o n d r o m a
O s t e o i d O s t e o m a
O s t e o b l a s t o m a
A n e u r y s m a l B o n e C y s t
G i a n t C e l l T u m o r
S a c r o c o c c y g e a l T e r a t o m a
E o s i n o p h i l i c G r a n u l o m a
C h o r d o m a
N e u r o b l a s t o m a , G a n g l i o n e u r o m a , a n d G a n g
O s t e o s a r c o m a
C h o n d r o s a r c o m a
E w i n g S a r c o m a
L e u k e m i a
N o n - H o d g k i n L y m p h o m a
M e t a s t a t i c D i s e a s e t o t h e S p i n e a n d E x t
I N T R A D U R A L E X T R A M E D U L L A R Y T U M O R S
N e r v e S h e a t h T u m o r
M e n i n g i o m a
S p i n a l L e p t o m e n i n g e a l T u m o r
I N T R A M E D U L L A R Y T U M O R S
A s t r o c y t o m a
E p e n d y m o m a
H e m a n g i o b l a s t o m a
M e t a s t a t i c D i s e a s e t o t h e S p i n a l C o r d
D E V E L O P M E N T A L I N T R A D U R A L M A S S L E S I O N S (
R E F E R E N C E S
Chapter 22: MRI of Spinal Trauma
A d a m E . F l a n d e r s , E r i c D . S c h w a r t z , a n d
M R I T E C H N I Q U E S
C H A R A C T E R I Z A T I O N O F S P I N A L I N J U R Y U S I N G
S P I N A L C O R D I N J U R Y
A C K N O W L E D G M E N T S
R E F E R E N C E S
Chapter 23: Vascular Disorders of the Spine and Spinal Cord
A n t o n V a l a v a n i s a n d R o b e r t W . H u r s t
V A S C U L A R A N A T O M Y
C L A S S I F I C A T I O N O F S P I N E A N D S P I N A L C O R D
A n a t o m y a n d P a t h o p h y s i o l o g y
C l i n i c a l P r e s e n t a t i o n
M a g n e t i c R e s o n a n c e
A n a t o m y a n d P a t h o p h y s i o l o g y
C l i n i c a l P r e s e n t a t i o n
I m a g i n g
R E F E R E N C E S
Chapter 24: Spinal Infection and Inflammatory Disorders
R e n a t o A d a m M e n d o n ç a
I N F E C T I O U S S P O N D Y L O D I S C I T I S
S P I N A L C O R D I N F E C T I O N S
B r u c e l l o s i s
N e u r o b o r r e l i o s i s ( L y m e D i s e a s e )
L i s t e r i o s i s
T u b e r c u l o s i s
T u b e r c u l o u s S p o n d y l o d i s c i t i s
T u b e r c u l a r S p i n a l A r a c h n o i d i t i s
M y c o b a c t e r i u m A v i u m - i n t r a c e l l u l a r e
C o c c i d i o i d o m y c o s i s
A s p e r g i l l o s i s
C a n d i d i a s i s
H i s t o p l a s m o s i s
S p i n a l C y s t i c e r c o s i s
S p i n a l C o r d S c h i s t o s o m i a s i s
S p i n a l E c h i n o c o c c o s i s
T o x o p l a s m o s i s
H e r p e s v i r u s
P o l i o v i r u s
H u m a n I m m u n o d e f i c i e n c y V i r u s
T r o p i c a l S p a s t i c P a r a p a r e s i s
R E F E R E N C E S
PART IV: ADVANCED APPLICATIONS
Chapter 25: MR Angiography: Techniques and Clinical Applications
W e n d e N . G i b b s a n d J o s e p h E . H e i s e r m a n
P h a s e E f f e c t s
I M A G I N G B L O O D F L O W
T w o - D i m e n s i o n a l T i m e o f F l i g h t
T h r e e - D i m e n s i o n a l T i m e o f F l i g h t
O v e r l a p p i n g S l a b A c q u i s i t i o n
k - S p a c e A c q u i s i t i o n S c h e m e s
E x t r a c r a n i a l C i r c u l a t i o n
T H E I N T R A C R A N I A L C I R C U L A T I O N
D i a g n o s i s a n d T r i a g e
A s s e s s m e n t o f V i a b l e B r a i n T i s s u e
C o l l a t e r a l C i r c u l a t i o n
I m a g i n g C h o i c e s i n A c u t e S t r o k e
I N T R A C R A N I A L A T H E R O S C L E R O T I C D I S E A S E
I m a g i n g M e t h o d s i n I A D
N e w T e c h n i q u e s t o A s s e s s H i g h - R i s k P a t i
Q u a n t i t a t i v e M R A
F r a c t i o n a l F l o w R e s e r v e
C e r e b r o v a s c u l a r H e m o d y n a m i c s
I N T R A C R A N I A L A N E U R Y S M
I m a g i n g T e c h n i q u e s
S y m p t o m a t i c A n e u r y s m s
S c r e e n i n g o f H i g h - R i s k P o p u l a t i o n s
I n c i d e n t a l U n r u p t u r e d A n e u r y s m s
D i a g n o s i s
T r e a t m e n t P l a n n i n g
P o s t T r e a t m e n t
A R T E R I O V E N O U S M A L F O R M A T I O N S
D i a g n o s i s a n d C h a r a c t e r i z a t i o n
T r e a t m e n t
P o s t t r e a t m e n t I m a g i n g
A d v a n c e s i n N o n i n v a s i v e I m a g i n g o f A V M
D U R A L A V F I S T U L A
N E U R O V A S C U L A R C O M P R E S S I O N S Y N D R O M E S
V E N O U S O C C L U S I V E D I S E A S E
I m a g i n g o f C V T
A C K N O W L E D G M E N T
R E F E R E N C E S
Chapter 26: MR of Fetal Brain and Spine
D a n i e l a P r a y e r , G r e g o r K a s p r i a n , C h r i s t
S A F E T Y I S S U E S
Chapter 27: Diffusion and Diffusion Tensor MR Imaging: Fundamentals
P e t e r J . B a s s e r
P H Y S I C A L U N D E R P I N N I N G S O F D I F F U S I O N N M R
D I F F U S I O N T E N S O R M R I
C O N C L U S I O N
G L O S S A R Y
A C K N O W L E D G M E N T S
R E F E R E N C E S
Chapter 28: Perfusion Magnetic Resonance Imaging
D a v i d C . A l s o p
D S C C O N T R A S T I M A G I N G
A R T E R I A L S P I N L A B E L I N G
S U M M A R Y
R E F E R E N C E S
Chapter 29: Psychiatric Disorders
P e r r y F . R e n s h a w , J i e u n E . K i m , a n d I n
G E N E R A L E X P L A N A T I O N O N M A G N E T I C R E S O N A N
W o r k i n g M e m o r y
E x e c u t i v e F u n c t i o n
S o c i a l C o g n i t i o n
N e u r o d e v e l o p m e n t a l D i s o r d e r s
S o c i a l C o g n i t i o n
L a n g u a g e a n d C o m m u n i c a t i o n
E x e c u t i v e F u n c t i o n
A t t e n t i o n - D e f i c i t / H y p e r a c t i v i t y D i s o r d e
D i s r u p t e d I n h i b i t o r y C o n t r o l
A l t e r e d F u n c t i o n a l C o n n e c t i v i t y
M o o d D i s o r d e r s
E m o t i o n a l S t i m u l i
R e s t i n g S t a t e
E m o t i o n a l P r o c e s s i n g D e f i c i t s
W o r k i n g M e m o r y a n d V e r b a l F l u e n c y
R e s t i n g S t a t e
A n x i e t y D i s o r d e r s
E x a g g e r a t e d F r o n t o l i m b i c F e a r N e t w o r k
D y s f u n c t i o n a l C o g n i t i v e S y s t e m
D i s t i n c t N e u r a l M e c h a n i s m f o r E a c h P h o b
A l t e r e d F u n c t i o n a l C o n n e c t i v i t y
N e u r a l M e c h a n i s m s R e s p o n s i b l e f o r P a n i c
A l t e r e d A m y g d a l a R e a c t i v i t y
C o g n i t i v e I n f l e x i b i l i t y
P l a n n i n g D y s r e g u l a t i o n
D e f i c i t F e a r E x t i n c t i o n
T r a u m a - a n d S t r e s s o r - R e l a t e d D i s o r d e r s
D y s r e g u l a t e d E m o t i o n a l P r o c e s s i n g i n N e
H y p e r a c t i v e C o n t r o l S y s t e m i n R e s p o n s e
I n h i b i t o r y D e f i c i t s
W e a k e n e d F r o n t o l i m b i c C o n n e c t i v i t y
P e r s o n a l i t y D i s o r d e r s
A f f e c t i v e D y s r e g u l a t i o n
S e l f - I n j u r i o u s B e h a v i o r a n d D i s r u p t e d P
I n t e r p e r s o n a l D i s t u r b a n c e s
D i s r u p t e d A m y g d a l a - D e p e n d e n t L e a r n i n g
I m p a i r e d P r e f r o n t a l C o r t e x - R e l a t e d R e p r
S u b s t a n c e - R e l a t e d D i s o r d e r s
G r a y M a t t e r
W h i t e M a t t e r
I m p a i r e d C o g n i t i v e C o n t r o l
D y s f u n c t i o n a l R e w a r d R e i n f o r c e m e n t
M e t h a m p h e t a m i n e
O p i a t e
C o c a i n e
N i c t o i n e
D T I
D y s r e g u l a t e d R e w a r d S y s t e m
D y s f u n c t i o n a l C o g n i t i v e C o n t r o l
A C K N O W L E D G M E N T S
R E F E R E N C E S
Chapter 30: MR Spectroscopy and the Biochemical Basis of Neurologic Disease
E v a - M a r i a R a t a i a n d R . G i l b e r t o G o n z á l e
I N T R O D U C T I O N
P H Y S I C S O F M R S P E C T R O S C O P Y
S p i n – L a t t i c e R e l a x a t i o n o r T 1 R e l a x a t i o
S p i n – S p i n R e l a x a t i o n o r T 2 R e l a x a t i o n
C H E M I C A L B A S I S O F T H E I N V I V O B R A I N M R
N - A c e t y l a s p a r t a t e ( N A A )
T o t a l C r e a t i n e ( C r )
C h o l i n e - C o n t a i n i n g C o m p o u n d s ( C h o )
M y o - I n o s i t o l ( m I )
G l u t a m a t e ( G l u ) a n d G l u t a m i n e ( G l n )
L a c t a t e ( L a c )
L i p i d s ( L i p )
γ - A m i n o b u t y r i c A c i d ( G A B A )
G l u t a t h i o n e ( G S H )
G l y c i n e ( G l y )
A l a n i n e ( A l a )
V a l i n e ( V a l )
O t h e r A m i n o A c i d s
M a c r o m o l e c u l e s
S i n g l e - V o x e l S p e c t r o s c o p y
M a g n e t i c R e s o n a n c e S p e c t r o s c o p i c I m a g i n
B 0 I n h o m o g e n e i t i e s
V o x e l L o c a t i o n
B 1 I n h o m o g e n e i t i e s
M o t i o n A r t i f a c t s
R e p r o d u c i b i l i t y
B I O L O G I C B A S I S O F T H E N O R M A L A N D A B N O R M
C L I N I C A L A P P L I C A T I O N S O F M R S P E C T R O S C O P
M R S o f B r a i n T u m o r s
M R S o f I n b o r n E r r o r s o f M e t a b o l i s m
F o c a l C N S I n f e c t i o n s
I s c h e m i a , H y p o x i a , a n d R e l a t e d B r a i n I n
E p i l e p s y
N e u r o d e g e n e r a t i v e D i s e a s e s
T r a u m a t i c B r a i n I n j u r y
H e p a t i c E n c e p h a l o p a t h y
P s y c h i a t r i c D i s o r d e r s
A C K N O W L E D G M E N T S
R E F E R E N C E S
Chapter 31: Functional MRI
S u s i e Y . H u a n g , B e h r o z e V a c h h a , S t e v e n
I N T R O D U C T I O N
P h y s i o l o g i c B a s i s o f B O L D f M R I
B i o p h y s i c a l P r i n c i p l e s o f B O L D f M R I
T h e B a l a n c e B e t w e e n O x y g e n S u p p l y a n d D
D e o x y h e m o g l o b i n C o n c e n t r a t i o n M o d u l a t e s
P e r i v a s c u l a r M a g n e t i c F i e l d P e r t u r b a t i o
T 2 ′ R e l a x a t i o n i n t h e A b s e n c e o f S p i n D
T 2 ′ R e l a x a t i o n i n t h e P r e s e n c e o f S p i n
E f f e c t o f I n t r a v a s c u l a r S p i n s o n R 2 ′
T h e D a v i s M o d e l f o r t h e N e t G R E B O L D f M
I m a g e A c q u i s i t i o n
E x p e r i m e n t a l D e s i g n
D a t a P r e p r o c e s s i n g
S t a t i s t i c a l A n a l y s i s
W h a t D o e s t h e S t a t i s t i c a l A n a l y s i s S e e k
C o n s t r u c t i n g a S i m p l e L i n e a r M o d e l
E s t i m a t i n g t h e M o d e l P a r a m e t e r s f r o m t h
C o m p u t i n g t h e t - S t a t i s t i c
T e s t i n g H y p o t h e s e s U s i n g t h e t - S t a t i s t i
E x t e n s i o n t o t h e B a s i c G L M A n a l y s i s P r e
S e n s o r i m o t o r a n d S u p p l e m e n t a r y M o t o r A r
L a n g u a g e M a p p i n g
M e m o r y M a p p i n g
B a c k g r o u n d o n R e s t i n g - S t a t e f M R I
A c q u i s i t i o n a n d A n a l y s i s M e t h o d s
A d v a n t a g e s a n d D i s a d v a n t a g e s o f r s - f M R I
A p p l i c a t i o n s o f r s - f M R I
R E F E R E N C E S
Index
T a b l e o f C o n t e n t s
T i t l e P a g e
C o p y r i g h t
D e d i c a t i o n
C o n t r i b u t i n g A u t h o r s
P r e f a c e
C o n t e n t s
P A R T I : P R I N C I P L E S
P A R T I I : B R A I N A N D S K U L L B A S E
P A R T I I I : S P I N E A N D S P I N A L C O R D
P A R T I V : A D V A N C E D A P P L I C A T I O N S
I n d e x

Citation preview

2

Magnetic Resonance Imaging of the Brain and Spine FIFTH EDITION Edited by

Scott W. Atlas,

MD

David and Joan Traitel Senior Fellow Hoover Institution Stanford University Stanford, California

3

Acquisitions Editor: Ryan Shaw Product Development Editor: Lauren Pecarich Production Project Manager: Bridgett Dougherty Design Coordinator: Teresa Mallon Senior Manufacturing Coordinator: Belth Welsh Marketing Manager: Dan Dressler Production Services: Aptara, Inc. Copyright © 2017 Wolters Kluwer Copyright © 2009 Lippincott Williams & Wilkins, a Wolters Kluwer business. Copyright © 2002 Lippincott Williams & Wilkins. Copyright © 1996 Lippincott-Raven Publishers. Copyright © 1991 Raven Press. All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via our website at lww.com (products and services). 987654321 Printed in China Library of Congress Cataloging-in-Publication Data Names: Atlas, Scott W., 1955- editor. Title: Magnetic resonance imaging of the brain and spine / edited by Scott W. Atlas. Description: Fifth edition. | Philadelphia : Wolters Kluwer, [2017] | Includes bibliographical references and index. Identifiers: LCCN 2016021554 | ISBN 9781469873206 Subjects: | MESH: Magnetic Resonance Imaging | Brain Diseases–diagnosis | Spinal Diseases–diagnosis | Diagnostic Techniques, Neurological Classification: LCC RC386.6.M34 | NLM WL 141.5.M2 | DDC 616.07/548–dc23 LC record available at https://lccn.loc.gov/2016021554 This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. LWW.com

4

To the critical thinkers

5

Contributing Authors Martina Absinta, PhD Neuroimaging Research Unit Institute of Experimental Neurology Division of Neuroscience San Raffaele Scientific Institute Vita-Salute San Raffaele University Milan, Italy Paula Alcaide-Leon, MD Neuroradiology Fellow Medical Imaging Department St. Michael’s Hospital University of Toronto Toronto, Ontario, Canada David C. Alsop, PhD Professor of Radiology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts Nolan R. Altman, MD Associate Professor Department of Radiology Florida International University Chief Department of Radiology Nicklaus Children’s Hospital Miami, Florida Scott W. Atlas, MD David and Joan Traitel Senior Fellow Hoover Institution Stanford University Stanford, California Richard I. Aviv, MRCP, FRCR (UK), FRCP (C), DABR Professor Medical Imaging Associate Vice Chair Research Brain, Spine and Nerve Department of Medical Imaging University of Toronto Neuroradiologist Sunnybrook Health Science Centre Toronto, Ontario, Canada Peter J. Basser, MD Section on Tissue Biophysics and Biomimetics National Institute of Health Bethesda, Maryland Aditya Bharatha, MD Assistant Professor Department of Medical Imaging 6

University of Toronto Division Head of Neuroradiology Department of Medical Imaging St. Michael’s Hospital Toronto, Ontario, Canada Larissa T. Bilaniuk, MD Professor of Radiology Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania Assistant Chief Pediatric Neuroradiology & MRI The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania Susan I. Blaser, MD Professor of Neuroradiology Medical Imaging University of Toronto Pediatric Neuroradiologist Diagnostic Imaging The Hospital for Sick Children Toronto, Ontario, Canada Jerrold L. Boxerman, MD Associate Professor Department of Diagnostic Imaging Alpert Medical School Rhode Island Hospital Brown University Providence, Rhode Island Richard A. Bronen, MD Professor of Diagnostic Radiology and Neurosurgery Departments of Diagnostic Radiology and Neurosurgery Yale University School of Medicine Vice Chair of Diagnostic Radiology New Haven, Connecticut Peter C. Brugger, MD, PhD Associate Professor Center for Anatomy and Cell Biology Medical University of Vienna Vienna, Austria Bradley R. Buchbinder, MD Assistant Professor of Radiology Harvard Medical School Director, Clinical Functional MRI Department of Radiology Division of Neuroradiology Massachusetts General Hospital Boston, Massachusetts Jan W. Casselman, MD, PhD Professor Faculty of Medicine & Health Sciences University of Ghent Ghent, Belgium 7

Chief Radiology Department of Radiology—Medical Imaging AZ St. Jan Brugge-Oostende av. Campus Bruges Bruges, Belgium Michael W. Chan, MD Radiology Resident Department of Medical Imaging University of Toronto Toronto, Ontario, Canada J. Levi Chazen, MD Assistant Professor of Radiology Division of Neuroradiology Weill Cornell Medical College New York, New York Asim F. Choudhri, MD Assistant Professor and Assistant Chair of Research Affairs Department of Radiology University of Tennessee Health Science Center Memphis, Tennessee Sidney E. Croul, MD, FRCPC Professor Department of Pathology and Laboratory Medicine Division of Anatomical Pathology Dalhousie University Professor Pathology QEII Health Sciences Centre Halifax, Nova Scotia, Canada Mary Beth Cunnane, MD Instructor in Radiology Harvard Medical School Radiologist Massachusetts Eye and Ear Infirmary Boston, Massachusetts Hugh D. Curtin, MD, FACR Professor of Radiology Harvard Medical School Chief of Radiology Massachusetts Eye and Ear Infirmary Boston, Massachusetts Leo F. Czervionke, MD Associate Professor/Consultant Department of Radiology Mayo Clinic Jacksonville Consultant, Department of Radiology St. Luke’s Hospital Jacksonville, Florida Francesco D’Amore, MD Research Fellow Department of Radiology Division of Neuroradiology 8

Keck School of Medicine of University of Southern California Los Angeles, California Bradley N. Delman, MD Associate Professor Department of Radiology Icahn School of Medicine at Mount Sinai Vice Chairman for Quality, Performance, and Clinical Research Department of Radiology The Mount Sinai Hospital New York, New York Sean C.L. Deoni Brown University Advanced Baby Imaging Lab School of Engineering, Brown University Providence, Rhode Island Department of Radiology University of Colorado School of Medicine Aurora, Colorado Huy M. Do, MD Professor of Radiology and Neurosurgery Stanford University School of Medicine Interventional Neuroradiologist/Endovascular Neurosurgeon Stanford University Hospital and Clinics The Lucille Packard Children’s Hospital and Clinics Palo Alto Veterans Administration Hospital Stanford Stroke Center Stanford, California Massimo Filippi, MD Associate Professor of Neurology Head Neuroimaging Research Unit Division of Neuroscience Institute of Experimental Neurology San Raffaele Scientific Institute Vita-Salute San Raffaele University Milan, Italy Adam E. Flanders, MD Professor of Radiology and Rehabilitation Medicine Department of Radiology Thomas Jefferson University Hospital Regional Spinal Cord Injury Center of the Delaware Valley (RSCICDV) Philadelphia, Pennsylvania Kar-Ming Fung, MD, PhD Professor Director of Neuropathology Department of Pathology University of Oklahoma Health Sciences Oklahoma City, Oklahoma Alisa Gean, MD Professor Department of Radiology University of California-San Francisco 9

San Francisco, California Wende N. Gibbs, MD, MA Assistant Professor Department of Radiology Attending Neuroradiologist Keck School of Medicine University of Southern California Los Angeles, California R. Gilberto González, MD, PhD Professor of Radiology Radiology Harvard Medical School Cambridge, Massachusetts Director of Neuroradiology Radiology Massachusetts General Hospital Boston, Massachusetts John C. Gore, PhD University Professor and Director Institute of Imaging Science Vanderbilt University Nashville, Tennessee Gerlinde M. Gruber, MD, MSc University Assistant Department of Systematic Anatomy Center for Anatomy and Cell Biology Medical University of Vienna Vienna, Austria Vivek Gupta, MD Assistant Professor of Radiology Consultant Neuroradiologist Department of Radiology Mayo Clinic Jacksonville, Florida Victor M. Haughton, MD Emeritus Professor Department of Radiology University of Wisconsin University of Wisconsin Hospitals and Clinics Madison, Wisconsin Joseph E. Heiserman, PhD, Barrow Neurologic Institute Phoenix, Arizona

MD

Jeremy J. Heit, MD, PhD Clinical Instructor Department of Radiology Interventional Neuroradiology Section Stanford University Attending Physician Department of Radiology 10

Interventional Neuroradiology Section Stanford University Hospital Stanford, California Matthew R. Hight, PhD Postdoctoral Research Fellow Institute of Imaging Science Vanderbilt University Medical Center Nashville, Tennessee Susie Y. Huang, MD Department of Radiology Division of Neuroradiology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Thierry A.G.M. Huisman, MD Professor of Radiology, Pediatrics, Neurology, and Neurosurgery Chairman Department of Imaging and Imaging Sciences Johns Hopkins Bayview Medical Center Director of Pediatric Radiology and Pediatric Neuroradiology Johns Hopkins Hospital Baltimore, Maryland Robert W. Hurst Professor of Radiology, Neurosurgery, and Neurology Perelman School of Medicine University of Pennsylvania Director of Interventional Neuroradiology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania L. Celso Hygino da Cruz Jr., Neuroradiologist Department of Radiology Americas Medical City Clinics CDPI and IRM Rio de Janeiro, Brazil

MD, PhD

David J. Irwin, MD, MSTR Assistant Professor of Neurology University of Pennsylvania Perelman School of Medicine Assistant Professor of Neurology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Clifford R. Jack, Jr., MD The Alexander Family Professor of Alzheimer’s Disease Research Department of Radiology Mayo Clinic Rochester, Minnesota Mahesh V. Jayaraman, MD Associate Professor of Diagnostic Imaging, Neurology, and Neurosurgery Warren Alpert School of Medicine at Brown University Director of Comprehensive Stroke Center Neurointerventional Services Rhode Island Hospital 11

Providence, Rhode Island James M. Joers, PhD Research Associate Radiology CMRR University of Minnesota Minneapolis, Minnesota Kejal Kantarci, MD Professor of Radiology Department of Radiology Division of Neuroradiology Mayo Clinic Rochester, Minnesota Richard T. Kaplan, MD Physician Department of Radiology Providence Saint John’s Health Center Santa Monica, California Gregor Kasprian, MD Associate Professor Division of Neuroradiology and Musculoskeletal Radiology Department of Biomedical Imaging and Image-Guided Therapy Medical University of Vienna Vienna, Austria Douglas A.C. Kelley, PhD Global Applied Science Laboratory GE Healthcare San Francisco, California Hillary R. Kelly, MD Assistant Professor Department of Radiology Harvard Medical School Assistant Radiologist Department of Radiology Massachusetts Eye and Ear Infirmary Assistant Neuroradiologist Department of Radiology Massachusetts General Hospital Boston, Massachusetts Richard P. Kennan, PhD Senior Principle Research Scientist Department of Translational Biomarkers Merck & Co., Inc. Kenilworth, New Jersey Jieun E. Kim, MD, PhD Department of Brain and Cognitive Sciences, Scranton College Department of Biomedicine, College of Medicine Ewha Brain Institute Ewha Womans University Seoul, South Korea 12

Walter Kucharczyk, MD, FRCPC Professor Departments of Medical Imaging and Surgery University of Toronto Director, Magnetic Resonance Imaging and Spectroscopy Joint Department of Medical Imaging University Health Network Mount Sinai and Women’s College Hospitals Toronto, Ontario, Canada Meng Law, MD Professor of Radiology, Neurology, Neurological Surgery, and Biomedical Engineering Director of Neuroradiology and Fellowship Program Director of ADRC Neuroimaging Core Keck Medical Center of USC Viterbi School of Engineering of USC Los Angeles, California Alexander Lerner, MD Assistant Professor Department of Radiology Division of Neuroradiology Keck School of Medicine Keck Hospital of USC University of Southern California Los Angeles, California In Kyoon Lyoo, MD Ewha Brain Institute Department of Brain and Cognitive Sciences, Scranton College Graduate School of Pharmaceutical Sciences Ewha Womans University Seoul, South Korea H. Charles Manning, MD, PhD Vanderbilt University Institute of Imaging Science (VUIIS) Associate Professor of Radiology, Chemistry, Biomedical Engineering, Neurosurgery, and Chemical and Physical Biology Vanderbilt Ingram Associate Professor of Cancer Research Director of Molecular Imaging Research and Center for Molecular Probes Nashville, Tennessee Luca Marinelli, PhD Scientific Program Manager Healthcare Technology Partnerships GE Global Research Center Niskayuna, New York Michael P. Marks, MD Professor Departments of Radiology and Neurosurgery Director Neuroradiology, Stanford Stroke Center Chief Interventional Neuroradiology Stanford University Medical Center Stanford, California David G. McLone,

MD, PhD

13

Professor Department of Neurosurgery Feinberg School of Medicine McLone Professor of Ped Neurosurgery Lurie Children’s Hospital Northwestern University Chicago, Illinois Renato Adam Mendonça, MD Director Educational Committee Paulista Society of Radiology Chief Department of Neuroradiology Delboni Auriemo Sao Paulo, Sao Paulo, Brazil Christian Mitter, MD Division of Neuroradiology and Musculoskeletal Radiology Department of Biomedical Imaging and Image-guided Therapy Medical University of Vienna Vienna, Austria Frances M. Murphy, MD, MPH President Sigma Health Consulting, LLC Silver Spring, Maryland Thomas P. Naidich, MD Mount Sinai Medical Center New York, New York Annette O. Nusbaum, MD Clinical Assistant Professor of Radiology Attending Radiologist Department of Radiology New York University Langone Medical Center New York, New York Puneet S. Pawha, MD Associate Program Director, Radiology Residency Division of Neuroradiology Icahn School of Medicine at Mount Sinai The Mount Sinai Hospital New York, New York C. Douglas Phillips, MD Professor Department of Radiology Weill Cornell Medical College Attending Physician Director of Head and Neck Imaging Department of Radiology NewYork-Presbyterian Hospital New York, New York Andrea Poretti, MD Assistant Professor 14

Section of Pediatric Neuroradiology Division of Pediatric Radiology Russell H. Morgan Department of Radiology and Radiological Science The Johns Hopkins University School of Medicine Baltimore, Maryland Daniela Prayer, MD Professor Division of Neuroradiology and Musculoskeletal Radiology Department of Biomedical Imaging and Image-guided Therapy Medical University of Vienna Vienna, Austria Otto Rapalino, MD Instructor in Radiology Associate Radiologist Radiology Massachusetts General Hospital Boston, Massachusetts Eva-Maria Ratai, PhD Assistant Professor Radiology Harvard Medical School Director of Clinical Spectroscopy Department of Radiology Massachusetts General Hospital Boston, Massachusetts Charles A. Raybaud, MD Professor Department of Radiology Hôpital Nord Marseille, France Gerard M. Reddy, MD Fellow Mount Sinai Hospital Icahn School of Medicine New York, New York Perry F. Renshaw, MD, PhD Brain Imaging Center McLean Hospital Belmont, Massachusetts Maria A. Rocca, MD Group Leader Neuroimaging Research Unit Institute of Experimental Neurology Division of Neuroscience San Raffaele Scientific Institute Vita-Salute San Raffaele University Milan, Italy Bruce R. Rosen, MD Professor Department of Radiology 15

Harvard Medical School Boston, Massachusetts Director Athinoula A. Martinos Center for Biomedical Imaging Massachusetts General Hospital Charlestown, Massachusetts John F. Schenck, MD, PhD Senior Principal Scientist MRI Laboratory General Electric Global Research Center Schenectady, New York Eric D. Schwartz, MD Staff Radiologist Shields Health Care Group Brockton, Massachusetts Deborah R. Shatzkes, MD Professor of Radiology Chief, Head, & Neck Radiology Lenox Hill Hospital The New York Head & Neck Institute Hofstra North Shore–LIJ School of Medicine New York, New York Mark S. Shiroishi, MD Assistant Professor Attending Neuroradiologist Department of Radiology Keck School of Medicine Keck Medical Center University of Southern California Los Angeles, California James G. Smirniotopoulos, MD Chief Editor, MedPix® Program Leader, Diagnostics and Imaging Center for Neuroscience and Regenerative Medicine Professor of Radiology Neurology, and Biomedical Informatics Uniformed Services University of the Health Sciences Professorial Lecturer Department of Radiology George Washington University School of Medicine Bethesda, Maryland Steven M. Stufflebeam, MD Assistant Professor Department of Radiology Harvard Medical School Boston, Massachusetts Medical Director Athinoula A. Martinos Center for Biomedical Imaging Massachusetts General Hospital Charlestown, Massachusetts Andres W. Su, MD Resident Physician 16

Department of Radiology Icahn School of Medicine at Mount Sinai New York, New York Sean P. Symons, BASc, MPH, MD, MBA Associate Professor Departments of Medical Imaging and Otolaryngology—Head & Neck Surgery University of Toronto Deputy Radiologist-In-Chief Department of Medical Imaging Sunnybrook Health Sciences Centre Toronto, Ontario, Canada Gordon Sze, MD Professor of Radiology Department of Diagnostic Radiology Yale University School of Medicine Chief Neuroradiology Department of Radiology Yale University School of Medicine New Haven, Connecticut Jason F. Talbott, MD, PhD Assistant Professor Radiology and Biomedical Imaging Zuckerberg San Francisco General Hospital San Francisco, California Nicholas A. Telischak, MD, MS Clinical Instructor Department of Radiology Stanford University School of Medicine Stanford, California Bruno Telles, MD Fellowship at Hospital Beneficencia Portuguesa—Medimagem Sao Paulo, Brazil Research Fellow at Keck School of Medicine of University of Southern California Los Angeles, California Attending Neuroradiologist CETAC/INC Curitiba, Brazil Keith R. Thulborn, MD, PhD Professor of Radiology, Physiology & Biophysics Center for Magnetic Resonance Research University of Illinois at Chicago Attending Neuroradiologist Department of Radiology University of Illinois Medical Center Chicago, Illinois John Q. Trojanowski, MD, PhD William Maul Measey-Truman G. Schnabel, Jr., MD, Professor of Geriatric Medicine and Gerontology Director, Institute on Aging Director, Alzheimer’s Disease Core Center Director, Udall Parkinson’s Research Center Co-director, Center for Neurodegenerative Disease Research and Marian S. Ware Alzheimer Drug Discovery Program 17

Professor, Department of Pathology and Laboratory Medicine Perelman School of Medicine at the University of Pennsylvania Philadelphia, Pennsylvania Behroze Vachha, MD, PhD Department of Radiology Division of Neuroradiology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts Anton Valavanis, MD Professor and Chairman Department of Neuroradiology Director Clinical Neuroscience Center University Hospital of Zurich Zurich, Switzerland Robert A. Zimmerman, MD Professor of Radiology University of Pennsylvania SOM Chief Pediatric Neuroradiology and MRI Radiology The Children’s Hospital of Philadelphia Philadelphia, Pennsylvania William B. Zucconi, DO Assistant Professor Radiology and Biomedical Imaging Yale University School of Medicine Associate Residency Program Director Assistant Neuroradiology Fellowship Director Radiology and Biomedical Imaging Yale New Haven Hospital New Haven, Connecticut

18

Preface

This fifth edition of Magnetic Resonance Imaging of the Brain and Spine is written with the benefit of time and decades of experience with MRI in diagnosis and treatment guidance of neurologic disease. A full 25 years have passed since the first edition of the book was published, back when 1.5 Tesla scanners were emerging as the concensus “state-of-the-art” technology. Much has changed, but much has remained the same. This remains a very challenging time for MRI, partly due to the disconnect between the cost of medical technology and unrealistic expectations of a naïve public and agenda-driven politicians about the need to pay for it. Everyone believes in early detection, and no field will be more important in this pursuit than diagnostic imaging, but little attention is paid to its costs. One fact that is undeniable that MRI has increased its dominance over other diagnostic methods for diseases of the brain and spine. In those neurologic disorders where MRI is secondary, it would be shortsighted to assume that MRI will not soon dominate. However, MRI technology remains beyond known or proven clinical applications, instrumentation is more complex than ever, and software for acquisition and image processing is still immature. Alongside the maturation of MRI, molecular biology and genetics have come into the clinical arena. The overused hyperbole of “personalized medicine” is beginning to show some value. Along with the advances, relentless evolution of demographics and diseases continues. The world’s population is aging, and soon the elderly will dominate the health care system resources of all developed nations. Globalization of disease profiles is also underway; the chronic diseases of developed nations, with their reliance on imaging for diagnosis and treatment, are projected to overtake the traditionally dominating infectious and nutritional diseases of developing countries. This is the time where the importance of guidance based on genuine expertise is at an unprecedented level, when the need for focused and relevant clinical research is at an all time high. More than ever, we should all remember that the diagnosis of neurologic disease must still be based on “the known”— neuropathology, genetics, clinical history, and proven imaging findings. Patients cannot afford to have their care misdirected by implementing new techniques solely because new techniques exist, and no one wants to waste their money on opinions not grounded in evidence. As in all previous editions, this book is published with several goals in mind, including reinforcing and analyzing the detail of clinically important imaging findings; defining the role of MRI findings in the clinical setting of neurologic disease; illustrating the pathologic basis for MRI findings; and exploring the use of emerging MRI methods in the context of new contributions to diagnosis and treatment. We tried to highlight recent trends and changes in the clinical diagnosis and treatment of CNS diseases, and to relate those changes to MRI findings. Novel imaging methodology, including hardware- and software-based, is explained and explored in a variety of clinical settings, particularly where they may have the most impact. Emerging clinically relevant research in well-established neurologic disorders, like stroke and brain tumors, as well as developing clinical applications in nontraditional areas, including neurodegenerative disease, psychiatric disorders, and fetal anomalies, are discussed in detail. As in past editions, I have attempted to produce a text where the authors are truly experts writing in their areas of expertise, and where clinical caveats are noted alongside new findings in an effort to suggest rationale for optimal utilization of emerging techniques. As usual, important limitations of imaging are noted. I tried to compile an author list filled with critical thinkers; if I failed to see that in the writing, then I admit that I inserted some of it myself (so, blame me for that, please, and spare the emails to the authors …). In the end, I believe the author list of this edition meets and perhaps even surpasses previous editions—a very high bar to meet, in my opinion, but one that the reader will ultimately judge. I hope the book is valuable to the entire spectrum of those interested in neuroradiology, from trainee to expert, from basic science researcher to clinician. I tried to make it useful to all of those involved in caring for these patients, including neuroradiologists, radiologists, neurologists, neuropathologists, neurosurgeons, orthopedists, neonatologists, oncologists, and psychiatrists; applied and basic researchers; and medical technology entrepreneurs and innovators. 19

Finally, I am grateful to all of my friends and colleagues in neuroradiology, clinical and basic neuroscience, and medicine throughout the world. I am thrilled that many of the top experts in the field are willing to write for this book—I can’t thank them enough. I remain honored to have been trained by so many of the best in the field, and I am delighted to maintain close relationships with dozens of my former trainees. The enduring value of this book for more than 25 years has been based to a great extent on your research, clinical contributions, effort, and advice … and of course, on the critical thinkers who have shaped my own thinking. I thank all of you for your generosity in allowing me to show your cases, and your sacrifices in personal time to contribute to what I hope is a special textbook. Scott W. Atlas, MD Stanford, CA

20

Contents

PART

I PRINCIPLES

CHAPTER

1 Instrumentation: Magnets, Coils, and Hardware Luca Marinelli, John F. Schenck, and Douglas A.C. Kelley

CHAPTER

2 From Image Formation to Image Contrast: Understanding Contrast Mechanisms, Acquisition Strategies, and Artifacts Sean C.L. Deoni

CHAPTER

3 Contrast Agents and Relaxation Effects John C. Gore, Matthew R. Hight, James M. Joers, Richard P. Kennan, and H. Charles Manning

PART

II BRAIN AND SKULL BASE

CHAPTER

4 Disorders of Brain Development Thierry A.G.M. Huisman and Andrea Poretti

CHAPTER

5 Central Nervous System Manifestations of the Phakomatoses Susan I. Blaser, James G. Smirniotopoulos, and Frances M. Murphy

CHAPTER

6 White Matter Diseases and Inherited Metabolic Disorders Maria A. Rocca, Annette O. Nusbaum, Martina Absinta,Otto Rapalino, Kar-Ming Fung, and Massimo Filippi

CHAPTER

7 Epilepsy William B. Zucconi, Vivek Gupta, and Richard A. Bronen

CHAPTER

8 Adult Brain Tumors Bruno Telles, Francesco D’Amore, Mahesh V. Jayaraman, Jerrold L. Boxerman, Meng Law, Mark S. Shiroishi, and Alexander Lerner

CHAPTER

9 Pediatric Brain Tumors Robert A. Zimmerman and Larissa T. Bilaniuk

CHAPTER

10 Intracranial Hemorrhage Scott W. Atlas and Keith R. Thulborn

CHAPTER

11 Intracranial Vascular Malformations and Aneurysms Nicholas A. Telischak and Huy M. Do

CHAPTER

12 Cerebral Ischemia and Infarction Jeremy J. Heit and Michael P. Marks

CHAPTER

13 Head Trauma Jason F. Talbott and Alisa Gean

21

CHAPTER

14 Intracranial Infection L. Celso Hygino da Cruz, Jr

CHAPTER

15 Normal Aging, Dementia, and Neurodegenerative Disease Kejal Kantarci, David J. Irwin, John Q. Trojanowski, and Clifford R. Jack, Jr.

CHAPTER

16 Skull Base Hillary R. Kelly, Jan W. Casselman, Mary Beth Cunnane, and Hugh D. Curtin

CHAPTER

17 The Sella Turcica and Parasellar Region Sean P. Symons, Michael W. Chan, Richard I. Aviv, Aditya Bharatha, Paula Alcaide-Leon, and Walter Kucharczyk

CHAPTER

18 Eye and Orbit J. Levi Chazen, C. Douglas Phillips, and Deborah R. Shatzkes

PART

III SPINE AND SPINAL CORD

CHAPTER

19 Congenital Anomalies of the Spine and Spinal Cord: Embryology and Malformations Thomas P. Naidich, Andres W. Su, Bradley N. Delman, David G. McLone, Robert A. Zimmerman, Susan I. Blaser, Charles A. Raybaud, Nolan R. Altman, and Asim F. Choudhri

CHAPTER

20 Degenerative Disease of the Spine Richard T. Kaplan, Leo F. Czervionke, and Victor M. Haughton

CHAPTER

21 Neoplastic Disease of the Spine and Spinal Cord Puneet S. Pawha, Gerard M. Reddy, and Gordon Sze

CHAPTER

22 MRI of Spinal Trauma Adam E. Flanders, Eric D. Schwartz, and Sidney E. Croul

CHAPTER

23 Vascular Disorders of the Spine and Spinal Cord Anton Valavanis and Robert W. Hurst

CHAPTER

24 Spinal Infection and Inflammatory Disorders Renato Adam Mendonça

PART

IV ADVANCED APPLICATIONS

CHAPTER

25 MR Angiography: Techniques and Clinical Applications Wende N. Gibbs and Joseph E. Heiserman

CHAPTER

26 MR of Fetal Brain and Spine Daniela Prayer, Gregor Kasprian, Christian Mitter, Gerlinde M. Gruber, and Peter C. Brugger

CHAPTER

27 Diffusion and Diffusion Tensor MR Imaging: Fundamentals Peter J. Basser

CHAPTER

28 Perfusion Magnetic Resonance Imaging David C. Alsop

CHAPTER

29 Psychiatric Disorders Perry F. Renshaw, Jieun E. Kim, and In Kyoon Lyoo 22

CHAPTER

30 MR Spectroscopy and the Biochemical Basis of Neurologic Disease Eva-Maria Ratai and R. Gilberto González

CHAPTER

31 Functional MRI Susie Y. Huang, Behroze Vachha, Steven M. Stufflebeam,Bruce R. Rosen, and Bradley R. Buchbinder

Index

23

PART

I

Principles

24

1 Instrumentation: Magnets, Coils, and Hardware Luca Marinelli, John F. Schenck, and Douglas A.C. Kelley

INTRODUCTION In Würtzburg, Bavaria, on November 8, 1895, Wilhelm Röntgen detected a new form of radiation coming from a cathode ray tube he was studying (1). By early January 1896, this discovery of x-rays had been reported in American newspapers and elsewhere, and by the end of that month equipment already available in the MIT Physics Department had been used to confirm Röntgen’s discovery. Clinically useful x-ray images were produced almost immediately, and F.H. Williams presented a live demonstration of skeletal imaging to a Boston medical society in April 1896 only 6 months after Röntgen’s discovery (2). Compare this with the 40 years that elapsed between the initial proposal of nuclear magnetic resonance (NMR) and the production of the first clinically relevant magnetic resonance (MR) images. The contrast between the time and effort required to develop x-ray imaging and that required to develop MR imaging (MRI) is an indication of the inherent complexity of MR basic science and technology. The Dutch physicist C.J. Gorter first proposed the NMR concept in 1936 (3). However, it was not experimentally demonstrated outside of vacuum chambers until the work of Bloch, Purcell, and their associates shortly after World War II (4–8). The initial applications of NMR concerned basic science research on the physical and chemical properties of matter. The early experimenters used either test tube–sized samples or beams of atomic or molecular particles traveling through evacuated chambers. For the most part, the magnets used were relatively small devices, available as standard equipment in the physics laboratories of the time. These basic science studies engaged some of the most prominent physicists and chemists of the postwar period, and it is interesting that many of these leaders initially doubted the practicality of human imaging (9). Between World War II and the 1970s, a few NMR studies on human or animal tissues were reported (10–14). However, the key to the modern clinical use of NMR was Paul Lauterbur’s 1973 suggestion (15) that operator-controlled magnetic field gradients could be used to encode position-dependent information in the NMR signal. This suggested the possibility of generating cross-sectional anatomic images of human beings. Several years elapsed before two groups, working more or less concurrently, at Nottingham University produced the first images of human anatomy in 1976 and 1977 (16–18). The development of a new category of magnets capable of creating very strong, very uniform, and very stable magnetic fields over an unusually large volume was an early requirement. In other words, it was necessary to scale the NMR apparatus up from a size designed to deal with samples in test tubes to a size capable of accommodating the human body (19,20). When such magnets became available in the late 1970s and early 1980s, experimenters were quickly able to generate useful NMR signals from an entire human head or torso. The NMR signal produced by a complex source, such as the human anatomy, is an intricate timedependent voltage trace, which cannot be deciphered by human inspection. The information content of these signals is determined by an elaborate set of time-dependent currents supplied to an array of specialized transmitter and receiver coils that are located, along with the patient, inside the magnet. Several methods for controlling these coil currents and converting the resulting NMR signals into images were proposed during the early development of the field. These suggested methods included the back projection (15), sensitive point (21), and field focusing (22) techniques. However, the vast majority of clinical scanning has been carried out using the Fourier techniques that were originally developed for NMR spectroscopy (23) and that were later adapted to imaging (24,25). In its most 25

commonly used form, this technique has become known under the name of spin-warp or spin-echo imaging (26). Despite the fact that MRI can now be considered a well-developed and well-accepted medical technology, intense technical development efforts and extensive clinical application studies continue to be conducted with the goals of reducing the costs of MRI and increasing its technical capabilities and the number of clinical indications for its use. This has resulted in the availability of a wide range of system configurations and price levels to meet the needs of differing clinical situations. To protect human subjects during the development and use of medical devices, the US Congress in 1976 amended the Food, Drug, and Cosmetic Act of 1938 to cover the introduction of new medical devices. In response, the U.S. Food and Drug Administration (FDA) issued regulations in 1980 that applied to manufacturers of new medical devices and to researchers using these devices. The regulations are analogous to those that control the introduction of new drugs in the United States. They require the generation of data on the safety and efficacy of new medical devices before they can be marketed. MRI was the first medical imaging modality subjected to these regulatory requirements (27–29). This chapter considers the main magnet and the gradient and radiofrequency (RF) coils that are unique to MRI scanners. It also discusses the computer hardware required by these devices. The chapter emphasizes the application of MRI to proton imaging, which has been by far the most important clinical use. Other applications, such as the spectroscopy of phosphorus, carbon, or other nuclei, involve generally similar instrumental considerations. A single chapter can provide only an overview of the technical aspects of MR scanners. Several book-length accounts are available (30–38). Impact of MRI in Medicine and Technology The development and widespread clinical utilization of MR scanners during the 1980s represented a technical tour de force. Engineering advances were combined with newly developed scientific and clinical understanding and with large financial investments to produce a completely new modality for the field of diagnostic imaging. It was possible to control the data acquisition process and to compute the resulting images in a reasonable time because of tremendous advances in computer technology. To avoid confusion with the field of nuclear medicine and also to avoid the negative connotations often associated with the word nuclear, the phrases nuclear magnetic resonance and NMR, which are commonplace in physics and chemistry, were not taken over into clinical applications. Instead, the presumably more agreeable phrases magnetic resonance imaging and MRI became universally accepted names for this clinical modality. Despite the inherent complexity of NMR, the technology was rapidly disseminated into the practice of medicine once human-size systems became generally available. Although precise numbers are not available, marketing studies suggest that, as of 2014, more than 65,000,000 clinical examinations are being performed worldwide each year. This indicates that more than 850,000,000 diagnostic MR studies were performed between the introduction of clinical MRI in the early 1980s and the end of 2014. The impact of MRI on clinical medicine is often cited as an example of the benefits to the society of basic research in physics and chemistry. Table 1.1 lists important scientific and technical advances that were crucial to the eventual development of MRI scanners. Also listed are the names of some of the investigators and approximate dates for these developments. It is, of course, not possible to acknowledge in a single table all of the contributors to the development of MRI. The purpose of the table is to provide orientation concerning the large number of basic science advances that were required before MRI could be developed and to emphasize how recently much of this basic understanding has been achieved. It is interesting to note that in the 1980s many elderly patients who were scanned by MRI had been born before the magnetic properties, or even the existence, of atomic nuclei were known. TABLE 1.1 Some Technical and Scientific Milestones in MRI

26

In 2001, a group of 225 physicians were surveyed and selected MRI, along with computed tomography, as the most important medical innovation in terms of advancing patient care in the previous 25 years (39). These results were particularly significant because (i) the surveyed physicians were not radiologists, who would logically be expected to be impressed by techniques that had changed their practices in major ways, but, rather, general internists, who ranked the innovations based on their impact on patient management, and (ii) the 25 years over which the innovations were evaluated had seen the introduction of many revolutionary medical technologies such as coronary artery bypass surgery, new treatments for depression, and so on. The early history of MRI has generated a degree of controversy regarding the priority of various discoveries and inventions and the ultimate capabilities of the technique (40,41). In 2003, many years after their original publications, the Nobel Prize in Physiology or Medicine was jointly awarded to Paul Lauterbur and Sir Peter Mansfield “for their discoveries concerning magnetic resonance imaging” (42–47). Magnetism and Magnetic Units The official metric unit for magnetic field strength in the units of the Système International (SI) is the tesla, and the official abbreviation for this unit is capital “T” (48,49). In addition to being officially sanctioned, the tesla is of a convenient size to specify the strengths of main magnetic fields used in MRI. However, another unit of magnetic field strength, the gauss (abbreviated “G”), although not an official SI unit, has had a long historical usage and is still widely used by physicists and chemists; it is of a convenient size to describe the smaller fields (e.g., gradient fields) associated with MR scanners. The two units have an easy-to-remember relationship: 1 T is equivalent to 10,000 G. In this chapter, we use whichever of these units are more convenient for the magnetic field under discussion. Magnetism was originally noticed more than 2,500 years ago as a property of certain rocks and minerals such as lodestone, which is now known to be the iron oxide (Fe3O4) and is called magnetite by geologists. Based on experiments with lodestones performed around the year 1600, the English 27

physician William Gilbert proposed that Earth is a huge magnet and that it produces what would now be described as a dipole field. Although they are generally unaware of it, everyone on Earth is continually immersed in this field. In 1820, the Danish physicist and chemist Hans Christian Oersted discovered that magnetic fields are also produced by electric currents flowing in wires. By the 1920s, modern atomic theory and quantum mechanics were developed to the point that the magnetic properties of lodestone and other magnetic materials could be described in terms of the motion of electrons within them. To achieve agreement with experiment, it was necessary to consider in addition to the orbital and translational motion of the electrons a further degree of freedom known as electron spin, which can be roughly visualized as a spinning motion of the electrons around their axes. In the presence of a steady magnetic field, the electron spins undergo a motion called precession that is analogous to the motion of a spinning top in a gravitational field. The spin axis precesses around the direction of the field at a fixed rate that is proportional to the strength of the applied field. This precessional motion repeats at a rate known as the Larmor frequency. All of the magnetic properties of materials and electric circuits can thus be explained in terms of the motion of electrons. Also, in the 1920s, certain subtle effects in atomic spectra were noted that could be explained by associating a spin degree of freedom with some atomic nuclei. This led to the development of the field of nuclear magnetism (50,51). The behavior of nuclear spins is similar to that of electron spins, but the magnitudes of their effects are very much smaller than those of electrons, and it was initially doubted whether direct macroscopic effects of nuclear magnetism would ever be observed. As mentioned previously, in 1936, Gorter proposed a resonance method as a possible means of detecting nuclear magnetic effects. His protocol, called NMR, consisted in exposing nuclear spins to a strong magnetic field for a time long enough to align many of them with this field and then exciting them by use of an RF field at right angles to the initial field. This methodology was eventually shown to work and is the basic working principle for modern MRI devices. Nuclei of many of the chemical elements can be studied using NMR, but far and away the most important for medical applications is the simplest atomic nucleus, the proton, which is the nucleus of atomic hydrogen. The magnetic moment of the proton is 658 times smaller than that of the electron, and this largely accounts for the difficulty in demonstrating macroscopic proton nuclear magnetism without the use of specialized equipment. The Larmor frequency for electrons and for all nuclear spins is linearly proportional to the applied magnetic field strength. For unshielded protons at 1 T, it is 42.577482 MHz. Whole-body clinical MRI studies have now been reported over at least the range from 0.02 to 9.4 T (200 to 94,000 G). This corresponds to a variation in Larmor frequency from 0.852 to 400 MHz. Therefore, the range of field strengths useful for medical imaging has been demonstrated to vary by a factor of at least 470. By using small magnets, much stronger fields can be obtained, and MRI studies of small animals and pathology specimens have been reported up to fields of at least 21.1 T, corresponding to a frequency of almost 900 MHz. The human body contains an enormous number of hydrogen atoms, particularly in its water and lipid components. The proton spins can be manipulated by applied magnetic fields generated by electric currents in coils located outside the body, and signals produced by the motion (precession) of these spins can be detected using receiver coils that are also located outside the body. It turns out that, at the levels required for MRI, these applied electromagnetic fields have very little measurable influence on human tissues other than those on the nuclear spins. Some exceptions that occur at very powerful field levels or in the presence of magnetic foreign bodies will be discussed later. The remarkable fact that the elaborate electromagnetic activity associated with MRI couples strongly to the proton spins throughout the body, while the other components of human tissues are to a high degree transparent to these fields is the physical basis of the highly noninvasive character of this imaging modality. The strength of Earth’s magnetic field is roughly 1/2 G, or 0.00005 T, and the proton Larmor frequency in Earth’s magnetic field is only about 2.1 kHz. The degree of nuclear spin magnetization in such a feeble field is far too small to result in an observable NMR signal without the use of special preparation techniques, and, as a result, Earth’s field is not useful in clinical MRI. The NMR signal is proportional to both the degree of spin magnetization and the rate of Larmor precession. In turn, these factors are both directly proportional to the magnetic field strength, Bo. Therefore, the NMR signal strength increases as the square of Bo. However, patient-generated electrical noise increases approximately linearly with frequency. This results in a signal-to-noise ratio (SNR) that increases, in strong fields, roughly in direct proportion to Bo, and this gives an SNR advantage to higher field scanners. This advantage must be balanced, of course, with other factors, such as cost and size, in 28

deciding on the Bo field to use for a given scanner.

TYPES OF MAGNETIC FIELD COILS MRI requires the application to a human patient of several strong and carefully crafted magnetic fields that are controlled and varied as precisely defined functions of space and time within the patient. Magnetic fields are commonly produced by electric currents in metallic conductors. Very intense magnetic fields are often produced by winding long metal wires into dense coil structures. When this is done, the field produced by the current in each turn is superimposed on those of the other turns, and a strong field can be produced from a relatively small current. For these historical reasons, the currentcarrying field sources in MRI are usually referred to as coils, although, in many instances, other conductor shapes (such as conductor patterns etched in sheets of copper) are used rather than wire coils. Every MR scanner contains several sets of coils that serve as sources of the different magnetic fields that are used to manipulate the magnetic spins within the patient. Scanners also contain receiver coils and associated electronics to detect and amplify the very weak RF fields that originate within the patients but that can be detected outside of them once appropriate patterns of spin orientation have been prepared. In a somewhat simplified view, a scanner requires the use of three types of coils. The first set of coils produces an intense uniform (i.e., homogeneous) main field that is constant in time and is used to align (or magnetize) the spins within the patient. This field also drives the Larmor precession of the spins once the transmitter coil has excited them. Second, there is a set of three gradient coils. Each of these coils produces a gradient field that can be pulsed on and off during the scan to give the field (and, therefore, the precessional motion) a slightly different time dependence at different positions within the patient. Finally, there is a spatially uniform RF magnetic field oscillating at or near the Larmor frequency of the protons and which is pulsed on and off to produce repetitive excitation of the spins within the patient. The main magnetic field needs to be very uniform in terms of its strength and direction. It defines a direction in space that is conventionally referred to as the z direction. The z component of the main field at the center of the magnet is designated Bo and is so strong that it completely dominates the effects of the small transverse fields (Bx and By) that are inevitably produced by the main magnet and the gradient coils. The transverse Bx and By fields are, therefore, usually inconsequential in determining the MR signal, and we will not be concerned with them any further. As discussed later, the z axis usually runs along the cylindrical axis of the main magnet and in the direction from the patient’s head to the feet (superior to inferior). Any variation in the longitudinal field, Bz, from its central value, Bo, has a significant effect on the motion of the spin system and, therefore, also on the MRI process. Consequently, the design of the main field coils is chosen to minimize variations in the strength of the Bo field over the desired region of imaging. Three separate gradient coils, one each for dBz/dx, dBz/dy, and dBz/dz, are used to produce controlled variations in Bz and, thereby, to permit slice selection and to encode position-dependent information in the MR signal. Ideally, the gradient coils produce longitudinal Bz fields that are precisely zero at the center of the scanner and that vary in a perfectly linear fashion over the region of imaging. Thus, we have three fields that can be independently specified, Bx = Gxx, By = Gyy, and Bz = Gzz. The parameters Gx, Gy, and Gz are referred to, respectively, as the x-, y-, and z-gradient strengths. They are usually specified in terms of tesla/meter or gauss/centimeter. It is important to realize that although each of the gradient coils individually produces a field in a specific Cartesian direction, a gradient field in any arbitrary direction in space can be generated by activating two or all three of the gradient coils, with the proper current levels, simultaneously. This makes it possible to select imaging planes in any one of the principal orientations—axial, sagittal, or coronal—and also in any oblique orientation. This flexibility to select any desired scan plane electronically and without moving the patient gives MRI one of its major advantages over computed tomography and other imaging modalities. An additional coil (or coils), called the transmitter coil, carries currents at radiofrequencies at or near the Larmor frequency and is used to excite the spins so that they begin to precess in the main magnetic field and to provide the signal that is used to construct the image. This signal is then detected by a receiver coil that is also tuned to the Larmor frequency. The receiver coil may be the same coil as the transmitter, or it may be a separate structure. The RF excitation field is at right angles to the main magnetic field. Therefore, it is a Bx or By field or some combination of these two components. The 29

components are of the general form Bx or By = B1 cos(ωt + φ), where the frequency, ω, is at or near the spin Larmor frequency. Ideally, the amplitude, B1, and the phase, φ, do not depend on position. Circularly polarized fields, produced by superimposing Bx and By fields with a 90-degree phase difference, are often used because they offer efficiency improvements over linearly polarized fields in both the transmit and receive modes. To summarize, an ideal scanner produces the following magnetic fields over the entire region to be imaged. There is an intense, perfectly uniform main field, Bz = Bo, which is constant in time and space. There are three gradient fields each varying linearly with position and of the form Bz = Guu with u = x, y, or z and, respectively, u = x, y, or z. Finally, there is an oscillating RF field in the direction perpendicular to z that is completely uniform in space. It is seen that a minimum of five separate coils— one main field coil, three gradient coils, and one RF coil, each producing a distinct field pattern—are required to construct an idealized MR scanner. The gradient and RF coils are independently activated under computer control to produce a desired pattern of time-dependent spin excitation and precession. The pattern of these gradient and RF excitations is called a pulse sequence (38). In addition to the three major coil types just discussed, MR scanners may contain a set of several additional static field coils called shim coils. These are specially patterned coils designed to correct inhomogeneities that may be present in the Bo field that result from manufacturing tolerances in the main field magnet or from other sources of field distortion. The currents in these shim coils are normally set to optimum values during scanner installation and are reset from time to time as part of the periodic scanner maintenance process.

MAIN FIELD MAGNETS The main field magnets are the key component of MR scanners, and more than any other factor they determine the appearance, cost, and capabilities of these devices. The most important characteristics of these magnets are: the magnetic field strength at the center of the imaging region; the uniformity of the magnetic field over the desired field of view; the temporal stability of the magnetic field for the duration of the image acquisition; the size of the magnet must be large enough to produce this strong, stable, uniform magnetic field over large regions of the adult human body; and the ability to keep the patient safe and comfortable for the duration of the study. There are also a number of secondary features that affect the suitability of a magnet for operation in a specific environment. These features include: the weight and external dimensions (height and length) of the magnet; the magnitude and the spatial extent of the fringing magnetic field surrounding the magnet; and the cryogenic requirements and the quench resistance for superconducting magnets. There are several basic options available for the design and construction of MRI main magnets: Permanent magnets made from “hard” magnetic materials. These magnets do not require any external power source. Electromagnets (iron-core magnets) made from “soft” magnetic materials and energized by electric currents flowing in wires wound around a portion of the magnet. Resistive magnets (sometimes called air-core magnets) that utilize electric currents in metallic wires or tapes (usually copper or aluminum) wound into a series of circular coils arranged along a cylinder surrounding the patient. Superconducting magnets using a coil geometry similar to that of resistive magnets but which utilize zero-resistance superconducting metal wires (a niobium–titanium alloy cooled to near absolute zero) as the current conductors. These magnets have an important property in common with permanent magnets in that, unlike electromagnets and resistive magnets, they require no external power source once energized. Hybrid magnets that combine features of more than one of these basic types. For example, a magnet might include both a set of permanent magnets and a set of superconducting coils to achieve a stronger field than could be produced by either set acting alone. Magnets of all these types have been used successfully for human MRI imaging. However, because of 30

their ability to produce very strong and highly uniform magnetic fields and to maintain a high degree of temporal stability, cylindrical superconducting magnets have dominated the field of MRI since the mid1980s. Nonetheless, scanners based on other types of magnets are used in various niche applications. These include low-cost systems and scanners restricted to limb imaging. Also, so-called open systems, using a hybrid structure containing both superconducting and permanent magnets, can provide advantages when imaging claustrophobic or extremely heavy patients (Fig. 1.1). Because of their dominant role in modern, high-performance neuroimaging, the rest of this chapter will discuss only superconducting magnets. Superconducting Materials for MRI Magnets Superconductivity was discovered as an exotic property of certain metals at very low temperatures in 1911 and subsequently became a major research topic of theoretical and experimental solid-state scientists. The most remarkable property of these materials is that they have absolutely no electrical resistance when cooled below their superconducting transition temperatures. However, this temperature is so low that liquid helium is required to cool the metals to the point where superconductivity appears. It is natural to try to build powerful magnets from any material with zero electrical resistance. Unfortunately, for the superconductors known before about 1950 (the type I superconductors such as lead, tin, and mercury), once the current density exceeds a rather low critical value, the superconductivity vanishes and the resistance returns. Magnets made from these materials are, therefore, limited to producing disappointingly weak magnetic fields—a small fraction of a tesla at most. This left superconductivity as a fascinating scientific phenomenon but with very little commercial significance. However, the discovery of a new class of high-field superconducting alloys (type II superconductors) in the 1950s opened the way to producing much more powerful magnets. After a great deal of metallurgical experimentation on hundreds or thousands of materials carried out in many laboratories, Berlincourt and Hake announced in 1962 (52) that an alloy of niobium and titanium could carry superconducting currents at densities 30 times the current densities that were feasible in copperwound resistive magnets. Moreover, it turned out that the Nb–Ti alloys had the very desirable metallurgical property of high ductility and could be readily formed into superconducting wires thousands of meters long. These wires could then be wound into superconducting coils capable of producing magnetic fields of several tesla. It has been emphasized that, although many materials with superior superconducting properties (superconducting transition temperature and critical current density) than Nb–Ti have been found, these materials have generally been brittle, expensive, and hard to fabricate into coils (53). Thus, the Nb–Ti alloys have dominated the superconducting magnet business to the present time because of its ductility which provides ease of fabrication and suitability for bulk production of reliable, cost-effective superconducting wire. However, except for customized magnets designed for research purposes, there was no large-scale commercial application of superconductivity, including these type II materials, prior to the advent of whole-body MRI in the early 1980s.

FIGURE 1.1 Hybrid electromagnet system. This design places the patient between two soft magnetic poles which are energized by superconducting coils to achieve a relatively strong field of 0.7 T. This “open magnet” configuration has advantages in imaging claustrophobic and extremely heavy patients. (Courtesy of Patrick Jarvis, General Electric Health Care.)

Superconducting Magnets 31

As the great clinical potential of MRI became appreciated during the early 1980s reservations regarding the technical and cost challenges associated with whole-body superconducting magnets rapidly gave way to enthusiasm for the advantages they offered. Superconducting magnets are designed to achieve a prescribed maximum field strength and, in principle, can be operated to produce any field strength up to this design value. In practice, however, they are almost always operated at a fixed, constant field, near the upper limit of their capabilities. Because of the superconducting properties of the magnet coils, once the desired field strength is reached and the superconducting circuit is closed, the power supply can be disconnected, and the magnet will operate in the persistent mode. That is, the full field strength can be maintained, without additional power input, for months or years. Typical performance specifications for these magnets are that, at the magnet center, the field is spatially uniform (i.e., homogeneous) to better than 10 parts per million (ppm) over a sphere 40 to 50 cm in diameter and that the drift of the field (i.e., temporal stability) is less than 0.1 ppm per hour. Generally speaking, the cost and manufacturing difficulty of building these magnets increase rapidly with the prescribed field strength and the diameter of the warm bore (the central opening where the patient is located during imaging). Although largely out of sight, the interior components of a superconducting whole-body magnet are remarkable hightechnology devices operating with very tight tolerances, at extremely low temperatures and supporting enormous magnetic forces (54–56). As mentioned above, whole-body superconducting magnets have been used in MRI clinical applications and research over a wide range of field strengths. However, for technical and historical reasons, the majority of superconducting whole-body magnets placed into clinical practice between the mid-1980s and the present operate at 1.5 T. Since approximately the year 2000 there has been a significant increase in the clinical use of whole-body scanners operating at 3 T. This is done to take advantage of the improved SNRs and improved resolution available at higher field strengths. Still more recently, whole-body systems operating at 7 T have been placed in a number of research centers. At the present time, there are roughly 25,000 1.5-T and 5,000 whole-body 3-T systems in place worldwide. 1.5-T magnets still account for about three-fourths of the new installations but the fraction of 3-T systems in new installations is increasing with time. Figure 1.2 is a cutaway drawing illustrating many of the features of modern MRI superconducting magnets. In this example, the field is produced by an intense current flowing through six coils that are connected in series. The structure that contains the cryogenically cooled coils is called the cryostat. A typical superconducting magnet has a total of about 5 to 7 main coils on coil forms of about 0.65 m radius surrounded by two shielding counter coils on a larger radius. The total length of the superconducting wire is on the order of 120 km or 75 miles. This total length of wire must be constructed without any interruption of its superconducting properties in order to achieve persistent operation and adequate temporal stability but the total wire length wire is made up of 10 to 20 shorter segments. The technical problem of joining shorter segments of wire while maintaining the superconducting properties at the linkages was one of the major challenges in the development of superconducting magnets. The total weight of the mass at helium temperature of a modern 3-T magnet (superconducting wire and its supporting structures) is on the order of 9,000 lb. The warm bore opening of the main magnet is normally in the range from 85 to 100 cm. After allowance is made to accommodate the gradient coils and RF transmit/receive coils, the diameter of the space available for the patient and the patient support system is on the order of 60 to 70 cm.

32

FIGURE 1.2 Cross-sectional drawing of a generic cylindrical design for a whole-body superconducting magnet. This is a multicoil design suitable over a range of fields including both 1.5 and 3 T. There are six main field coils and additional superconducting shim and shield coils all maintained at a temperature close to absolute zero. This low temperature is provided by a bath of liquid helium and an associated cryocooler/recondenser that recycles helium as it boils and reduces the need for refilling the helium bath. The patient table can be moved into the center of the magnet under computer control. Only in the region labeled FOV (field of view) near the center of the cylindrical bore is the field strength and homogeneity satisfactory for MRI. (Reproduced with permission from Luvovsky Y, Stautner EW, Shang T. Novel technologies and configurations of superconducting magnets for MRI. Supercond Sci Technol 2013;26:1–71. All rights reserved.)

FIGURE 1.3 A 3-T superconducting magnet for magnetic resonance imaging. The region of highly homogeneous magnetic field, in which imaging is possible, is located at the center of the bore. A computer-controlled table permits precise positioning of the patient within this region. (Courtesy of General Electric Healthcare.)

The superconducting coils are immersed in a bath of liquid helium at 4.2 K or somewhat colder to cool the niobium–titanium alloy well below its superconducting transition temperature, which is about 9.2 K. In the original superconducting magnet designs, the transition from liquid helium temperatures to room temperature (298 K) was made through an intermediate liquid nitrogen stage at 77 K. With improved technology such as the use of cryogenic refrigerators, it is now no longer necessary to include an intermediate stage at liquid nitrogen temperature. Nonetheless, there is an inexorable boiling of the cryogenic liquids due to thermal energy entering the helium bath from the outside. This necessitates periodic refilling of the cryogenic fluids. These refills were originally required every few weeks. Now it is possible to go for several months, and even longer in many cases, between helium refills. Figures 1.3 and 1.4 show, respectively, the appearance of a 3-T and a 7-T magnet. To maintain the superconducting state the conductor must be kept below its transition temperature. If even a small region of the wire is heated above this temperature, it begins to dissipate heat and the 33

temperature increases still further. The result can be a self-propagating process leading to a magnet quench, wherein the entire stored energy in the magnetic field is converted into heat and the metal returns to its normal resistive state. This raises the temperature of the liquid helium above its boiling point and it quickly evaporates as the magnetic field collapses. Magnets are designed to sense the onset of a quench and to rapidly activate heaters that spread the energy deposition throughout the coils. Otherwise, the deposition of the total stored energy in a single location could melt the wire locally and destroy the magnet. In a controlled quench, the field will decrease from its initial value to nearly zero in about 1 minute. Provision must be made to permit the safe removal of the helium gas that is produced during a quench. This gas is very cold and direct contact with it should be avoided. Also by displacing room oxygen, a quench, if the gas is not properly vented, represents a suffocation risk to people nearby. All the wires in a superconducting magnet are subject to intense forces that can cause slight movement and local frictional heating that may be sufficient to initiate a quench. This possibility is minimized by a process called training. This is one of the final steps in magnet manufacture and involves cycling the magnet to fields somewhat above its planned operating field to assure stable operation at the rated field. Quenches are also possible if a cryostat vacuum fails or if necessary refills of the cryogenic liquids are not made on time. Superconducting magnets are supplied with an emergency switch system that permits a deliberate, but nondestructive, quench in the event that someone has become trapped against or inside the magnet by a ferromagnetic object, such as an oxygen bottle.

FIGURE 1.4 High-field research system. A 7-T research magnet with patient table is shown. This magnet is roughly twice the length of the 3-T magnet (Fig. 1.3) because a compensated solenoid winding geometry is used here rather than the discrete coil approach commonly used at lower field strengths. The solenoidal coil design requires the use of more superconducting material than does the discrete coil design. However, it substantially reduces the maximum field strength at the superconducting coils.

In recent years, both the cost and availability of liquid helium have become somewhat problematic. Helium is generally collected as part of natural gas extraction and is produced from radioactive decay of neutron-rich materials like uranium. Since helium is much lighter than nitrogen (the predominant gas in the Earth’s atmosphere) and is generally nonreactive chemically, once released as a gas it floats away and is lost. Three technologies are generally considered important candidates for reducing helium consumption. First, “zero boiloff” magnets incorporate recondensing compressors (often called “cold heads”) that rely on the Gifford–McMahon cycle to extract heat from the helium gas and recondense it to a liquid, maintaining the low temperature for the superconductor. Human-sized magnets with field strengths up to 7 T have been produced using recondensing compressors. Second, “cryogenless” magnets rely on a large mass of metal that, once cold, can maintain a low temperature. While these systems can operate with very little helium, care must be taken that, should a quench occur, heat will be extracted from the superconducting wire quickly enough to prevent damage to the wire. While few magnets to date have been built using this technology, it is likely to become an important technology particularly at clinical field strengths (1.5 and 3 T). Third, more exotic superconducting materials, such as MgB2, are able to maintain a superconducting state at a higher temperature, permitting the use of more readily available cryogens. These materials are generally less ductile and far more expensive than Nb–Ti alloys, limiting their applicability for the foreseeable future. 34

Shim Coils There are inevitable imperfections in the coil locations within a manufactured magnet. These imperfections lead to the presence of error fields which reduce the uniformity of the field within the field of view (FOV) below what it would have been if the coils could have been wound and positioned exactly as in the ideal design. Various shimming techniques are used to tweak the final magnetic field to correct for these inevitable manufacturing errors and for additional errors that result from the magnetization of magnetic materials, such as building girders, in the vicinity of the magnet. Passive shimming, somewhat analogous to tuning a piano, is accomplished by positioning small ferromagnetic strips at specific locations within slots around the bore of the magnet (Fig. 1.2) to counteract field inhomogeneities once they have been mapped and characterized (57). Active shimming is an additional method for improving magnet homogeneity. This technique makes use of sets of specially designed coils placed within the magnet each of which is designed with a specific symmetry to produce a field closely approximating an idealized field referred to mathematically as a spherical harmonic. If superconducting shim coils are used as shown in Figure 1.2, they are located, like the main coils, within the cryostat and are maintained at liquid helium temperature. To make it possible to change the current in superconducting shim coils, it is necessary to provide current leads to an external power supply. These leads can be switched from one shim coil to another and a set of currents can be built up in the array of coils to cancel out each of the harmonic fields for which a shim coil has been provided. Superconducting switches are used to restore each coil to the persistent mode once the power supply has brought the shim current to the desired value. An alternative or supplement to the use of superconducting shim coils is to provide a set of resistive shim coils which can be located within the room temperature bore of the magnet adjacent to the gradient coils (not shown in Figure 1.2). Each of these coils also is designed to produce primarily a single harmonic field but, in this case, each coil is permanently connected to its own power supply. This makes it relatively easy to reset the resistive shim coils as necessary. Many magnets are built with both resistive and superconducting shim coil sets. The more powerful superconducting shims are used to more or less permanently cancel out the major fixed inhomogeneities and the resistive shims are used for more frequent fine-tuning of the field. A given scanner set may contain 10 to 15 separate coils in each set but those corresponding to low order harmonics, e.g., the Bo shim that adjusts the main field and the gradient shims, x, y, and z, are most crucial to image quality. Magnet Shielding For siting purposes it is usually desirable to limit the extent of the fringing field by shielding the magnet (58). Active shielding is the use of additional superconducting coils with current flowing in the opposite direction to that in the main coils. This technique is almost always employed in modern, whole-body clinical magnets. The countercoils are usually much larger in diameter than the main coils and located well outside them. They can greatly reduce the dipole moment and thereby the fringing field. Drawbacks to the use of active shielding include the substantially increased magnet size and weight and the fact that the countercoils reduce the useful field in the center of the scanner. Passive shielding is accomplished by surrounding the room containing the magnet with a soft iron frame to guide the flux from one end of the magnet to the other and thereby reducing the fringing field outside of the shield. The use of external iron shielding has the agreeable property that, although it decreases the external fringing field, it increases the strength of the useful field in the center of the magnet. The disadvantages of passive shimming are that it increases the weight of the system substantially and it distorts somewhat the homogeneity of the imaging field, thus putting more of a burden on the shim coils. Current Trends and Future Developments For about 30 years the technical design of whole-body magnets operating at 1.5 T has been the subject of an enormous engineering effort and these designs have reached a high level of performance and efficiency. Similar efforts have been made on clinical 3-T magnets for roughly the last 15 years. However, as we already mentioned, the worldwide commercial availability and cost of liquid helium has become volatile and it is likely that efforts to improve the cryogenic performance and efficiency of these magnets will continue to be a significant focus of magnet engineering. For the past two decades another major goal in MRI magnet research and development has been the construction and evaluation of whole-body magnets capable of producing fields substantially higher 35

than those of the clinically standardized 1.5-T and 3-T systems. This permits investigation of the improved MRI SNR and improved spatial and temporal resolution available at these high field strengths. Most of these high-field scanners are in principle capable of whole-body imaging, but in practice, most of this research has concentrated on brain imaging. In 2007, there were about 20 whole-body 7-T research scanners in service worldwide and that has grown to approximately 60 in 2015. In addition to the 7-T magnets, there are a handful of whole-body imagers operating at higher field strengths, e.g., 9.4 T (University of Illinois, Chicago, IL) (59) and 10.5 T (University of Minnesota, Minneapolis). Whole-body magnets designed to operate at 11.75 T are nearing completion at the NIH (Bethesda) and at Neurospin (Saclay) (60). Whole-body magnets operating at these high field strengths are massive structures—the Neurospin magnet is 5 m long and weighs 132 tons. Building magnets of this size is a major engineering and financial effort requiring large investments and 5 years or longer may be required to complete the design and manufacturing stages. To achieve the highest possible magnetic fields for MRI research purposes it is necessary to reduce the magnet bore size substantially below what is required for imaging intact human beings. Figure 1.5 shows the current maximum field strength MRI magnet now in operation. It operates at 21.1 T, has a 10.5-cm warm bore and is in place at the National High Magnetic Field Laboratory (NHMFL) in Tallahassee, FL (61). This magnet has been used to show that high-quality MRI can be performed on rodents (62) and material dissected from postmortem human brains (63) at the very high frequency of 900 MHz.

FIGURE 1.5 A 21.1-T magnet for small animal imaging. (Courtesy of Schepkin V, Markiewicz WD, Roberts K, National High Magnetic Field Laboratory, Florida State University.)

A new class of superconducting materials with very high transition temperatures was discovered in 1986 (64). It was initially hoped that these so-called high-temperature superconductors (HTS) would revolutionize the design of superconducting magnets and possibly eliminate the need for liquid helium. Unfortunately, these new materials have turned to be quite brittle and difficult to form into long wires and have yet to demonstrate sufficient current-carrying capability and cost effectiveness to be widely used in present-day MRI magnets. With further research on the metallurgical properties of these materials they may eventually begin to play a larger role in MRI. Dedicated MRI magnets specialized for human head imaging are also under development, although this had been developed in the past with limited implementation.

GRADIENT COILS The “resonance” in MRI comes from the fact that the hydrogen nuclei in water molecules respond strongly to electromagnetic energy when the frequency of that energy matches the magnetic field strength (multiplied by a constant called the gyromagnetic ratio, which is a fundamental characteristic of the nucleus). This frequency is called the Larmor precession frequency. If the field strength varies in a controlled way, then frequency content of the signal will vary in the same way, and an image of the spin distribution can be created. This observation led to the award of the Nobel Prize in Physiology or Medicine to Paul Lauterbur and Peter Mansfield (65,66). The gradient coils create this controlled variation by adding a small shift to the main magnetic field which is proportional to the position. This shift is generally used in three ways in a pulse sequence— 36

selective excitation, frequency encoding, and phase encoding. Each gradient coil produces a field whose Z component (along the axis of the magnet, for a conventional high-field system) varies linearly with either X (typically the right–left direction for supine or prone positioning), Y (anterior–posterior), or Z (superior–inferior) (67,68). Combinations allow linear encoding in any spatial direction, a unique feature of MRI among other imaging modalities. If a gradient field is applied during an RF pulse, the spins will only absorb energy from the pulse if the frequency content of the pulse includes the Larmor frequency of the spins in question. The RF pulse is typically amplitude modulated, where a narrow-band (typically a few kilohertz) pulse shape or kernel is multiplied by a sine wave at the Larmor frequency of the center of the slice of interest. The modulation spreads the spectrum of the sine wave over the bandwidth of the shape, and if a gradient field is applied at the same time as the pulse, only spins in a particular slice through the object will absorb energy from the pulse. The slice is selectively excited. The selective excitation gradient is only needed during the RF pulse (but can leave a phase variation across the slice that can be corrected by reversing the gradient amplitude for a short period of time depending on the details of the RF pulse shape). After an excitation pulse, the spins will precess at the Larmor frequency, generating a free induction decay (FID). If we apply another gradient during the FID, then the Larmor frequencies will depend on the position of the precessing spins. If we collect the signal from the precessing spins with a receiver coil, the frequency content of the signal will encode the density of spins along the axis of the gradient. The density can be recovered mathematically by a Fourier transform (possibly with some resampling). This process is called frequency encoding. If we apply a short pulse along a third spatial direction, the spin density along this axis will be encoded as a phase shift in the precession. The Larmor frequency is altered by this third gradient for a short time, and the difference in precession frequency for spins at different locations along this direction will lead to a phase shift proportional to the amplitude of the pulse and its duration (the integral of the pulse). Repeating the experiment several times with slightly different amplitudes for the phase-encoding gradient allows full encoding of the spin density at the desired resolution.

FIGURE 1.6 A z-gradient coil. A coil wound on a cylindrical surface with a spiral pattern and with overwinding near the end of the coil. This pattern produces a z gradient with a high degree of linearity in the imaging region. To produce the gradient field, the winding reverses direction at the center (z = 0), and the turn density increases as the winding moves away from the center. The overwinding begins at z = a, where a is the coil radius. The design shown produces a gradient field that is linear over a much larger region than that of the simpler Maxwell pair, which would . (Courtesy of General Electric Healthcare.) have coils at

The gradient fields must be switched on and off several times within a pulse sequence. Gradients are typically characterized by the maximum gradient strength (often in millitesla per meter) and the maximum switching rate (usually in millitesla per meter per millisecond), Typical whole-body gradients operate at 40 to 50 mT/m and 150 to 200 (T/m)/s. Gradient coils are constructed as large loops of wire on a cylindrical former that sits inside the magnet but outside the patient bore tube. A z-gradient field, like the main field, may be produced by a set of circular coils placed symmetrically along the z axis (Fig. 1.6). However, the current in the coils on the opposite sides of the central plane must now be in opposite directions. Transverse gradient coils may also be wound on the surface of a cylinder, but the current pattern is more complex (Fig. 1.7).

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FIGURE 1.7 Transverse gradient coil. The outer coil pattern of an actively shielded gradient pair. (Courtesy of General Electric Healthcare.)

Since the magnet is generally made of conductive material (or at least contains conductive structures within the outer enclosure), switching the gradient field within the patient bore to generate the encoding described above will generate eddy currents in the conductive structures of the magnet. These eddy currents will oppose the change in field and distort the encoding needed to generate the image. Since the strengths of these currents are proportional to the rate of change of the gradient field, switching the gradients quickly requires compensating for the eddy currents in some way (often filtering the gradient waveforms to compensate the smoothing effect of the eddy currents). The active shielding technique mentioned above for magnets—adding an extra set of windings whose field cancels out the field from the primary windings at a particular distance—was first applied in MRI to reduce the eddy currents generated by the gradient coils (69,70). All modern high-performance gradient coils use this technique and can be thought of as two opposed gradient coil sets, one inside the other. Shielding allows the gradient to be switched quickly without exciting significant eddy currents. Modern whole-body gradient coils typically produce eddy currents less than 0.1% after 1 millisecond with minimal waveform adjustment. Switching the gradients quickly leads to two other safety-related effects. First, switching a magnetic field produces an electric field, and under some circumstances these electric fields can produce peripheral nerve stimulation. Modern clinical MRI systems are calibrated so that painful or severe stimulation will not occur. The complexity arises in that the threshold at which stimulation occurs depends upon several factors, including the position and orientation of the patient. Regulatory guidelines regard severe stimulation as a significant risk, and so the system must be calibrated to operate well below the threshold. Finally, the main magnetic field will exert a force on the gradient windings, causing the gradient former to deform slightly as the gradient waveform is applied. This motion will displace the air within the gradient coil, producing sound. If the force is strong—as when a large current pulse is applied to a gradient coil in a high magnetic field—the sound generated will also be loud, and care must be taken to limit the patient’s exposure to loud noise (71). Several aspects of the design of the gradient coil and the magnet allow reduction in the noise generation. Impregnating the gradient windings in epoxy and joining the primary and shield windings together increase the mass and reduce the net vibration of the coil set. Enclosing the gradient coil in a fiberglass shell designed to dissipate and disperse the acoustic energy generated at the inner surface of the gradient coil also reduces the sound pressure level within the patient bore. Two other components of a typical gradient coil for a clinical MRI system are an RF shield, to reduce interactions between the body RF transmitter coil and the gradients, and resistive and passive magnetic shims. Passive shims are simply small pieces of ferrous material which can slightly adjust the magnetic field within the gradient bore, compensating for manufacturing variation in the magnet windings or environmental effects (such as ferrous structural materials outside the magnet room but nearby). Passive shims are typically optimized during system installation and not adjusted later. Resistive shims are present in high-field systems for demanding applications like echo-planar imaging (EPI) and spectroscopic imaging, to compensate the small distortions in the magnetic field produced by the patient. These windings can be thought of as very low-power gradient coils with higher order spatial variation. The currents in these shims must be optimized for each patient (and generally for each technique or scan location) and typically rely on automatic optimization procedures.

RADIOFREQUENCY COILS 38

The RF coils are required to perform two functions: transmitting and receiving signals at and near the Larmor frequency of the precessing spins (72,73). The term radiofrequency is used loosely to describe a huge frequency range. Standard AM radio broadcasting uses the frequency range from 0.54 to 1.6 MHz, which is well below the proton Larmor frequency in most MR scanners. The frequency range from 3 to 26 MHz is used for short-wave radio broadcasting, and the range from 54 to 216 MHz is used for FM radio and UHF television. To put this in perspective, note that the proton Larmor frequency at 1.5 T is 63.86 MHz. This frequency is located in the band from 60 to 66 MHz that is allocated to broadcasting on television channel 3. It is not surprising, therefore, that many of the electronic components in the MRI transmitter and receiver chains, such as the coaxial cables, matching and tuning networks, power amplifiers, and lowlevel preamplifiers, are similar to their counterparts in radio and TV systems. This also explains the need for careful shielding of MR scan rooms to prevent contamination of the extremely weak NMR signal that originates inside the patient with extraneous signals at the same frequency. Contaminating RF fields can originate either in the operation of broadcasting stations or as adventitious electromagnetic noise created during the operation of electronic equipment such as computers. It is common for MRI scanners to be surrounded by copper mesh–screened rooms so that the received NMR signal can go through at least one stage of amplification before encountering environmental electromagnetic noise. Electronic filters are used to prevent noise from entering the scan room along electrical wiring cables, such as those used to provide current to the gradient coils. Although the frequencies may be the same, the spatial patterns of the electromagnetic waves encountered in MRI are much different from those that are used in radio and TV broadcasting. The radio or TV signal is received at a great distance from its source and is transmitted over this distance as a traveling wave whose energy is equally divided between the electric and magnetic components. On the other hand, the electromagnetic energy of an NMR signal is almost entirely in its magnetic field and is always detected only a short distance from the precessing magnetic dipoles within the patient which are its source. In other words, the transmitting and receiving functions for NMR are carried out in the socalled near-field or standing wave zone where the source and the receiver are separated by much less than one wavelength. For example, at 1.5 T the wavelength of the proton signal is 4.5 m, which is much larger than the size of any of the coils involved in generating or detecting the NMR signal. As a consequence, except at the very highest field strengths, the wavelength of the NMR signal is not an issue in coil design. Another consequence of the differing field patterns is that entirely different receiving and transmitting antennas are required for NMR than for radio and TV. A wide range of RF coil designs are used for MRI. However, they all operate on similar principles and all of them can, at least theoretically, be used as transmitter coils, receiver coils, or both. It is useful to distinguish among head coils, body coils, and surface coils. Head and body coils are designed to surround the region being imaged. They are referred to as volume coils and are designed to produce an RF magnetic field that is essentially uniform across the region of the patient to be imaged. Body coils must be large enough to surround the patient’s chest and abdomen and, often, also the table on which the patient is lying. Body coils are usually constructed on cylindrical coil forms and typically have a diameter of 60 to 70 cm and a length of 70 to 80 cm. Head coils (Fig. 1.8), of course, can be smaller and are typically 40 cm long and 28 cm in diameter. The term surface coil (74) is used loosely to describe a wide range of coil designs that fit closely over some specific anatomic region and provide SNR advantages for its imaging. These coils include circular (e.g., coils for the orbit and the temporomandibular joint) and rectangular coils (e.g., coils for the lumbar, spine), as well as irregular shapes designed for regions such as the cervical spine and the shoulder. A common approach to highresolution imaging is to use separate coils—a large coil (e.g., the body coil) as a transmitter and a comparatively small surface coil as the receiver. This approach takes advantage of the uniform pattern of excitation produced by the large coil and of the high sensitivity of the surface coil over local regions. The sensitivity of the surface coil, of course, is not uniform over its field of view, but this is balanced by the improved SNR for anatomic regions near the coil. When separate coils are used as transmitter and receiver careful attention should be given to their interaction because both coils are tuned to the same frequency. Therefore, any current in one coil tends to excite strong currents in the other coil. This interaction can also be blocked by the appropriate use of crossed diodes and coaxial cables (75). If coil decoupling is not dealt with properly, both the transmit and receive portions of the imaging sequence can be unsatisfactory.

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FIGURE 1.8 Birdcage resonator. A head coil designed to operate at 170 MHz corresponding to the proton resonant frequency at 4 T. Normally, only two of the four inputs would be driven. Driving two adjacent ports with equal signals 90 degrees out of phase produces a circularly polarized field. This design has 16 struts along the z direction, whereas the saddle coil design has 4. The tuning capacitors are barely visible in the end rings. By varying the values of these capacitors while leaving the rest of the structure unchanged, it is easy to change the resonant frequency to work at different static magnetic fields.

The ideal RF field is transverse to Bo, that is, it is in the x or y direction and is completely uniform in space. For head and body coils it can be shown that a z-directed current on an infinitely long cylindrical surface and varying as the sine or cosine of the azimuthal angle would produce this ideal, perfectly uniform B1 field. Of course, in practice, the coil has to be terminated at some finite length and return current paths must be provided. It turns out that the longer the coil is along the z axis, the more nearly the RF field approaches the desired goal of perfect uniformity. In practice, these coils have lengths that are one to two times their diameter. The birdcage resonator (Fig. 1.8) was invented to meet the needs of clinical MRI for a coil that (i) can produce a very uniform B1 field, (ii) can resonate at higher frequencies than the saddle coil, and (iii) is large enough to surround the entire head or body (76). It also possesses advantages in terms of field homogeneity (Fig. 1.9) and can easily be operated in a quadrature mode (72), providing an SNR advantage relative to linear modes as described later. The birdcage design consists of several connected loops arranged around the cylindrical surface and having series capacitances in each of the loops. A common version utilizes 16 loops to span the cylinder. A birdcage resonator has several resonant modes and frequencies, but only one of these modes is useful for imaging purposes. In this mode, which provides a highly uniform B1 field as is desired for MRI, the current in the struts of the coil varies as cos φ, where φ is the azimuthal angle taken at the center of the coil. Whole-body–sized birdcage coils have been demonstrated to resonate readily at frequencies well above 170 MHz. A related form of multimode resonant coil, referred to as the transverse electromagnetic (TEM) resonator, is also useful for head and body imaging, particularly at high field strengths (77).

FIGURE 1.9 Radiofrequency homogeneity patterns. If the radiofrequency field is not homogeneous across the field of view, the nominal 90- and 180-degree flip angles will not be precise and will vary with position, and image-shading artifacts will result. The field in the central axial plane (z = 0) of the saddle coil design, which has its length equal to its diameter (A), has substantially less homogeneity than that of a 16-strut birdcage coil with length equal to 1.5 times

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its diameter (B). (From Hayes CE, Edelstein WA, Schenck JF, et al. An efficient, highly homogeneous radiofrequency coil for whole-body NMR imaging at 1.5 T. J Magn Reson 1985;63:622–628, with permission of Academic Press.)

The birdcage and TEM designs automatically provide a second mode of oscillation identical to the first, except that the current varies as sin φ rather than as cos φ. The first mode produces a highly uniform Bx field, and the second mode produces a highly uniform By field. Each of these fields is linearly polarized. In quadrature excitation both modes are excited simultaneously but with a 90-degree phase shift (78). This produces a circularly polarized rather than a linearly polarized RF field with no additional complexity in coil design. The quadrature operation allows a saving of one-half in the power required during the excitation phase, and it enhances the SNR by a factor of during reception. Although the basic problems of designing RF coils for MRI scanners have been solved, this remains an area in which incremental improvements, particularly in the development of new surface coils, has the potential significantly to enhance the capabilities of this modality. An example is the development of surface coil arrays (79,80). Sometimes referred to as phased arrays, these designs make it possible to obtain the SNR advantages of surface coil with the large FOV capabilities of head and body coils. As discussed later, the development of RF transmitter and receiver arrays in search of enhanced performance is an active area of MRI research and development.

MRI AT HIGHER FIELD STRENGTHS From the beginning of NMR research it has been recognized that increasing the static field strength increases the signal detected in MRI (81–83) through two mechanisms: increasing magnetization and increasing detection efficiency. Most MRI scanners produce spin polarization by applying the static field to a spin system that is in thermal equilibrium with its surroundings (Boltzmann polarization), and, in this case, the equilibrium magnetization increases linearly with field strength. As an aside, it is noted that for MRI based on hyperpolarized spin systems where nuclear polarization is produced by other means, such as dynamic nuclear polarization, the spin magnetization is independent of the imaging field strength (84,85). The detected signal is proportional to the rate of spin precession, and this leads to a detection efficiency that increases linearly with field strength (86). The combination of increased magnetization and increased spin detection efficiency leads to an increase in signal strength that is proportional to the square of the applied field. However, to determine the overall advantage of increasing the field strength and, therefore, the operating frequency, it is necessary to consider the frequency dependence of the noise voltages that are inevitably present. The noise voltages are superimposed on the signal voltage and will impair the ability to construct an image from the signal voltage unless the SNR of the system is sufficiently large. There are three classes of noise that need to be considered. The first noise source is the stray radiation at the MR frequency that is present in the examination room from local broadcasting stations and from electronic devices in the vicinity of the scanner. These noise sources are mitigated by surrounding the scan room with copper shielding and by using filters on all the electrical wires and cables entering and leaving this room. The second class of noise results from random voltages, mostly of thermal origin, added by the electronic components of the receiver system. Because of the great advances that have been made in the field of low-noise electronics, this noise source is normally very small compared to the third class of noise—thermally generated noise that originates in the patient. Patient-generated noise results from the random thermal motion of charged particles, particularly electrolytes, such as sodium and chloride ions, within the patient’s tissues. It can be considered as the RF portion of the blackbody radiation generated by the patient at the temperature of the human body, and there is no practical means of avoiding it. As an aside, note that at infrared frequencies this noise field surrounding the patient is the basis of night vision devices. This noise field results from the random motion of an enormous number of particles in the patient and it is not possible to calculate it directly. However, by the use of standard principles from physics and by straightforward laboratory measurements, the amplitude of this noise can be readily determined for a given configuration of the receiver coil and its position with respect to the patient. Note that whereas the coil inductance and capacitance are determined almost completely by the design and structure of the coil, the resistance is composed of a part (usually small) originating in the coil and a second (usually much larger) component originating in the patient. The Nyquist relation in electronic circuit theory is a special case of a general theorem in statistical mechanics known as the fluctuation–dissipation theorem (72,87). These relations state that the In turn the noise power, PN, is amplitude of the thermal noise in a circuit is proportional to 41

proportional to the square of the noise voltage and to the product σf 2B12, where σ is the electrical conductivity of the tissue, f is the Larmor precession frequency, and B1 is the magnetic field of the receiver coil. The noise voltage is thus linearly proportional to the Larmor frequency and proportional to the square root of the tissue conductivity. In most tissues, the conductivity increases weakly with frequency, and, as a result, the thermal noise level generally increases slightly faster than linearly with increasing field strength (88). The combination of these effects predicts a slightly less than linear increase in SNR with field strength. In fact, making an objective comparison of SNR at different field strengths is complicated by a number of factors. These include the change in RF magnetic field distribution with frequency, the changes in relaxation behavior with field strength, the effects of chemical shift and static field distortions produced by the sample, and the need to use somewhat different RF coil designs at the different field strengths. A linear increase in SNR translates roughly into a doubling of SNR from 1.5 to 3 T, and a further increase by a factor of 2.3 from 3 to 7 T. The linear spatial resolution for MRI is proportional to the cube root of the SNR, and thus the resolution of MRI using isotropic voxels varies more slowly than the SNR with increasing field strength. When comparing human images from 3-T and, particularly, 7-T systems to those from 1.5-T scanners, one is struck by the remarkable increase in anatomic detail that is visible. Although the increase in available SNR noted earlier plays a role, several other factors are also involved. Tissues generally differ slightly in chemical shift and diamagnetic susceptibility as well as in T1 and T2 relaxation times. All of these effects lead to changes in signal intensity, which are amenable to changes in pulse sequence timing to optimize the contrast between particular tissues. For example, the decrease in diamagnetic susceptibility of deoxygenated blood compared to the surrounding tissue gives rise to a local dephasing effect, producing significant contrast in a delayed gradient echo acquisition. Because this effect is localized to the neighborhood of the structures in question, the increase in tissue contrast can be quite striking (Fig. 1.10). Image Uniformity at High Field Strengths At 1.5 T and lower field strengths, a uniform B1 field and, therefore, a uniform image sensitivity can be maintained across an FOV large enough for cross-sectional imaging of an entire human torso. However, there is usually a degree of shading present in 3-T and 7-T images using large FOVs. This shading results in part from an inevitable variation of B1 that is present within the patient at high field strengths. Image shading also arises to some degree from the static field variations produced by the magnetic susceptibility of the tissues (89).

FIGURE 1.10 A: High-resolution (0.39 mm × 0.39 mm × 4 mm) T2*-weighted gradient echo image (TE 11.3 ms, TR 250 ms, flip angle 20 degrees) of a normal volunteer at 7 T acquired in 6:20 (three acquisitions). The red nuclei are visible near the center. The signal dropout seen anteriorly is due to the magnetic susceptibility discontinuity at the air–tissue interface of the underlying sinus cavity. The image was acquired using a two-channel volume transmitter coil and an eight-channel receiver array. B: Similar to panel A, but at a higher level. Note the signal heterogeneity within the white matter and the prominent contrast associated with small veins.

RF uniformity was recognized as an early challenge to imaging at high field strength, and initially it was felt that this might limit MRI to quite low frequencies, not much more than 10 MHz (90). 42

Fortunately, this supposed limit on RF penetration (the skin effect) turned out to be essentially inconsequential up to fields of at least 1.5 T (64 MHz). However, with the introduction of scanners operating well above 1.5 T, the calculation of the B1 field within the patient becomes considerably more complex. A time-dependent magnetic field (B1) will always be accompanied by an electric field, E, which will, in turn, produce a current density, J, at the Larmor frequency within the patient’s tissues (91). The induced current density is the sum of two terms. The first is just σE, where, as before, σ is the conductivity of the patient’s tissues. This term is simply the familiar conduction current density. The second term is less familiar and is referred to as the polarization or dielectric current density. It is 90 degrees out of phase with the conduction current, and its magnitude is given by ∊r∊oωE, where ∊o is a constant called the permittivity of free space, ∊r is called the dielectric constant or the relative permittivity of the tissues, and ω = 2πf is the angular frequency of the B1 field. The induced electric field itself is proportional to the frequency, so that the conduction current density is proportional to the frequency, and the dielectric current density is proportional to the frequency squared. The conduction current density is in phase with E and, therefore, produces a Joule heating effect and energy deposition into the tissues. This energy deposition tends to heat the tissues and is measured by the specific absorption rate (SAR), which is proportional to σ. The dielectric current density is out of phase with E, and consequently it does not produce tissue heating. The induced current density in the patient increases strongly with frequency, and this has profound implications for high-field MRI. At sufficiently high frequencies, the B1 field itself is modified by the electric currents induced within the patient. At low frequencies, say below about 20 MHz, the induced currents are essentially negligible and the B1 field is determined entirely by the currents in the conducting wires of the RF coil. At these frequencies the patient may be considered to be transparent to the RF field. As the frequency is increased, the conduction currents within the patient become sufficiently strong that power deposition within the tissues (SAR) must be considered and kept within safe limits. For a range of frequencies, roughly from 20 to 80 MHz, conduction currents are the main source of induced current effects. At still higher frequencies both conduction and dielectric current densities affect the MRI process. At these frequencies the total B1 field is determined not only by the currents in the RF coils but also by the induced currents within the patient. Although conduction currents tend to screen the center of the patient from the penetration of the RF field, the induced dielectric currents have the opposite effect. Thus, when volume coils (e.g., birdcage coils) are used it is found that B1 increases toward the center of spherical water phantoms, and a similar process occurs in human tissues (92–96). As transmitter power is increased, the field first reaches the level necessary for a 90-degree pulse at the center of the phantom. This produces the high-field phenomenon referred to as center brightening (Fig. 1.11). It is quite unlike the skin-effect shielding of the object’s center that was originally expected. This is because the original analyses considered only the conduction current and neglected the dielectric currents, which become important at high frequencies. The dielectric currents are proportional to the relative permittivity or dielectric constant of the material being imaged. Water has one of the highest dielectric constants of any common substance and is the primary determinant of the dielectric constant of human tissues. The high dielectric constant of human tissues contributes substantially to the prominence of B1 variations and center brightening at field strengths of 3 T and above. In the MR literature the effects of the induced dielectric currents in the patients have sometimes been referred to as “dielectric resonances.” This term is misleading because the word resonance refers to a situation in which a system subjected to an RF power input responds strongly over a narrow frequency band. However, the dielectric response of human tissues is a monotonically increasing function of frequency. Therefore, a different term, for example, dielectric current effects, more closely captures the physics of this phenomenon. Although analytic model calculations of dielectric current effects can be carried out on simple phantoms, such as spheres, the complicated B1 patterns present in human tissues at high frequencies require numerical, computer-based calculations to provide an adequate insight into these crucial considerations (97).

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FIGURE 1.11 A: Gradient echo image of a 17-cm-diameter sphere filled with a low-dielectric constant (2.3–2.8) silicone oil (polydimethylsiloxane). The image was acquired with a gradient echo sequence on a 512 × 512 matrix, with a 22-ms echo time and a 1-s repetition time, with an FOV of 200 mm × 200 mm and a 3-mm slice thickness. Note the absence of the center-brightening artifact in this low-dielectric constant material. B: Gradient echo image of a 17cm-doped water phantom acquired using a two-channel volume transmit/receive coil. Note the prominent centerbrightening artifact associated with the high dielectric constant (∼80) of water. C: Gradient echo image of a 17-cmdoped water phantom acquired with an eight-channel receiver array and the same parameters as in panel A. The array sensitivity variation toward the periphery has not been corrected. The center-brightening artifact using this array of receivers is smaller than in panel B.

On Contrast and Sensitivity at Very High Field Strengths As discussed above, higher field strength generates higher intrinsic SNR. However, in analyzing MR images, the diagnostic goal is to differentiate signals from different structures—image contrast, rather than simply signal, is the ultimate goal. Contrast in images is determined by several factors, primarily differences between the magnetization density and the transverse and longitudinal relaxation times for different tissue types. Contrast is generally manipulated in one of two ways—changing characteristics of the RF pulses (such as the flip angle, generally related to the amplitude and duration of the pulse, and the bandwidth of the pulse) used in the pulse sequence, and changing the timing of the pulses. Herein lies a complication for higher field strengths—since the RF magnetic field strength is not uniform across a brain (typically varying by as much as a factor of 3 at 7 T for an optimized volume coil, and far more for a surface transmitter), the contrast produced by a given pulse sequence generally varies substantially over an extended region, making accurate detection of lesions far more difficult. While some strategies are available for reducing this variation (including adiabatic RF pulses and “parallel transmit” systems, where multiple pulse shapes are applied to produce a more uniform excitation), these approaches are not generally applicable although they are successful in some situations. Relaxation times are also dependent on field strength. In general, longitudinal relaxation times for brain and related tissue increase with field strength (98). Transverse relaxation times, on the other hand, generally decrease. Higher field strength has been shown in recent years to improve one novel contrast mechanism in particular—magnetic susceptibility. While the exact mechanism involved remains an active research topic, what is clear is that myelination and accumulation of iron in tissue produce detectable changes in magnetic susceptibility which can be measured through quantitative modeling of signal phase variations 44

and seen in gradient echo images. These techniques allow more robust detection of some anatomical features (such as the claustrum) as well as in some cases detection of pathology related to Alzheimer disease and Parkinson’s disease. One should finally consider the effects of higher field strength on diffusion imaging. The degree of diffusion weighting in a voxel is determined by the diffusivity of the water within the voxel and the gradient area that can be applied to encode the effects of water diffusion (often called the “b” value). Since diffusivity does not vary with field strength, similar degrees of encoding are required to characterize tissue properties at all field strengths. The reduction in T2 noted above, however, means that the available signal for a given b value will be reduced at higher field strengths. In addition, most diffusion acquisition methods rely on the use of spin echoes, which suffer from the B1 inhomogeneities noted above. One can assert, then, that for long echo times (greater than twice the transverse relaxation time), lower field strength diffusion data will generally have higher sensitivity than higher field strength data. Improvements in gradient technology, however, can in the future permit higher diffusion encoding in less time, reducing the minimum echo time and improving higher field strength data to the point that the higher intrinsic sensitivity can be traded for smaller voxels and better characterization of the tissue characteristics.

SAFETY OF MRI Since the introduction of MRI, patient and operator safety have been of paramount importance in the design and operation of MRI scanners (37,99–104). As long as precautions are taken to avoid the presence of ferromagnetic foreign bodies, excessive rate of change of gradient fields, excessive levels of acoustic noise, and excessive deposition of RF energy, MRI is inherently a very safe imaging modality. For example, it should always be remembered that, during the RF transmitter pulse, large instantaneous RF voltages are present on the transmitter coil and cables. Care should be taken to avoid coupling between these coils and cables and other conductors such as electrocardiogram leads and surface coil cables in the proximity of the patient. Otherwise, the possibility exists of patient injury through RF arcing (105). Review articles cover the safety of the static magnetic fields (106–108), the time-varying gradient fields (109), the RF heating (110), and the acoustic noise (111) associated with MRI scanners. The possibility of nerve or muscle stimulation by the rapidly switched gradients is of concern in highspeed imaging techniques in which extremely rapid gradient switching is used. The rate of change of the magnetic field, dB/dt in tesla per second, is ordinarily used to quantify the level of this stress, although the induced electric field, E in volts per meter, is more directly relevant to tissue stimulation. The present generation of EPI scanners can produce a low degree of peripheral nerve stimulation (112), and a prudent approach is certainly warranted. However, in assessing the risks and benefits of EPI, it should be borne in mind that so-called transcranial magnetic stimulation in both peripheral and central nervous tissue at dB/dt and electric field levels far beyond those present in EPI has been widely used in clinical practice without evidence of injury (113–115). In 1976, the US Congress approved the Medical Device Amendment to the 1938 Food, Drug, and Cosmetic Act. This required the FDA to regulate the safety and effectiveness of medical devices. MRI was the first major medical imaging modality to undergo this regulatory process. The FDA established levels of magnetic field exposure that it deemed nonsignificant risk based on the literature and accumulated experience. From time to time, as experience with MRI has increased, the FDA has increased their guidance with regard to this field (Table 1.2). TABLE 1.2 Evolution of U.S. Food and Drug Administration Guidance on Nonsignificant Risk (NSR) for Whole-Body Exposure to Static Magnetic Fields

MRI SYSTEM ARCHITECTURE 45

Introduced in the early 1980s as a diagnostic imaging modality about 10 years after x-ray tomography (computed tomography [CT]), today’s MRI has become a well-established imaging tool. Major advantages of MRI include the lack of dose limits and the availability of a multitude of contrast mechanisms that can be manipulated through spin physics. Although initially very similar in general layout, modern MRI and CT scanners have little more in common than the host computer and its general functions. As a result of intensive ongoing imaging physics development, ever-increasing data processing demands have resulted in a changing emphasis in the digital hardware and related software. Primary differences exist, for example, when acquiring approximately 1,000 detector matrix inputs at a low rate (1 kHz) in CT versus possibly several MRI receiver coil inputs (from 1 up to 128 separate input channels) at a much higher rate (∼1 MHz). Subsequent data processing in MRI requires spectral content analysis and filtering followed by temporal and spatial reconstruction. This section discusses the basic requirements for the digital hardware and software for MRI and describes implications of recent developments for the evolution of current systems. An overview of the primary scanner components is presented in Figure 1.12. It is difficult to define the “core” of an MRI system because all systems perform a critical function. A function-specific viewpoint, however, identifies the magnet, RF coils, and gradient coils as specific to MR. All other components can be categorized as generic, although specific requirements may result in MRI-optimized elements such as the gradient amplifiers and the RF amplifiers. The two primary dedicated digital control systems are the pulse generator and the data acquisition system. Gradient and RF Waveforms Specific gradient waveforms are required for slice selection, phase encoding, and readout. These signals maybe presented via a linear matrix rotation process allowing for nonorthogonal scanning. For example, the x-, y-, and z-gradient drive currents may be presented to the three physical x, y, and z coils in such a manner that the resultant gradient vectors define directions in a general three-dimensional (3D) volume rather than in the direct geometric planes of the specific coils. Digital synchronization is provided for the receive signal analog-to-digital converter, such that the detected signal samples correlate with the applied gradient and RF signals. In addition to the RF, gradient, and digital signals, additional outputs may be used to drive resistive magnet shims to correct homogeneity or to provide scan-specific corrections. Pulse sequence generation continues to be the primary area of interest for future MRI developments, and the hardware needs to provide sufficient flexibility and expandability to deal with these challenges in a timely manner. The pulse sequences to be used are determined by the clinical requirements of the scan and are selected from specific protocols presented to the user. Following this determination, scan details, including resolution, image size, number of slices, and T1 versus T2 weighting, are input to the console. The result is a sequence description that is executed as a series of waveform updates and data processing (reconstruction) indicators, such that a full series of either 2D or 3D images can be provided for study.

FIGURE 1.12 Magnetic resonance system overview. The host computer integrates the excitation of the spin dynamics within the patient with the data acquisition and image reconstruction and performs a large number of ancillary functions as well. RF, radiofrequency.

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Data Processing and Image Reconstruction Data can be collected from one or more receiver coils, which may be combined in the analog domain but preferably in the digital domain to allow for better correction and spatial match up. A consequence of using more coils rather than one large coil is that although the coils are smaller and closer to the area of interest and thus receive less unwanted signal, the total collected signal energy is also reduced. Therefore, the ability to receive signals farther away from the coil will drop off rapidly, and, as a result, a single small-area coil will see less deeply into the patient. For example, a spinal coil array with eight coils may use 8-cm-diameter coils with some overlap to cover 50 cm in the axial direction and 12 and 16 cm in the transverse direction, thus defining the coil-determined coverage of the selected FOV. Data processing from multiple channels in the digital domain allows for some correction of the inhomogeneous sensitivity of the receiver coils and enhances the ability to provide an acceptable image over a desired FOV. The required data acquisition rate scales with the number of channels that are simultaneously being sampled. As an example, consider a situation in which a bandwidth of 100 kHz is desired. The need to record the data as pairs of in-phase and quadrature signals immediately doubles the required rate to 200 kHz. On theoretical grounds the sampling frequency should be twice the receiver bandwidth to meet the Nyquist criterion for faithfully sampling the in-band signal. However, to permit adequate filtering, a more generous factor of three to four times the bandwidth will help system design. In this example this would require the use of a 400-kHz rate on two converters or an 800-kHz rate on one switched (I/Q) converter. In this example the resultant output data rate for an N-channel system is N × 800,000 samples/s. The samples are likely to be at least 12 bits wide (72 dB of signal + noise + headroom), but it is more desirable to use 14 or 16 bits to allow for better noise averaging and adequate dynamic range. For proper noise suppression, good detail of the small-amplitude noise components is critical, and hence the use of 16 bits offers a significant advantage for high-resolution imaging. In the case of 3D imaging, the signal detail is an order of magnitude smaller, requiring additional bits of input resolution. Eighteen bits would be desirable for a high-performance 3D acquisition system and would provide a good balance between system noise and signal noise. Note that on a ±5-V, 20-bit converter, a single count represents 10 μV, and this is in the range of the thermal noise voltages and the contact noise in the system. In the future, improved performance may be achieved by the use of direct analog-to-digital conversion on or very near the receiver coil to minimize unwanted side effects. Modern high-frequency integration cell phone technology has made this a reasonable consideration. Once the data are acquired, they are usually directly filtered and subsequently stored in a largememory array. The memory array is usually a solid-state memory, but it is possible to construct a very large-memory/cached disk system. Data rates into high-performance disk drives now exceed 200 MB/s for an enterprise system. This rate could just about keep up with the data rates per channel of about 2 MB/s (800-kHz samples, 2 bytes wide) in the aforementioned example, considering that the largest number of receiver channels found in commercial scanners today is 128. At the time of writing, the cost of 1 GB of disk space is less than $0.50, even for the highest-performance disk drives. Disk drives can also be configured to provide automatic data backup, with no or little impact on performance. Note that independent of the number of slices, image resolution, or mode, the sample frequency and the number of simultaneously acquired channels determine the maximum data rate through the system. The actual instantaneous rate can be less this maximum value due to acquisition quiet time within a pulse sequence, such as during excitation. For system design, however, it is best to plan for the maximum rate because shortcuts here will likely sooner or later reemerge as a system bottleneck. For example, fast spin-echo sequences have idle time windows that are separated by long windows of continuous acquisitions, making a choice below maximum rate dubious. Until recently, a dedicated algorithm-optimized processor was preferred. Recently, however, workstation processors have become so powerful that even a general-purpose laptop computer is capable of reasonable reconstruction performance. Computer servers have recently become an integral part of high-performance reconstruction engines. As with other important components of scanner hardware, computer servers offer scalability and modularity. Computer servers exist in a variety of forms, and rack-mount servers have been adopted by several manufacturers to maximize network bandwidth at the expense of node density. The reconstruction engine can be targeted to the specific application just like the number of receiver channels or RF coils. Moreover, reconstruction algorithms can be implemented in such a way as to take advantage of the multiple processors or even graphics processor unit (GPU) to distribute the computational load, thus achieving large speedup factors in image 47

processing and reconstruction performance. This development has a significant effect on parallel imaging reconstruction applications with many receiver channels. On more traditional single-processor reconstruction engines, such image reconstruction algorithms could take upward of several hours to run. After the image is reconstructed, it may be displayed for instantaneous viewing or stored in a database for subsequent review. In most cases many images need to be presented to allow for the search of a particular feature in the image set. In this case image manipulation tools are essential such that all images are presented with similar contrast regardless of location in the imaging volume. For archiving purposes a local database is usually formed on the system. Alternatively, many hospitals have adopted a networked approach in which images from many systems—MRI, CT, and other modalities—are managed at a more central location. In this case the images are accessible from either the database of the imaging system or from the central database.

RF SURFACE COIL ARRAYS AND ACCELERATED IMAGING Unlike other imaging modalities, MRI is intrinsically SNR limited. The physics that describes nuclear magnetism can be combined with the principles of electrodynamics to calculate the ultimate SNR that can be expected in an MR measurement (116–118). MR scientists have focused on developing new technology to allow them to approach this fundamental limit. As pointed out in an earlier section, surface coils have been used to detect MR signals because noise is proportional to the sensitivity volume of the coil, which is much smaller for a surface coil than for a volume coil. On the other hand, the FOV of a single surface coil is limited and the coil sensitivity varies dramatically across its FOV. It was recognized (80) that an array of surface RF coils could be built to achieve large FOV coverage (similar to a volume coil) with the enhanced SNR of small surface coils. The coils are electromagnetically decoupled from one another by properly selecting the overlap between neighboring coils so that nearest-neighbor mutual inductance vanishes and by using low-impedance preamplifiers to isolate coils with nonvanishing mutual inductance. Figure 1.13 shows a 32-channel cardiac research coil (119). The hexagonal arrangement of coils and the extent of their overlap are chosen to minimize mutual inductance between coil elements.

FIGURE 1.13 Research 32-channel cardiac array. Left: Posterior panel with 11 coil elements. Right: Anterior panel with 21 elements. (Courtesy of General Electric Global Research Center.)

Several manufacturers offer scanners that support coils with large number of channels. Recently, research coils with up to 128 channels have been described (120,121). The ultimate intrinsic SNR introduced previously is calculated assuming that the coils and electronics are lossless and all the noise is due to thermal fluctuations in the sample or patient (Johnson noise). To maintain a constant FOV, the size of the coil elements must shrink as the number of channels grows. The design and realization of high-performance 128-channel coils represent a true engineering tour de force to ensure meeting the condition that sample noise dominates overall losses. Field strength plays an important role as well because sample noise grows linearly with field strength, whereas electronics and coil losses are independent of field strength. Therefore, component choice and layout are less critical in a high-channel 3-T coil than in a 1.5-T coil. In an MR scan, spatial and temporal resolution, FOV coverage, and scan time are intimately linked. Routine exams can sometimes require exceedingly long scan times, which can lead to image quality degradation and artifacts because of patient motion. With an ever-increasing number of MR exams performed, efficient clinical workflow is also becoming critical. For these reasons, MR scientists have always been interested in finding ways to shorten MR scans without compromising image resolution and 48

quality. Spatial encoding of the MR signal requires localization in three dimensions. For example, in single-slice Cartesian 2D imaging, one first excites the nuclear spins in a thin slice, then plays a phaseencoding gradient pulse to impose a definite phase relationship across one in-slice direction, and finally reads out the signal while a linear magnetic field gradient is played in the perpendicular in-slice direction (frequency encoding). This sequence of RF and gradient pulses is repeated for each phaseencoding gradient, and finally a 2D Fourier transform of the acquired signal reconstructs the image. We immediately see that the scan time is proportional to the number of phase encodes, and therefore any effort to significantly reduce scan times of MR exams has to address the issue of acquiring fewer phase encodes without reducing image resolution (related to the area under the largest phase-encoding gradient pulse) or FOV (related to the spacing between phase encodes). Single-shot pulse sequences such as EPI are commonly used for high-speed brain imaging. A single RF pulse excites the spins in the selected slice, and a train of phase-encoded echoes is collected sequentially. The MR signal decays throughout the acquisition time, and, in this case, shorter scan times translate directly into improved image quality, reduced artifact generation, and higher SNR. One technique to reduce the number of phase encodes, called partial-Fourier acquisition, is based on the fact that a real image f (x, y) has a Fourier transform that satisfies the Hermitian symmetry F(−kx, −ky) = F(kx, ky)*, where the asterisk denotes complex conjugation. The phase of a static, on-resonance sample can be chosen so that the image representing it is purely real. Therefore, only half of the phaseencoding lines (Fourier or “k-space”) need to be acquired to reconstruct the image. In practice, there will always be some amount of off-resonance behavior either because of magnetic susceptibility, field inhomogeneity, motion and flow (Doppler frequency shifting), or presence of several chemical species with slightly different Larmor frequency (e.g., fat and water in human tissues). For this reason, a few additional lines of k-space have to be acquired to correct for slow phase rolls across the image and the image reconstruction technique goes under the name of homodyne reconstruction (122). Although homodyne reconstruction is a very general technique, its usefulness is limited to at most a factor of two in scan-time reduction. The image resolution and FOV are not affected, although SNR is reduced (relative to a full acquisition) and some image artifacts can be introduced. A more general approach to acceleration of image acquisition was proposed as early as 1987 (123), but it was not until multiple-channel scanner hardware and phased-array coils became more prevalent that this developed into one of the most active research areas in MRI—parallel imaging. The original idea was to synthesize odd phase-encoded echoes from the uniform and gradient signal (picked up with two decoupled receiving cylindrical coils, one a uniform saddle coil and the other a coil configured to have a response proportional to location in the phase-encoded direction) of even phase-encoded echoes. In this way, only half as many lines of k-space had to be acquired to reconstruct an image with the same FOV and resolution. This work preceded the introduction of phased array coils, but it already contained the essential idea of parallel imaging: If a coil can be built with several independent receiving elements with distinct spatial sensitivity, one can use the knowledge of the coil sensitivity patterns to substitute for a subset of phase-encoded k-space lines. Because of the early-stage hardware available, this technique initially only produced an acceleration factor of two. From an information content point of view it is seen that if the signals acquired from each of the coils are truly independent and if there are Nc coils, in the absence of noise, there will be at most a reduction factor of Nc in the number of phase-encoding lines necessary to reconstruct the image without artifacts. In practice, the coil sensitivity profiles are designed to overlap slightly to cover the whole sample adequately and to minimize the mutual inductance between the nearest-neighbor coil elements. Therefore, a maximum reduction factor significantly lower than Nc should be expected. Parallel imaging reduces acquired data and scan time by using spatial information inherent in the coil sensitivity patterns to replace some of the spatial information conventionally developed by use of a sequence of phase-encoding pulses. The reconstructed image from each coil individually contains aliasing or wraparound artifacts caused by undersampling of k-space relative to the Nyquist criterion for a given FOV. It was recognized (124) that linear combinations of individual coil signals could be tailored to mimic the effects of phase-encoding gradients. This technique was named simultaneous acquisition of spatial harmonics (SMASH), and it reduces the number of gradient steps needed to acquire an image, thereby shortening the scan time. Linear combinations of measured coil sensitivities are used to form composite sensitivity profiles with sinusoidal spatial sensitivity (spatial harmonics), and the same linear combinations can be applied to phase-encoded coil data to generate the missing phaseencoding pulses. The filled-in coil data are then Fourier transformed, and the individual coil images are combined to generate a final image. 49

Shortly after the introduction of SMASH, the sensitivity-encoding (SENSE) technique was developed (125). The SENSE approach is more general and more widely applicable than SMASH. In particular it is much less dependent on coil arrangement and slice geometry. The most common implementation of SENSE reconstruction to regularly sampled MR data uses measured coil sensitivity maps to unwrap the Nyquist-aliased images. This is done following Fourier transformation of the undersampled individual coil data. SENSE theory shows how to translate the computation of the optimal unfolding matrix, given coil sensitivities, into a linear algebra problem. In particular, for regularly sampled MR data, this problem has a computationally inexpensive solution. Considerable attention has been given to producing accurate estimates of the coil sensitivity functions. Unfortunately, the scan-time reduction in parallel imaging has its cost. There is an inherent tradeoff between SNR and acceleration factor. Not only does the acquisition of fewer phase-encoded lines of kspace reduce statistical averaging of thermal noise, but also the conditioning of the linear algebra problem to unfold the aliased individual-coil images depends on the acceleration factor. Both effects degrade overall image SNR. Recently, a number of data acquisition schemes and parallel imaging reconstruction algorithms going beyond SMASH and SENSE have been developed to address some of the shortcomings of these early techniques—the most notable example being GRAPPA, generalized autocalibrating partially parallel acquisitions (126). In the past few years, a new category of accelerated imaging methods has been developed based on “compressed sensing” information theoretic framework (127,128). Unlike parallel imaging, compressed sensing can be applied to any number of data channels individually or jointly. The fundamental idea is that medical images (and in fact most categories of natural images) often admit a sparse representation (a representation in which most coefficients of the corresponding basis function are zero) in a suitable transform domain. For example, wavelet bases provide a compact representation for large classes of natural images, including medical images. The central result of compressed sensing is that in the case of strictly sparse signals in the transform domain, one can devise a sampling scheme (often involving random undersampling of the original signal domain, for example, k-space) and a nonlinear reconstruction algorithm that allows perfect reconstruction of the original signal with a number of measurements proportional to the number of nonzero coefficients in the transform domain. This result holds approximately also in the case of signals that are not exactly sparse in the transform domain, but whose expansion in the transform basis decays rapidly. This class of methods was brought to the attention of the MRI community by Lustig (129,130) and applied to 3D imaging, 2D multislice imaging and hyperpolarized 13 C spectroscopic imaging. Because this method relies on redundancy in the pixel representation of medical images and not on the number of receiver channels or spatial distribution of coils, it can be used to accelerate acquisition in domains other than the spatial domain, to which parallel imaging may not apply. For example, Menzel et al. (131) applied compressed sensing to undersample diffusion encoding in q-space for diffusion spectrum imaging (132). Compressed sensing and parallel imaging can also be combined to achieve higher acceleration factors without incurring an exceedingly large g-factor SNR penalty. While SNR is reduced by the square root of the acceleration factor (reduction in noise averaging), for compressed sensing there is no g-factor penalty. However, excessive acceleration with compressed sensing will result in image blurring and artifacts in the shape of the sparsifying basis functions. In conclusion, acceleration methods have proven beneficial under conditions in which the need for scan speed outweighs SNR concerns. For example, real-time cardiac imaging has seen dramatic advances achieving faster frame rates, and breath-held acquisitions have been shortened. Analogously, single-shot techniques, common in brain imaging, have benefited from shorter echo trains (reduced artifacts and improved SNR).

ACKNOWLEDGMENTS It is a pleasure to acknowledge helpful discussions with Drs. V. Schepkin, D. Markiewicz, P Jarvis and E.W. Stautner, M. Xu, and K.M. Amm.

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2 From Image Formation to Image Contrast: Understanding Contrast Mechanisms, Acquisition Strategies, and Artifacts Sean C.L. Deoni

One of the great advantages of magnetic resonance imaging is its extreme versatility in investigating tissue structure, composition, and function. This flexibility stems from the ability to sensitize the MRI signal to an extensive and diverse array of structural properties, metabolic or chemical attributes, and physiologic processes through relatively subtle adjustments in acquisition strategy. Perhaps the most direct clinical illustration of this flexibility is the ability to generate an unparalleled degree and range of contrast between tissues, which lends the method ideally to the task of detecting disease and pathology. The contrast generated in an MR image depends not only on the intrinsic MR properties of tissue, such as the longitudinal and transverse relaxation times (T1 and T2) and proton density (PD) (which each are related to the microstructural, biophysical, and biochemical characteristics of the tissue), but also on the acquisition strategy (i.e., pulse sequence and acquisition parameters), imaging hardware (e.g., field strength and radiofrequency [RF] coil geometry), and image reconstruction methodology. Throughout clinical MRI protocols, the acquired signal is typically weighted toward one or more of these intrinsic properties in order to produce a desired contrast between tissues. However, it is important to appreciate that while the obtained contrast may be primarily related to T1 differences—for example, in a T1 weighted image—it remains a complex function of each of the listed effects, and modulated by patient positioning and coil loading. The choice of contrast mechanism (T1, T2, diffusion, etc.), pulse sequence, and acquisition parameters may mask subtle tissue alteration, and challenge the direct interpretation of signal changes within or between tissues. Further, errors or artifacts introduced by the choice of reconstruction methodology may further impair clinical interpretation, or obscure subtle alteration. The goal of this chapter is to provide an abbreviated overview of MR signal contrast mechanisms, acquisition strategies, and reconstruction approaches relevant to radiologists. We aim to provide a foundation for understanding the biophysical basis of the MRI signal, how contrast may be manipulated through acquisition, and what artifacts may be introduced through the imaging process.

PART I: FUNDAMENTALS OF IMAGE DATA ACQUISITION Acquiring a 2D Image Three central concepts are fundamental to generating an image by MRI: (1) The raw signal acquired in an MRI experiment corresponds to the two-dimensional (2D) or three-dimensional (3D) Fourier transform of the object being imaged; (2) The use of magnetic field gradients define a trajectory through the acquired Fourier transform (also termed “k-space”); and (3) The object image is obtained by calculating the inverse Fourier transform on the acquired k-space data. In MRI nomenclature, the temporal or spatial domain of data points is denoted “image space,” and their corresponding frequency domains as “k-space.” The most common approach to acquiring 2D kspace data is line-by-line, in a raster pattern. To better understand the relationship between the applied frequency and phase-encoding gradients, and the corresponding position in k-space, it is helpful to introduce an imaging sequence timing diagram (Fig. 2.1), which provides a graphical illustration of an acquisition sequence. The relationship between the sequence diagram and k-space position is shown in Figure 2.2. Recall that the position in k-space is related to the strength of the linear field gradient, and the length of time 55

it is applied. The gradients act to move our position through k-space, with phase encoding used to select the ky position, and frequency encoding used to select the kx position. During the application of the positive frequency-encoding gradient (Fig. 2.2), the signal is sampled at uniform timing increments, acquiring each kx point along the selected ky line. This process is then repeated N times, with the Gy amplitude uniformly altered to acquire N ky lines (2-3A) and fill in the complete k-space. Once the desired k-space has been acquired, the 2D inverse FT is calculated to recover the image (2-3B).

FIGURE 2.1 Sequence timing diagram for a basic 2D acquisition. Following an RF excitation, the Gy gradient is applied, followed by the Gx gradient during which the signal is acquired. The sequence is then repeated with Gy incremented. This process is repeated N times to acquire N ky lines in k-space.

FIGURE 2.2 The relationship between the timing diagram and position in k-space. Following an RF excitation we are located at the origin. The application of the Gy gradient (with a negative amplitude) moves our position to −ky. The negative Gx gradient likewise moves us to −kx. Finally, a positive Gx gradient is applied, which moves us to +kx. During Gx, the signal is sampled, “filling in” each kx point along the selected ky line.

The 2D k-space can be considered a look-up table of the spatial frequencies that make up the image. Each point within k-space (kx,ky) corresponds to a particular spatial frequency oriented at the same angle as the angle of the line from (kx,ky) through the origin (Fig. 2.4). Further, recall that the acquired signal is complex; that is, it has both a “real” and “imaging” component as provided by quadrature detection. Thus, k-space is also complex (Fig. 2.5). The real (Re) and imaginary (Im) components can be combined into magnitude (|S|) and phase (Θ(S)) values at each 56

point, as and

The magnitude of each k-space point is the amplitude of the corresponding spatial frequency wave, and the phase is its phase shift. For example, if all spatial frequencies correspond to 2D cosine waves, a point with phase = π/2 would be a sine wave. From 2D to 3D Acquisitions Acquisition of 3D images can be accomplished in one of two ways: multi-slice 2D imaging, or true 3D imaging. Multi-slice imaging, as the name suggests, involves the acquisition of multiple 2D images (slices) arranged in a stack so as to cover a 3D volume. To perform multi-slice imaging, the RF excitation portion of the imaging sequence is modified so that only the desired slice is excited. Once this is achieved, 2D FT imaging is used to acquire the FT of the slice. The process is then repeated, with the excited slice moved along the object. To make the excitation spatially selective, we again exploit the relationship linking magnetic field strength and precessional frequency, as well as the requirement that an RF pulse must be applied at the precessional frequency in order to tip the net magnetization. Here, a linear gradient is applied along the z axis of the object, Gz, inducing a dispersion of precessional frequencies in this direction. Application of a band-limited RF pulse (i.e., an RF pulse containing a specific range of frequencies) at the same time as Gz result in only the magnetization from a specific region of the object being tipped into the transverse plane (Fig. 2.6).

FIGURE 2.3 A: The sequence is repeated with Gy uniformly incremented to acquired each desired ky line. B: Once the desired k-space has been acquired, the inverse FT is calculated to recover the 2D image.

FIGURE 2.4 Each point in k-space corresponds to a specific spatial frequency that, together, produce the image.

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FIGURE 2.5 Since the acquired signal is complex (having real and imaginary components), k-space is also complex. The real and imaginary components can be combined into magnitude and phase, which describe the amplitude of each spatial frequency in the reconstructed image, and its phase offset.

An alternative to multi-slice imaging is fully 3D imaging using phase encoding along the third dimension. In 3D imaging, a volume-selective RF pulse excites spins throughout the entire object, and then the object’s 3D k-space is acquired analogously to the 2D case. The Gz gradient acts as an additional phase-encoding gradient, so that the phase of the signal is related to both Gy and Gz, and the received signal is

FIGURE 2.6 Selective excitation of a 2D slice. A linear gradient, Gz, applied along one dimension of an object causes the spins along that dimension to vary in precessional frequency. Applying an RF pulse containing a narrow range of frequencies will excite only a thin slice of the object.

Again, we can write γ Gzt as kz(t), where

Just as the duration and strength of Gx and Gy defined our (kx,ky) position in the 2D FT (Fig. 2.2), the duration and strength of Gx, Gy, and Gz now define a point (kx,ky,kz) in the 3D FT. The 3D FT is acquired as with the 2D case, with the phase-encoding gradients (Gy and Gz) used to define a line in kspace, and the frequency-encoding gradient (Gx) used to sample that line. This process is then repeated, with Gy and Gz uniformly incremented (2-7A). Finally, a 3D inverse FT is calculated to reconstruct the object’s image (2-7B). The primary advantages of 3D over multi-slice acquisitions relate to spatial resolution and image quality. To achieve high resolution in the through-plane (z) direction, “narrow” RF pulses (i.e., pulses containing a small range of frequencies) and a strong Gz gradient are required. In contrast, highresolution 3D acquisitions can be acquired simply by collecting higher frequency k-space data. An improvement in image quality is also obtained through an increase in the signal-to-noise ratio (SNR), a common metric used to quantify the degree of noise within an image. In simple terms, SNR refers to the “graininess” of image (Fig. 2.8), and is calculated as the ratio of the signal within the object of interest to the background noise, 58

FIGURE 2.7 3D k-space imaging. A: The additional phase-encoding gradient, Gz, is used to “step through” the third dimension of k-space. B: A 3D inverse FT is then performed to recover the 3D image volume.

where S– is the mean signal calculated from a desired region of interest (ROI), and σS is the standard deviation of the signal in a background ROI. If the background noise is gaussian (as is typically the case), a common approach to increasing SNR is by averaging a set of replicate measures (i.e., signal averaging). This increases the SNR by the square root of the number of averaged measurements. Though not obvious, acquisition of a 3D image over 2D multi-slice volume has the same effect as signal averaging, with SNR increasing as where nkz is the number of kz phase-encoding “slices” in the 3D image, and SNR2D is the SNR for the 2D multi-slice acquisition covering the same volume. As can be seen, significant improvements in SNR can be realized through fully 3D imaging. Before moving on, a note about gradient nomenclature is in order. We have defined Gx as the frequency-encoding gradient, and Gy and Gz as phase-encoding gradients. In reality, any dimension may be chosen for frequency encoding. Important Properties of k-Space Since k-space plays such a central role in MRI, it is worth detailing some of its properties that relate to image quality and potential artifacts. The first of these is the relationship between k-space extent and image information content. Briefly, the low-frequency center of k-space contains most of the image content (i.e., structure and contrast), whilst the high-frequency outer portion of k-space contains the image detail (Fig. 2.8). Thus, acquisition of higher-frequency data in k-space results in increased detail in the final image (Fig. 2.9). However, this carries the potential dual penalties of increased scan time and decreased image SNR. The second important point about k-space is that phase information is important. This is best illustrated through the following example (Fig. 2.10) in which the FTs of two images were calculated and the inverse FT performed using the magnitude from image 1 and the phase from image 2. As can be seen, the resultant image more closely resembles image 2. Therefore, it is critical that processes that alter the phase from its true value be avoided or minimized. A quick examination of Table 2.1 reveals one particularly troublesome process: motion! By the shift theorem, motion of the object results in a phase shift in the FT. We will examine this in greater detail in the following section. 59

FIGURE 2.8 Information in the FT. The low-frequency center of k-space contains information related to the main structure of the image (top row), whilst the higher frequency outer portion of k-space contains information related to image detail (bottom row).

FIGURE 2.9 Relationship between acquired k-space and image detail. As the extent of acquired k-space increases, so does the image detail (left to right panels). There is a direct relationship between the number of points acquired in k-space and the number of points in the reconstructed image. If the field of view is held constant, image spatial resolution increases with the k-space matrix size. For the 32 × 32 and 64 × 64 matrix examples, the inverse FT reconstructed images were enlarged to the same size as the 128 × 128 example.

Alternate k-Space Trajectories While the Cartesian–raster pattern sampling approach remains the most common in practice, there is a practically infinite number of potential alternative trajectories with which to acquire k-space. Using the basic principles described in the preceding section it is possible to imagine any gradient trajectory that can be used for imaging. To expand on our prior discussion, we will briefly detail three of the more commonly used alternative trajectories: radial, echo-planar, and spiral.

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FIGURE 2.10 The importance of ensuring correct phase. After calculating the FTs of the two images, hybrid k-space data were created using the magnitude information from image 1 and the phase information from image 2. The inverse FT of this hybrid data reveals an image that more closely resembles image 2, demonstrating the importance of phase information to the appearance of the reconstructed image.

TABLE 2.1 Some Useful Fourier Relationships and Properties that Are Relevant to MRI

Radial Sampling: Radial sampling of k-space (Fig. 2.11) was one of the earliest approaches to MRI, though reconstruction was conventionally performed using filtered back projection rather than Fourier inversion. The primary advantages of a radial sampling approach include the following: (1) The short time between excitation and sampling the center of k-space, which can be useful when imaging tissues or objects with short T2 relaxation times; and (2) Its differential sensitivity to motion compared to Cartesian trajectories. The main disadvantage of the strategy is the variable density with which k-space is sampled. In order to sample the periphery of k-space sufficiently to avoid aliasing, the centre of kspace is vastly oversampled. Thus, the approach is less time efficient than a Cartesian trajectory. Echo-Planar Imaging (EPI): EPI represents a direct extension of the line-by-line Cartesian trajectory we are well familiar with. The primary advantage of EPI is that an entire plane of k-space can be acquired after a single excitation pulse (Fig. 2.12), facilitating a significant reduction in imaging time. Typical acquisition times may be as short as 40 milliseconds, allowing motion to be “frozen.” Following the RF pulse, an initial Gy gradient is used to move to the starting point on the ky axis. A low-amplitude Gy gradient is then combined with an oscillating Gx gradient to produce a sinusoidal trajectory across the slice. Because the readout gradient sweeps back and forth k-space in alternating directions there can be misalignment in the signal amplitudes for every other line (i.e., a phase shift). This can result in a blurred image or a subtle offset ghost image in the reconstructed image. The effect of structured and random phase shifts on image quality will be discussed later in this chapter as part of the effects of motion. An additional confound with EPI is the decay of the magnetization during the readout. As will be seen later, the transverse magnetization typically decays with a time constant on the order of tens of 61

milliseconds, requiring the image to be acquired very rapidly.

FIGURE 2.11 Pulse sequence diagram and k-space trajectory associated with a 2D radial sampling strategy.

Due to its speed and resilience to motion, EPI is used in several neuroscience applications, including functional and diffusion imaging. Spiral Acquisition: Spiral acquisition strategies (Fig. 2.13) offer an alternative to EPI trajectories. These maintain some of the speed advantages of EPI, while placing reduced demand on the gradient systems since it is not necessary to reverse the gradient direction with each line of k-space. Since the center of kspace is acquired immediately following excitation, spiral acquisitions are particularly well suited to imaging tissues whose signals decay quickly. Further, like radial acquisitions, spiral trajectories are less sensitive to motion effects. However, the primary disadvantages of spirals are variable sampling density in the center versus the periphery of k-space, and the sensitivity to gradient nonlinearities. If the gradient waveforms are not performed ideally, there will be mismatch between where one thinks they are in k-space and where they actually are. This can lead to errors in k-space filling, which result in image quality degradation and artifacts.

SPATIAL RESOLUTION, FIELD OF VIEW, AND ARTIFACTS As Figures 2.8 and 2.9 suggest, the region and extent of the acquired 2D or 3D k-space can significantly impact the quality and detail of the reconstructed image. In addition to these basic aspects, the sampling rate also plays an important role. The Fourier relationship that links the acquired “raw” k-space data to the final image introduces an additional confound when discussing signal sampling and other aspects of image acquisition, for while we view the results in image space, we must consider what has occurred in k-space.

FIGURE 2.12 Pulse sequence diagram and k-space trajectory associated with a 2D gradient echo planar imaging sequence.

FIGURE 2.13 Pulse sequence diagram and k-space trajectory associated with a 2D spiral sampling strategy.

Sampling While frequency-encoding or readout gradient is turned on, we are also sampling the continuous MR signal, S(t), as discrete measurements separated by a uniform time increment, Δt. Sampling is performed using an analog-to-digital converter (ADC), which converts the continuous sinusoidal voltage signal from the RF coil into a digital value that reflects the signal’s amplitude. The primary goal of the sampling process is to obtain a set of measurements that faithfully characterizes the original signal, allowing its accurate reconstruction. 62

As a simple example, consider the need to sample a sinusoid F(t) with frequency ω0 (Fig. 2.14). Perhaps ideally, we would acquire as many samples of F(t) as possible. However, this would place significant burdens on the ADC, as well as require substantial memory to digitally store all the samples. A more practical and pragmatic approach is to determine how few samples of F(t) are needed to faithfully reconstruct it. We can see from Figure 2.14 that if the sampling rate (ωs) is less than 2ω0 we can represent F(t) with a lower-frequency sinusoid. This effect is called aliasing, that is, the highfrequency signal is aliased by a lower-frequency signal. A real-world example of aliasing is the television video of a car wheel spinning. As the car speeds up, the tire’s rotation appears to speed up, then stop, then reverse, stop, speed up again, and so on. Obviously, the tire is not reversing whilst the car is traveling forward. The tire’s whacky behavior is a result of aliasing. The condition that ωs should be greater than, or equal to, 2ω0 is termed the Nyquist–Shannon sampling theorem (1), with the Nyquist sampling rate being the minimum rate that satisfies the theorem.

FIGURE 2.14 Sampling a signal. To accurately reconstruct the original sinusoidal signal (A), samples need to be acquired at the Nyquist sampling rate, ωs = 2ω0 (D). When the sampling rate is less than this limit (B and C), a lower frequency, or aliased, signal can appear.

Mathematically, we can describe sampling as the multiplication of the continuous signal by a Dirac comb function, which is a series of impulse functions at regularly spaced intervals, t (Fig. 2.15). It is important to recall that in MRI, the signal acquired is not of the object itself, but rather the FT of the object. Therefore, it is useful to consider the sampling process not in the image domain, but in k-space (2-16A), where each sample is a measurement of the object’s Fourier transform, and the temporal step between samples corresponds to an increment in spatial frequency, Δkx, We can examine the relationship between k-space and image space sampling through the Fourier relationship of each step (making use of Fig. 2.15 and Table 2.1). The multiplication of the continuous FT by a Dirac comb function with spacing Δkx in k-space corresponds to the convolution the object’s image with a Dirac comb function with spacing 1/Δkx (2-16B) in image space. The result of this convolution is a set of images that repeat with spacing 1/Δkx. A rectangular window of width 1/Δkx centered about the origin corresponds to the reconstructed image area. The number of points in the reconstructed image (also termed pixels, or picture elements) is equal to the number of samples acquired in k-space, Nx, and 1/Δkx is the image field of view in x (FOVx). Therefore, the spatial resolution of the image is equal to FOVx/Nx. Typical values for Nx and FOVx for brain imaging 256 and 25 cm, respectively, result in an image spatial resolution of approximately 1 mm. With an appreciation of the relationship between sampling in k-space and the resultant image field of view (FOV) in image space, we can now better understand the occurrence of aliasing (Fig. 2.17). Decreasing the sample rate in k-space corresponds to a decrease in the spacing of the Dirac comb function in image space (i.e., the FOVx becomes smaller). As a result, the repeated images are no longer separated, but overlap within the reconstructed image window (2-17C). These repeated images are commonly termed “ghosts,” or “fold-over” or “wrap-around” artifacts. Image Bandwidth 63

In image space, the FOV and spatial resolution are defined by the pixel and image bandwidth (BW), which are equal to the range of frequencies contained within a pixel or across the whole object. Along x, the resonant frequency difference, Δω, between two points, xmin and xmax, as a result of the linear field gradient Gx is

FIGURE 2.15 Common Fourier transform pairs that appear throughout MRI signal acquisition, sampling, and image reconstruction.

If xmin and xmax define the end points of an object (Fig. 2.18) with corresponding minimum and maximum frequencies ωmax and ωmin, the Δω is related the field of view of the image along x (FOVx) as, If we can accurately sample the range of frequencies across the FOVx (i.e., our sampling rate meets the Nyquist limit) then the reconstructed image will be free of aliasing.

FIGURE 2.16 The relationship between sampling in k-space and sampling in image space. A: In k-space, the FT of the object is discretely sampled, which mathematically corresponds to multiplying the continuous signal by a comb function with spacing Δkx. B: In image space, this procedure is equal to convolving the objects image with a comb

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function with spacing 1/Δkx, which is equal to the image field of view (FOV). If the sampling is performed quickly enough (i.e., equal to the Nyquist limit), the FOV is large enough to contain only a single “copy” of the object.

FIGURE 2.17 Undersampling and aliasing. When the spacing of samples in k-space are too far apart (i.e., sampling is performed too slowly) (A), the field of view in image space is reduced and contains multiple “copies” of the object (B). These additional copies are termed aliases.

Spatial resolution can, likewise, be considered within the context of the frequency range contained within each pixel. From the relationship between the image BW and FOVx, the pixel BW across each of the Nx pixels is Δωp = Δω/Nx (Fig. 2.18). Since resolution is a measure of how close two point sources can be and still be distinguished in an image, spatial resolution is directly related to the pixel BW. If the frequency difference between two point sources (Δω12 = γGx(x2−x1)) is less than or equal to the pixel BW (i.e., Δω12/Δωp ≤ 1), the points will be indistinguishable and appear superimposed in the same pixel. So What Determines the FOV? There may, at first glance, be confusion regarding the relationship between FOV, image BW, gradient strength, spatial resolution, and sampling rate, since each parameter can be related to the others. We can reconcile this by remembering that the FOV is best characterized as the range of frequencies we can accurately sample (Δω). Thus, for a given field gradient strength, Gx, an increased FOV corresponds to increased range of frequencies across the object. In order to accurately sample the maximum frequency in the object, the sampling rate (ωs) must meet the Nyquist criterion, ωs ≥ 2ωmax. The sampling rate is directly related to the time interval of individual samples (Δt), which is also directly related to Δkx. Therefore, the minimum value of Δt that can be performed by the ADC (termed the receiver BW) directly determines the maximum range of frequencies that can be sampled accurately and, consequently, the maximum FOV.

FIGURE 2.18 Image bandwidth, field of view, and spatial resolution. The range of spin frequencies induced across the object by the linear field gradient is termed the image bandwidth (Δω), and corresponds to the image FOV. Image bandwidth divided by the number of pixels along the object is termed the pixel bandwidth (Δωp) and defines the minimum difference in frequencies that can be resolved. If the frequency difference between two points (Δω12) is less than the pixel bandwidth, the signal from each will appear superimposed in the same pixel.

In our example, if the total number of samples (Nx) and Gx are held constant as the FOV is increased, then the increased pixel BW results in a reduced spatial resolution. 65

In general, an MR operator need not directly worry about receiver BW, gradient strength, and so forth. Rather, based on the user’s desired FOV and spatial resolution, the scanner computer will determine the appropriate BW and gradient strength. However, an astute operator will aim to minimize the BW for a given scan time, thereby maximizing the sampling interval Δt. This increases the SNR of the resulting image since more signal is acquired per voxel. This is analogous to signal averaging . discussed previously, with SNR scaling as Sampling in 2D and 3D 2D and 3D imaging are illustrated by the pulse sequence diagrams in Figures 2.3 and 2.6. The phaseencoding steps, Δky and Δkz, are analogous to Δkx, and define the FOV in the y and z dimensions. As a general rule, steps between phase-encoding points are larger than between frequency-encoding points, resulting in aliasing more commonly being associated with phase-encoding directions. Consequently, aliasing is also termed “phase-wrap.” Motion For correct image reconstruction, it is imperative that the phase increments (Δky and Δkz) are constant between successive phase-encoding lines. Phase information contributes substantively to the final image, and phase errors between phase-encoding steps can significantly degrade image quality. For example, applying an artifactual 90-degree phase shift to alternating lines in a 2D image introduces a “ghost” into the reconstructed image, shifted by 1/2 FOV (2-19B). When random phase errors are added to each phase-encoding line, this create a separate ghost for each line, with each shifted in the phaseencoding direction by a different amount (2-19C). This latter case is analogous to patient motion in the phase-encoding direction. As seen in Table 2.1, subject motion in image space corresponds to a phase shift in k-space. It is useful to note that the motion-related ghosts only appear in the direction that the motion occurred (i.e., motion only in the x direction results in ghosting along x, 2-19D). Motion consisting only of rotation has a different appearance since, by Table 2.1, rotation in image space is also rotation in k-space. Thus, rotation motion will appear as rotating ghosts in the image.

FIGURE 2.19 Phase errors resulting from inconsistent phase-encoding increments or motion can substantially corrupt the reconstructed image. Ideal image (A); A phase increment of π/2 added to every other phase-encoding line (B); Random phase errors added to each phase-encoding line, mimicking motion in the phase-encoding direction (C); Random phase errors added to each readout line, mimicking motion in the frequency-encoding direction (D).

Image Bandwidth, Chemical Shift, and Geometric Distortion In addition to defining the image FOV and spatial resolution, BW plays an important role in understanding some common image artifacts, including chemical shift and off-resonance image distortion. As illustrated in Figure 2.18, if the gradient-imposed frequency difference between two points of interest is less than pixel BW (i.e., Δω12/Δωp ≤ 1), the two points will appear to overlap in the same pixel. Similarly, we expect that points separated by Δωp will appear one pixel apart. However, differences in spin frequency as a result of chemical composition or variations in the magnetic field can disrupt this carefully arranged relationship between frequency and spatial location.

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FIGURE 2.20 Fat–water chemical shift. Due to the difference in resonant frequency between fat and water, the signal from fat can appear shifted in the image depending on the pixel bandwidth. In this example, the fat signal appears shifted 2 pixels to the left.

Chemical shift artifacts stem from differences in resonant frequency among spins owing to differences in gyromagnetic ratio or variations in the magnetic field experienced by the nucleus due to surrounding electrons or atoms. A common example in MRI is the hydrogen nuclei associated with fat, which has a chemical shift of ∼147 Hz/T (∼225 Hz at 1.5 T and 450 Hz at 3 T). That is, the hydrogen spins associated with fat have a resonant frequency ∼147 Hz/T less than hydrogen spins associated with water. As a result, if the pixel BW is less than 225 Hz at 1.5 T (or 450 Hz at 3 T), the fat signal will be shifted by at least 1 pixel relative to water signal, even if the fat and water signal originated from the same location (Fig. 2.20). To minimize chemical shift artifacts, the pixel BW must be increased at the expense of SNR. Shifts in resonant frequency can also result from magnetic susceptibility differences between tissues. When a person is placed in the MRI scanner, not all tissues become magnetized to the same degree. As a result, similar to chemical shift, the resonance frequency of some tissues may be slightly different to other tissues, causing a similar artifact as shown in Figure 2.20 at the tissue boundary. This effect can be most pronounced at tissue–air interfaces, such as near the sinuses or inner ear, where the local magnetic field is significantly altered. This air–tissue susceptibility difference can result in geometric distortions, such as that shown in Figure 2.21.

FIGURE 2.21 Geometric distortions induced by magnetic susceptibility differences at air–tissue interfaces (in this example, the inner ear). As a result of the altered resonant frequencies in pixels near the interface, they are misplaced in the final image.

Filtering Referring to the Nyquist–Shannon sampling theorem, in order to avoid aliasing, the sampling frequency in k-space must be chosen to be at least twice the highest spatial frequency contained within the object. However, real-world objects comprise effectively infinite spatial frequencies. To deal with this, the incoming signal is first low-pass filtered, the purpose of which is to filter out frequencies larger than the Nyquist limit (i.e., those larger than 1/2Δkx). While this process is normally transparent to the MR technologist or radiologist, an incorrectly set filter may cause a sharp drop in image signal intensity 67

beyond a certain distance from the image center.

SIGNAL EVOLUTION AND RELAXATION To this point in our discussion we have allowed the excited net magnetization vector to rotate in the transverse plane without considering its evolution with time. Following excitation by an RF pulse, the net magnetization vector is tipped into the transverse plane where it rotates about the external field at the Larmor frequency, giving rise to the MR signal. A second action of the RF pulse causes the spins to recovers back to align in orientation, or become phase coherent in the transverse plane. Over time equilibrium, with the individual spins returning to their parallel or anti-parallel orientation, and losing reforms along the z-axis, parallel with the applied main magnetic their phase coherence. As a result, field , and with a magnitude of M0. This return to equilibrium is characterized by two orthogonal processes: longitudinal (T1) and transverse (T2) relaxation, governed by the T1 and T2 relaxation time along the longitudinal (z) direction (with the T1 constants. T1 relaxation describes the recovery of time corresponding to the recovery of 63% of the equilibrium value), whilst T2 characterizes the loss of phase coherence in the transverse plane (with the T2 time corresponding to the loss of 63% of the initial value). Each of these processes can be described by exponential functions, with the longitudinal component of (Mz) returning to its equilibrium value, M0, by

and the transverse component of

(Mxy) decaying from its initial value (Mxy,0) to 0 as

Each of these functions are illustrated in Figure 2.22. Decay of the transverse magnetization by T2 processes assumes a perfectly homogeneous magnetic field. In practice, this is impossible to achieve and, as a result, the transverse magnetization decays according to a modified T2 relaxation constant, T2*, where T2′ reflects the dephasing due to macroscopic magnetic field inhomogeneities. In general, T2* < T2 5T1), this may be enough to model the signal at TE, which is given by the quadrature summation of the transverse components, More likely, however, it is useful to perform several iterations, setting M(t = 0) = M(TR) and recalculating Eqns. [25–27]. In this case, additional sequence parameters, such as gradient spoiling may also be incorporated. Perfect gradient spoiling can be included by simply setting the transverse magnetization components to zero prior to each RF pulse step. For example, we can simulate the evolution of the gradient echo signal for white matter at 3 T (T1 = 1,084 milliseconds, T2 = 56 milliseconds, PD = 1,000) with α = 30 degrees, TE = 15 milliseconds, and TR = 150 milliseconds as shown in Figure 2.32. (MATLAB code for this example is provided in Appendix A.)

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FIGURE 2.32 Simulated signal evolution for a simple gradient echo pulse sequence for the tissue and sequence parameters shown in the image legend.

FIGURE 2.33 Comparison of white and gray matter signals over a range of acquisition parameters (top row), and the corresponding gray matter–white matter contrast (bottom row).

As our interest lies in evaluating and optimizing tissue contrast, we can use this approach to simulate the signal from different tissues, and across different acquisition parameters. For example, we can evaluate the gradient echo gray and white matter signal at 3 T (using relaxation parameters from Table 2.2) over a range of TE, TR, and flip angles, Figure 2.33. From these signal curves, we can also quickly calculate the signal difference (contrast) between the two tissues to determine what combination of parameters provides optimized contrast. However, even for a relatively simple sequence, the “searchspace” (i.e., the 3D grid of potential TE, TR, and α combinations) can become large. Mathematically, we can also use the discrete-time approach to determine the close-form signal equations for various pulse sequences. For example, assuming TR > 5T1, the gradient echo signal becomes In reality, however, because the gradient echo sequence does not compensate for macroscopic magnetic field inhomogeneities, the signal decay should be parameterized by T*2 and not T2. Thus, this simulation approach does require a priori knowledge with respect to whether T2 or T*2 values should be used. Nevertheless, it does offer an easy and intuitive method of examining and analyzing pulse sequences, and optimizing acquisition parameters for desired image contrast.

ACHIEVING T1, T2, T*2, AND PROTON DENSITY WEIGHTING In conventional qualitative T1, T2, and PD-weighted imaging, contrast is created by sensitizing the acquired signal to tissue differences through the manipulation of acquisition parameters, such as TE, TR, or flip angle. However, it is important to note that while the contrast in these images does depend on the intrinsic tissue properties, it is also sensitive to extraneous hardware factors (such as RF receiver coil geometry, sensitivity, patient positioning, coil loading, and electronic signal amplifier gains). This can be illustrated mathematically by contrasting the ideal signal equation for an IR experiment

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which assumes uniform coil sensitivity and gain, and perfect and homogeneous 180-degree inversion and 90-degree sampling pulses, with a more generalized and realistic expression,

which include the effects of spatial variability in coil sensitivity (B1−) and amplifier gain (ζ), as well as imperfect inversion pulse efficiency (β), and sampling pulse flip angle inhomogeneity (B+1). Thus, although the IR signal, and resultant image contrast, can be preferentially “tuned” to maximally exploit tissue T1, T2, T*2, or PD differences, the influence of extraneous and inconsistent hardware factors cannot be completely removed. Further, while the contrast may be preferentially weighted toward individual relaxation processes or PD, all of these intrinsic parameters will still contribute, even if only subtly, to the acquired signal. In addition to highlighting the complex and muddled nature of the acquired MRI signal, Eqns. [30] and [31] also demonstrate that while certain pulse sequences may be traditionally considered as “T1 weighted sequences” or “T2 weighted sequences,” in reality, any sequence can be made sensitive to T1, T2, or PD differences. That being said, some sequences provide T1 or T2 sensitivity with greater efficiency than others. It is based on this metric that we will categorize sequences throughout this section. T 1 and PD Imaging Using Inversion Recovery Methods While not employed in most clinical neuroradiology protocols today, perhaps the grande dame of T1 weighted imaging is the IR method (shown in Fig. 2.34 with a spin echo readout), whose signal is governed by Eqn. [30]. As a result of its lengthy acquisition times, the method as presented in Fig. 2.34 is seldom used in clinical imaging settings. The sequence comprises an initial 180-degree inversion pulse, which tips the longitudinal magnetization from +M0 to −M0. Following a delay of TI (the inversion time), a 90-degree saturation pulse is applied to tip the recovered magnetization into the transverse plane. A gradient echo or spin echo readout is then used to sample the magnetization. If TE is short compared to T2 or T2*, the signal becomes heavily dependent on T1. Further, if TR is term, and the signal, as a function of TI, can be modeled by much larger than T1, we can ignore the the simplified expression

as shown in Figure 2.35 for white matter, gray matter, and CSF at 3 T. While the signal in Figure 2.35 is shown to recover from −M0 to +M0, in reality most MR images are of the signal magnitude and do not contain negative numbers. An important aspect of this sequence is that the signal crosses through zero at 1.5 T when TI = 0.69T1. This is exemplified visually in the image series Figure 2.36. This has utility for nulling particular tissues, such as in fluid attenuated inversion recovery (FLAIR), where the long T1 CSF is nulled to identify areas of necrosis, inflammation or edema, or provide improved visualization along tissue (e.g., CFS-gray matter) boundaries. An example of T2 weighted FLAIR image of a patient with multiple sclerosis (MS) is shown in Figure 2.37 alongside PD and T2 weighted spin echo images, and demonstrates the ability to differentiate lesions that impinge on the CSF boundary.

FIGURE 2.34 Pulse sequence timing diagram for an inversion recovery (IR) sequence with a spin echo readout.

Fat saturation is another commonly employed application of signal nulling, which is particularly 77

useful in spine and musculoskeletal imaging applications, where it highlights abnormal tissues with increased T1 and/or T2 against a suppressed background of normal tissue and nulled fat. This approach can be combined with a second inversion pulse to null the signal from an additional tissue, or to eliminate the signal associated with flowing blood (i.e., “black blood” sequences) (10). Though more complicated than the conventional IR signal equation (Eqn. [30]), the double IR (DIR) sequence (11) (238A) signal can be modeled as

FIGURE 2.35 A: Evolution of signal (real values [data values retain their true signs] and magnitude) plotted as a function of inversion time (TI). The dashed line in the signal plot corresponds to the magnitude of the signal. The solid line corresponds to the real signal. B: Contrast (measured as the difference between the magnitude signals) plotted as a function of TI for both 1.5 and 3 T. A repeat time of 4,000 milliseconds and an echo time of 40 milliseconds, which are typical in the clinical scenario, are assumed for simulating the curves.

Figure 2.38B contains a DIR image of an MS patient in which signal from both CSF and white matter were nulled, providing improved visualization of abnormal white matter tissue and lesions. T 1 and PD Imaging Using Partial Saturation and Rapid Gradient Echo Sequences In its most basic form, the partial saturation pulse sequence is analogous to the gradient echo sequence described above (Fig. 2.31). The sequence consists of a train of RF pulses (usually chosen to be 90 degrees) separated by a uniform interval, TR. The term “partial saturation” stems from the fact that the spins experience a second RF pulse before the longitudinal magnetization has fully recovered. If the transverse magnetization is spoiled before each RF pulse, and a gradient echo readout is used, the signal can be modeled as

If TE is much smaller than T2*, than can be approximated as 1. Thus, the resultant image contrast is due to differences in T1 and PD. At short TR, T1 differences constitute the main contrast mechanism. approaches 1) and the signal However, as TR is increased, the influence of T1 diminishes (i.e., becomes predominately PD weighted. Using Eqn. [34] we can predict the signal for different tissues (provided their representative T1 values are known) as TR is increased, and compare this with acquired data (Fig. 2.39). The choice of TR that maximizes T1 tissue contrast (e.g., between white and gray matter) can be found as the value that satisfies

When T1,a = 1,084 milliseconds (white matter) and T1,b = 1,804 milliseconds (gray matter), the TRC is approximately 1,380 milliseconds. This agrees well with our simulation result in Figure 2.33 (bottom left panel).

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FIGURE 2.36 Normal 1.5-T brain inversion recovery images corresponding to a repeat time of 2.5 seconds and inversion time (TI) values of 100 (A), 200 (B), 300 (C), 400 (D), 500 (E), 600 (F), 700 (G), 800 (H), 900 (I), 1,000 (J), and 1,200 milliseconds (K). Note the complicated evolution of the relative signal intensities as TI increases. At first, white matter is hypointense to gray matter (TI 100 to 400 milliseconds), whereas cerebrospinal fluid (CSF) changes from hypointense to hyperintense. A second reversal of relative CSF signal intensity first occurs for white matter and subsequently also for gray matter. Finally, at long TI (> 1, slow diffusion or large vessels) gradient echo relaxation varies approximately linearly with M, while spin-echo relaxation varies quadratically. For intermediate relaxation (1 < ΔωτD < 10), the gradient-echo relaxation can vary anywhere from linear to quadratic whereas the exponent of spin-echo relaxation varies from 1.5 to 2. For fast diffusion with weak field gradients, the relaxation is in a motionally narrowed regime and the relaxation varies quadratically for both spin-echo and gradient-echo measurements. Each of the above mechanisms can be exploited and is relevant in the design of susceptibility contrast agents. Superparamagnetic iron oxide crystals and dysprosium–DTPA have been shown to be extremely effective agents at reducing T2 and T2*, and there are strong indications that the change in the relaxation rate produced by such materials when they remain intravascular is significantly greater than is predicted by consideration of the blood volume fraction of the tissue alone (59). This greater efficiency is believed to be due to the fact that the susceptibility difference produced by the agents in blood capillaries sets up magnetic field gradients between the intravascular and extravascular tissue spaces. Water molecules diffusing among these tissue spaces experience a significant dephasing effect and consequently the apparent T2 is reduced. The effect is directly proportional to the fractional volume of tissue occupied by the blood capillaries (52) yet at the same time the effect is extended over a greater volume of the tissue than is occupied by the capillaries themselves. Susceptibility agents, therefore, offer a potentially more powerful method of affecting the overall tissue signal in NMR imaging experiments. Such effects can be used to discriminate regional variations in tissue blood volume, and in conjunction with very fast imaging methods, to detect regional blood perfusion differences. TABLE 3.4 Relaxation Rate Change ΔR2 (s−1) per Concentration of Iron (mg Fe per g Medium) for AMI-25 Particles in Different Media at 20 MHz Measured by a CPMG Sequence

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Superparamagnetic iron oxide particles are clearly effective and although the precise mechanisms by which they operate in any situation are as yet poorly documented, the relaxation rate changes produced by them are a combination of the mechanisms described earlier. The effects of prototype agents have been shown to be field dependent (60). The measured transverse relaxation time is also dependent on the echo time TE and the specific type of pulse sequence used for the measurements, for example, single-echo and multiple-echo sequences will show different degrees of reduction at the same TE values (61). Indeed, in strict analysis, the decay of the transverse magnetization cannot be completely described by a single time constant. A further important point is that the effects of susceptibility agents in any medium will depend on the detailed geometrical arrangement of the particles since this influences the pattern of the field gradients. For example, when they remain intravascular, the spacing and cross-sectional areas of capillaries will likely influence their efficacy even for the same mean concentration (52). Therefore, the proportionality constant between concentration and relaxation rate may be a variable between different tissues, or between normal and abnormal states, which will complicate the quantification of tissue concentrations and the calibration of flow measurements. Evidence for such effects is afforded by Table 3.4 which shows the measured relaxation rates per unit concentration of iron oxide in different media. Furthermore, the dependence is also sensitive to the precise choice of pulse sequence. The relative efficacies of various magnetic materials which have been shown to influence tissue contrast in MRI via susceptibility effects are shown in Table 3.5 which lists the volume susceptibilities of the chelates of gadolinium and dysprosium, Gd-DTPA, Dy-DTPA, as well as one superparamagnetic iron oxide compound, AMI-25 (52). For a typical 70-kg person with a 5-L blood supply, the distributed equilibrium concentration of an intravascular agent (assuming it is not removed from the circulatory system) will be 13.6*X (mM L−1), where X is the dose in millimoles per kilogram. Table 3.5 shows the volume susceptibilities for representative equilibrium blood concentrations of 1 mM L−1 for Gd- and Dy-DTPA and AMI-25 (X = 75 μmol kg−1). Table 3.5 also shows the effect on the transverse relaxation rate and the calculated signal reduction this induces at TE = 50 ms. For intravascular agents at 1.5 T one can achieve equivalent contrast using AMI-25 at 1/10 the concentration of Gd-DTPA and 1/8 the concentration of Dy-DTPA. At lower field strengths the superparamagnetic species will be even more efficient than the paramagnetic agents because of saturation effects, that is, the magnetization of the paramagnetic species will decrease linearly with decreasing field strength while the superparamagnetic material will remain saturated. TABLE 3.5 Comparison of Susceptibility Agents

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FIGURE 3.14 Comparison of gradient-echo and spin-echo relaxation rates at TE = 50 ms calculated for gadoliniumDTPA (A) and dysprosium-DTPA (B). The capillary volume fraction was taken as 3%, D = 0.65 × 10−5 cm2 s−1, for a collection of parallel capillaries of diameter 5 μm. (From Kang YS, Gore JC, Armitage IM. Studies of factors affecting the design of NMR contrast agents: manganese in blood as a model system. Magn Reson Med 1984;1:396–409, with permission.)

Figure 3.14 shows the calculated relaxation rate enhancement as a function of intravascular concentration for Gd-DTPA and Dy-DTPA evaluated at 85 MHz. The water diffusion coefficient was taken to be 0.65 × 10−5 cm2 s−1, with a blood volume of 3%, and a capillary diameter of 5 μm, which is typical for brain. Figure 3.14A shows the spin-echo and gradient-echo relaxation rates for gadolinium while Figure 3.14B shows the same information for dysprosium. In both cases, we ignore dipolar relaxation mediated by exchange across the endothelial wall which is valid when the water exchange rate is slow in brain tissue. We can see that over the range of concentrations shown (0 to 10 mM) dysprosium is about 60% more effective in a gradient echo and 80% more effective in a spin echo. In both cases, the gradient echo shows greater sensitivity to the presence of contrast agent which is characteristic of the intermediate diffusion regime.

CONCLUSIONS In this chapter, the important concepts that are invoked to explain a variety of relaxation processes in tissues are summarized. Relaxation in heterogeneous media embraces several different types of interaction, but in aqueous media, such as tissue, the dipole–dipole coupling dominates spin–lattice relaxation, whereas there are other effects that can be important in influencing transverse relaxation. Contrast agents for MRI can be seen as agents that employ the same physical processes as those that affect the intrinsic relaxation of tissues. The design factors for both paramagnetic relaxation agents as well as susceptibility agents can be interpreted largely in terms of the same relaxation theory that describes water behavior in heterogeneous media. In this chapter, little attempt has been made to discuss the in vivo behavior of agents in any particular application. Whatever the method of delivery, or the circumstances of the application, the same underlying basic principles determine the effectiveness of the agent at altering tissue relaxation times.

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4 Disorders of Brain Development Thierry A.G.M. Huisman and Andrea Poretti

CENTRAL NERVOUS SYSTEM EMBRYOGENESIS In order to understand the classification and pathogenesis of developmental disorders of the central nervous system (CNS) shown on imaging, it is useful to first review the fundamental steps in embryogenesis of the CNS. On day 1, fertilization of an egg by a sperm results in the zygote. The zygote undergoes mitotic division, which results in daughter cells called blastomeres. Approximately 3 days after fertilization, at the 12- to 16-cell stage, the conceptus is termed the morula. Approximately 4 days after fertilization, at the 50- to 60-cell stage, the conceptus is termed the blastula and has divided into two components: an inner cell mass called the embryoblast, and an outer cell mass called the trophoblast that gives rise to part of the placenta. During the second week of gestation, the embryoblast (inner cell mass) becomes bilaminar. The lamina of cells that faces the amniotic cavity is termed the epiblast, and the lamina of cells that faces the yolk sac is called the hypoblast. By the second week, the conceptus is composed of two layers. During the third week of gestation, the conceptus becomes trilaminar, and the process by which the bilaminar embryo becomes trilaminar is termed gastrulation. Conveniently, one can remember that during the third week, the conceptus is composed of three layers. This process of conversion begins with the appearance of a thick, linear band along the dorsal caudal surface of the epiblast termed the primitive streak. Epiblast cells accumulate along the primitive streak, which results in cranial elongation of the streak. Epiblast cells begin to migrate between the epiblast and the hypoblast. At this time of migration, the embryo is considered trilaminar: the epiblast is renamed the ectoderm, the migrated mesenchymal epiblastic cells are termed the mesoderm, and the hypoblast is renamed the endoderm. While the primitive streak is developing, it thickens at its cephalic end to form a structure called the Henson’s node. A portion of the invaginating cells will remain in the midline and migrate along the craniocaudal axis of the primitive streak to form the notochordal process. After resorption of the floor of the notochordal process, the resulting prochordal plate will transform into the definitive notochord (at 20 days). The notochord defines the primitive axis and skeleton of the embryo and will eventually be replaced by the vertebral column. It extends throughout the entire embryo and reaches as far as the level of the future midbrain, where it ends in the region of the future dorsum sella. Most importantly, the notochord induces the transformation of the overlying ectoderm into neuroectoderm with formation of the neural plate. The notochord secretes a protein called sonic hedgehog (SHH) which plays a critical role in signaling the development of motoneurons. Between days 18 and 20, the neural plate transforms into a neural groove which starts to close into a neural tube at day 21 of gestation (1). While the neural tube is closing, the neuroectoderm progressively detaches from the adjacent surface ectoderm and will “dive” into the space between ectoderm and endoderm. The adjacent surface ectoderm will close dorsally to the neural tube. During the fourth week of gestation, the neural tube bares two open ends: the rostral/anterior neuropore and the cauda/posterior neuropore. The anterior and posterior neuropores will close at day 25 of gestation (Fig. 4.1), and provides a summary glimpse of the neural tube and cell migrations that occur around 24 to 25 days gestation. After closure of the rostral neuropore, the cranial end of the neural tube undergoes segmentation into neuromeres and rhombomeres. The neuromeres give rise to the prosencephalon (forebrain), which further divides into the telencephalon (cerebral hemispheres) and the diencephalon. The rhombomeres give rise to the 135

mesencephalon (midbrain) and the rhombencephalon (hindbrain). Simultaneously, the spinal cord and paraspinal tissues will develop. Cells at the border of the neuroectoderm and ectoderm will detach to form the neural crests. The neural crests subsequently fragments and give rise to the primordial of the ganglia which again give rise to the sensory innervations. The corresponding level of the neural tube and later spinal cord furnishes the motor innervations. A somite plate develops on each side of the neural tube which also becomes segmented (somite). At the end of the fifth week of gestation, 42 pairs of somites are noted. The somites will develop a central cavity; the internal side will give rise to the sclerotome which again migrate toward the notochord and will become the vertebral primordial. Cells include fibro-, chondro-, and osteoblasts. The part of the somite which remains in place will become the dermomyotomes. The dermomyotomes are subsequently divided into dermatomes and myotomes. The myotomes give rise to the vertebral muscles. The notochord regresses at the level of the vertebral bodies but persists at the level of the intervertebral discs and will become the nucleus pulposus. The paraxial musculature derived from the somites remains segmental, allowing the musculature to bridge from one vertebral body to the next. The spinal nerves remain segmental and consequently leave the spinal canal between the intervertebral foramina. In the further development of the brain, multiple, complex, interacting and programmed processes guide and determine the migration of the precursors of the neurons from, for example, the germinal matrix to the central and cortical gray matter. Subsequent intracortical migration and networking will determine the thickness, complexity, and shape of the internal and superficial architecture of the cortex. Many functional networks and connections develop. Finally, progressing white matter myelination is observed in well-determined sequences. The development of the fetal brain does not end with birth but continues well into the first and partially second decade of postnatal life.

FIGURE 4.1 The neural tube at 24 to 25 days gestation. Scanning electron micrograph of a 10-day-old mouse embryo (equivalent human age 29 days). The neural tube (white outline), somites (ovals), pharyngeal arches, and neural crest cell migration are depicted schematically. Following closure of the anterior neuropore at 24 days gestation, the cranial neural tube undergoes segmentation: the three most cranial segments are termed neuromeres: N1 corresponds to the prosencephalon, and N2 and N3 to the mesencephalon. The next eight segments are termed rhombomeres, R1 to R8, and comprise the rhombencephalon. At 19 to 21 days gestation, the paraxial mesoderm condenses around the neural tube into cuboidal bodies termed somites. The seven most rostral somites are less well defined and are termed somitomeres (dashed ovals). By 29 days gestation, the four pharyngeal arches have appeared as surface elevations along the primitive oral cavity and pharynx. The maxillary prominence (MxP) and the mandibular prominence (MnP) comprise the first pharyngeal arch. The second (II), third (III), and fourth (IV) pharyngeal arches may be seen at this age. Neural crest cells form from surface ectoderm at the dorsal crests of the neural tube. There is an anatomic registration between the segments of the neural tube and neural crest cell migration, giving rise to the craniofacial primordia, depicted here as migrational streams (arrows). Neural crest cell migration from N1, N2, and N3 (dashed white arrows) gives rise to the cranial vault and calvaria (membranous neurocranium). Neural crest cell migration from the rhombomeres (black arrows) heralds the formation of the pharyngeal arches and gives rise to formation of the viscerocranium (face, jaws, middle ears). The cranial base (cartilaginous neurocranium) originates from the paraxial mesoderm (curved gray arrows). (Courtesy of K. Sulik, University of North Carolina, Chapel Hill, NC.)

The reader is referred to neuroembryologic texts for a more comprehensive review of CNS embryogenesis (1).

CLASSIFICATION OF CNS MALFORMATIONS Over the past two decades, significant progress in pre- and postnatal neuroimaging techniques, 136

development of next-generation genetic sequencing, and animal model research has allowed advancement of the correct definition/classification of congenital brain abnormalities and, as a consequence, a better understanding of their pathogenesis. Indeed, classifications of congenital brain abnormalities have been proposed based upon neuroimaging, molecular genetics, or developmental biology (2–4). Neuroimaging plays a key role in the primary diagnosis of congenital brain abnormalities. Accurate diagnoses of these complex abnormalities are of paramount significance for three primary reasons: (1) to determine inheritance pattern and risk of recurrence, (2) to document involvement of other systems (e.g., kidneys and liver in Joubert syndrome [ JS]), and (3) to assist with understanding prognostic implications for the child and family. Additionally, the neuroimaging findings may allow the definition of subphenotypes within a group of congenital brain anomalies and establish correlations between the neuroimaging phenotype and genotype (e.g., in lissencephaly [LIS]). The first question that has to be answered in any diagnostic workup of an anomalous pediatric brain is if the encountered findings are resulting from an inherited (genetic) versus an acquired (disruptive) cause. A malformation is defined as a congenital morphologic anomaly of a single organ or body part due to an alteration of the primary developmental program caused by a genetic defect (5). Gene mutations causing malformations may be “de novo” or be inherited following different patterns that imply a different recurrence risk for further offspring. Typical examples include a syndromal corpus callosum agenesis, holoprosencephaly (HPE), JS, or rhombencephalosynapsis (RES), to mention a few. A disruption is defined as a congenital morphologic anomaly due to the breakdown of a brain structure that had a normal developmental potential or was initially, intrauterine well developed (5). Disruptive causes include, for example, prenatal infection, hemorrhage, or ischemia. The etiology of prenatal hemorrhages is manifold and includes both maternal (e.g., trauma, sepsis, preeclampsia, and drugs abuse) and fetal (e.g., vascular malformations, congenital tumors, and alloimmune thrombocytopenia) causes. Typical examples of prenatal disruptions affecting the supratentorial brain include hydranencephaly or hemi-hydranencephaly (4-2A), twin disruption sequence (4-2B), and the fetal brain disruption (FBD)-like phenotype. Disruptions are acquired lesions with very low recurrence risk. However, a genetic predisposition to disruptive lesions may be present resulting in an overlap between both etiologies. Dominant mutations in COL4A1 lead to change of the basal membrane of capillaries resulting in microangiopathy (Fig. 4.3). Within the brain, the microangiopathy may lead to hemorrhages and/or ischemias and result in porencephaly or unilateral cerebellar hypoplasia (6). In addition, recently homozygous mutations in NED1 have been shown to cause severe microcephaly, agenesis of the corpus callosum, scalp rugae, and the FBD-like phenotype.

FIGURE 4.2 Examples of prenatal disruptions affecting the supratentorial brain. A: Axial T2-weighted image of a child with left hemihydranencephaly shows almost complete absence of the left cerebral hemisphere with the exception of part of the left frontal lobe matching the vascular territory of the left anterior cerebral artery. B: Coronal T2-weighted image of a neonate after fetal twin–twin transfusion reveals severe symmetric brain tissue loss and marked, secondary ventriculomegaly.

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FIGURE 4.3 An 8-month-old child with bilateral spastic cerebral palsy and COL4A1 mutation.(A–C) Axial and (D) coronal T2-weighted images show unilateral left cerebellar hypoplasia as the results of a prenatal disruptive lesion, bilateral T2-hyperintense signal of the periventricular white matter, and mild ventriculomegaly.

There are many old and new classification systems. Some are based upon historic discoveries and reports, while others are based upon the predominant clinical presentation, neuropathologic findings, genetic and/or molecular data, or on neuroimaging studies. Any classification should be comprehensive and practical, but most importantly correct in order to provide relevant information about prognosis, treatment options, and likelihood of recurrence. Neuroimaging has long served as a noninvasive alternative to neuropathology to determine or confirm a clinically suspected diagnosis. Today, neuroimaging has evolved from a confirmatory diagnostic tool into a modality in which the correct identification and classification of morphologic and microstructural neuroimaging findings initiate the targeted search for a genetic basis of a brain anomaly (e.g., the detection of an anomalous decussation of the superior cerebellar peduncles (SCP) in children with a so-called tectocerebellar dysraphia suggested that this malformation is related to the well-known JS). In this chapter, we have opted for an updated classification based on the neuroimaging pattern, one that is usable in daily clinical work. This classification also incorporates our current knowledge about macro- and microscopic embryology, axonal guidance and signaling, genetics, and microstructural/functional neuroimaging findings. Anomalies of Dorsal Prosencephalon Development Anomalies of the Corpus Callosum and Other Cerebral Commissures DEFINITION. The corpus callosum may be completely absent (agenesis) or partially formed (hypogenesis). Additionally, malformations of the other commissures (anterior and hippocampal commissures) may be associated with corpus callosum agenesis or hypogenesis leading to a complex spectrum of various commissural disorders (7). Moreover, in addition to anomalies of the other telencephalic commissures, anomalies of the corpus callosum are often associated with additional cerebral or cerebellar abnormalities such as interhemispheric cysts, malformations of the cortical development, cerebellar dysgenesis, cephaloceles, or hypothalamic anomalies. CLINICAL FEATURES. Although asymptomatic isolated callosal agenesis has been reported, the vast majority of affected patients present with seizures, developmental delay, cognitive impairment, or 138

hypothalamic dysfunction. Callosal anomalies may be isolated or part of many complex syndromes such as Aicardi syndrome, fetal alcohol syndrome, Chiari II malformation, Dandy–Walker malformation (DWM), nonketotic hyperglycinemia, or pyruvate dehydrogenase deficiency (8). The most frequent is probably the Aicardi syndrome, a likely X-linked dominant disorder characterized by the triad of callosal agenesis, infantile spasms, and chorioretinal lacunae. Typical additional structural brain abnormalities include polymicrogyria (PMG) predominantly frontal and perisylvian, periventricular or subcortical nodular heterotopias, intracranial cysts, enlargement of the tectum in about the half of the patients, and cerebellar anomalies (9). As can be expected, the associated findings are often the main cause of clinical symptoms. PATHOGENESIS. Many scientists have studied the development of the corpus callosum and many misconceptions resulted. The false concept that the corpus callosum develops from anterior (genu) to posterior (splenium) and that the rostrum appears at the very end of the development survived for many decades. Scientists including Jim Barkovich and Charles Raybaud as well as many others have authored several concept manuscripts detailing the complex development of the corpus callosum. We would like to defer to the respective articles (7). Most important is that each neuroradiologist is familiar with the wide variation in shape, length, and thickness of the normal corpus callosum, and that he/she knows to accurately differentiate between a corpus callosum malformation (isolated versus syndromal), corpus callosum destruction (e.g., adjacent hemispheric infarction), and a high-grade corpus callosum thinning (high-grade hydrocephalus). The functional prognosis and outcome vary accordingly. IMAGING FINDINGS. On conventional T1- and T2-weighted MRI, the main finding in callosal anomalies is absent or hypoplastic corpus callosum itself (Figs. 4.4 and 4.5). Most frequently, the posterior part and inferior genu and rostrum are absent. However, many degrees and variations of hypogenesis/agenesis may be present. Parallel coursing, mildly lateralized and separated lateral ventricles, colpocephaly, and upward extension of the third ventricle into the interhemispheric fissure between the lateral ventricles are characteristic neuroimaging findings of callosal agenesis (Figs. 4.6 and 4.7) (7). Other MR findings in the absence of the corpus callosum include lack of definition or inversion of the cingulate gyrus (Fig. 4.8), crescent-shaped lateral ventricles (caused by an impression upon the medial walls of the ventricles by the medially positioned bundles of Probst), separated leaves of the septum pellucidum, malrotation of the hippocampi, and absence of the inferior cingulum (Figs. 4.4 and 4.6) (7). The Probst bundles refer to the white matter tracts that would normally have crossed the interhemispheric fissure within the corpus callosum but instead run parallel to the interhemispheric fissure in an anterior to posterior extension (Fig. 4.9). Due to the lack of the inversion of the cingulate gyrus, the cingulate sulcus is absent/shallow and, consequently, the sulci along the mesial hemispheric surface appear to radiate toward the third ventricle.

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FIGURE 4.4 Complete agenesis of the corpus callosum. A,B: Midsagittal T2-weighted images show complete absence of the corpus callosum, cingulate gyrus, and cingulate sulcus, radiation of the medial hemispheric sulci toward the cerebral hilum, and expansion of the roof of the third ventricle, which is not maintained by the commissural plate. C: Normal midsagittal T2-weighted image of a healthy child for comparison (the white line delineates the cingulate sulcus).

FIGURE 4.5 Partial agenesis of the corpus callosum. A: Midsagittal T1-weighted image shows a rudiment of the corpus callosum close to the anterior commissure, small posterior fornix, and hippocampal commissures, which are attached to the splenium. This means that the commissural plate is virtually complete even though it is very short. B: Axial T2-weighted image reveals colpocephaly.

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FIGURE 4.6 Complete agenesis of the corpus callosum. A,B: Coronal T2-weighted images show widely separation of the lateral ventricles, that have a “Texas longhorn” configuration and contain the heavily myelinated bundles of Probst (A, white arrows); the cingulate gyri are not inverted (the white line delineates the left cingulate gyrus); the third ventricle is extended upwards into the interhemispheric fissure between the lateral ventricles; there is absence of hippocampal rotation. C: Normal coronal T2-weighted image of a healthy child for comparison (the white line delineates the left cingulate gyrus, which is physiologically inverted). D: Coronal necropsy specimen shows a concave frontal horn due to a combination of the Probst callosal bundle (open arrows) and an everted cingulate gyrus (closed arrows).

FIGURE 4.7 Complete agenesis of the corpus callosum. A,B: Axial T2-weighted images reveal extension of the third ventricle between the cerebral hemispheres, parallel course of the lateral ventricles (white line) with medially located heavily myelinated bundles of Probst, and colpocephaly.

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FIGURE 4.8 Normal cingulate gyrus and cingulate sulcus formation. A: Spin-echo 600/20 image of normally inverted cingulate gyri. B: Sagittal necropsy specimen, showing normal cingulate gyrus and sulcus. C: Sagittal necropsy specimen in posterior agenesis of the corpus callosum. When the corpus callosum forms, one consequence of the normal crossing of the callosal fibers is inversion of the cingulate gyri (CG in A,B) with resultant formation of the cingulate sulci (A,B, arrows). In callosal agenesis (C), the lack of formation of a well-defined cingulate sulcus results in mesial hemispheric sulci radiating in an uninterrupted fashion to the roof of the third ventricle in the region of the absent corpus callosum.

FIGURE 4.9 The formation of the lateral callosal bundles (of Probst). As a result of a lack of normal formation of the commissural plate, axons from the cerebral hemispheres do not cross the midline. Instead, on reaching the medial hemispheric wall, the fibers turn to course parallel to the interhemispheric fissure. The fibers run parallel to and indent the medial walls of the lateral ventricles. Broken lines represent normal callosal fibers. Solid lines represent fibers that fail to cross the midline and instead form the lateral callosal bundles.

Occasionally, an interhemispheric cyst is seen in close proximity to the high-riding third ventricle (Fig. 4.10). Although arachnoid cysts can occur in the interhemispheric fissure in association with agenesis of the corpus callosum, more commonly, this cerebrospinal fluid (CSF) collection is lined by ependymal cells. It may communicate with the third ventricle or one or both of the lateral ventricles. Because the corpus callosum is only one of the three major commissures next to the anterior and 142

hippocampal commissures, these additional commissures should be carefully evaluated for associated anomalies. Furthermore, in syndromal corpus callosum malformations like, for example, Aicardi syndrome, additional brain anomalies like migrational abnormalities, disorders of cortical organization, and myelination abnormalities should be excluded (Fig. 4.11). Diffusion tensor imaging (DTI) and fiber tractography (FT) allow to better understand and explore corpus callosum malformations. In patients with agenesis of the corpus callosum, next to the lack of the left–right crossing commissural fibers, the most obvious DTI finding is the presence of the bundles of Probst as large, anterior–posterior oriented (green on color-coded Fractional anisotropy (FA) maps), intrahemispheric, heterotopic white matter tracts coursing along the medial and superior wall of the lateral ventricles (Fig. 4.12). The bundles of Probst may already be depicted by fetal DTI (Fig. 4.13). The bundles of Probst have been shown to connect anterior regions of the hemisphere with more posterior parts exhibiting at least a partially topographic organization. The bundles of Probst are contained in the separated leaves of the septum pellucidum and appear to be continuous with the superior cingulum and fornices. In patients with agenesis of the corpus callosum, a DTI study showed an abnormal microstructure of the right ventral cingulum bundle (as reduced FA values) and bilateral reduction in length and volume. Abnormalities of the cingulum may mirror the observed clinical deficits in executive function and social–emotional processing in patients with callosal agenesis. In patients with agenesis of the corpus callosum, DTI also showed that the fornices are dysplastic and widely separated. In partial agenesis of the corpus callosum, DTI and FT typically show crossing fibers in the partially developed parts of the corpus callosum. Two DTI studies focused on callosal connectivity in partial agenesis of the corpus callosum. The first study showed a relatively consistent pattern of anteriorly located callosal fragments with primarily homotopic frontal connectivity. The study also revealed heterotopic callosal fibers that coursed from right anterior frontal lobe to left occipitotemporal lobes. The second study demonstrated a greater diversity of partial callosal connectivity, including a number of heterotopic tracts that are absent in normally developed, healthy subjects. The patterns of the callosal connections could not be predicted from the appearance of the callosal fragments on conventional MRI. These studies suggest that partial agenesis of the corpus callosum may result from more complex processes than just arrested callosal development.

FIGURE 4.10 Complete agenesis of the corpus callosum with interhemispheric cysts. A: Sagittal CISS image shows complete absence of the corpus callosum. B: Axial T2-weighted image reveals a right interhemispheric cyst (IC,

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interhemispheric cyst; III, third ventricle; LL, left lateral ventricle; RL, right lateral ventricle). C: Coronal T1-weighted image shows a “Texas longhorn” configuration of the lateral ventricles, an upwards extension of the third ventricle, a right interhemispheric cyst, and lack of rotation of the hippocampi.

FIGURE 4.11 Aicardi syndrome. A: Midsagittal T1-weighted image shows absence of the corpus callosum and septum pellucidum. B: Axial T2-weighted image reveals asymmetric dilatation and deformity of the anterior horn of the right lateral ventricle with subependymal, nodular heterotopia (short arrows) and polymicrogyria of the overlying cortex (long arrows). C: Coronal T2-weighted image shows absence of the corpus callosum and asymmetric dilatation and deformity of the anterior horn of the right lateral ventricle with subependymal, nodular heterotopia (short arrows) and polymicrogyria of the overlying cortex (long arrows). (Reprinted with permission from Hergan B, Atar OD, Poretti A, et al. Serial fetal MRI for the diagnosis of Aicardi syndrome. Neuroradiol J 2013;26:380–384.)

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FIGURE 4.12 Complete corpus callosum agenesis. (A) Axial and (B) coronal color-coded FA maps show the bundles of Probst as large, longitudinally oriented (green on color-coded FA maps) white matter tracts that are running along the medial and superior wall of the lateral ventricles. C: Tractography superimposed on an axial T2-weighted image confirms the bundles of Probst. (Reprinted with permission from Poretti A, Meoded A, Rossi A, et al. Diffusion tensor imaging and fiber tractography in brain malformations. Pediatr Radiol 2013;43:28–54.)

FIGURE 4.13 Complete corpus callosum agenesis. Fetal tractography superimposed on a coronal T2-weighted image shows the Probst bundles as thick, parallel bundles coursing medially to the lateral ventricles. (Reprinted with permission from Meoded A, Poretti A, Tekes A, et al. Prenatal MR diffusion tractography in a fetus with complete corpus callosum agenesis. Neuropediatrics 2011;42:122–123.)

Finally, it should be mentioned that a corpus callosum malformation can easily be detected by neonatal head ultrasound examinations (Fig. 4.14). However, the associated anomalies including migrational abnormalities, malrotation of the hippocampi or, for example, a concomitant absence of the anterior, or hippocampal commissure cannot be excluded by ultrasound studies. Malformation of Cerebral Cortical Development The development of the human cerebral cortex is a highly complex process that is regulated by a high number of genes and can be divided into three broad and overlapping steps: (1) neural stem cell proliferation and cell-type differentiation, (2) neuronal migration, and (3) cortical organization and connectivity (4). Any abnormality that interferes with one or more of these processes may result in a malformation of the cortical development. These abnormalities may include (1) gene mutations causing a primary malformation, (2) destructive events (e.g., infection or hemorrhage) causing a disruption, and (3) exogenous toxins (e.g., drugs or alcohol from maternal ingestion, or endogenous toxins from metabolic disorders such as Zellweger syndrome).

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FIGURE 4.14 Complete corpus callosum agenesis. Coronal and sagittal head ultrasound images show the characteristic “Texas longhorn” configuration of the lateral ventricles, radiation of the mesial sulci from the region of the third ventricle, and colpocephaly. Incidental note is made of a resolving right germinal matrix hemorrhage grade 2. (Reprinted with permission from Orman G et al., J Neuroimaging, 2015;25:31–55.)

FIGURE 4.15 Fetal brain, 14 weeks gestation. (A) Axial and (B) coronal images from three-dimensional gradientecho sequence obtained on a fetal anatomy specimen show smooth brain without sulcal development. Note germinal matrix (A, arrows) and normal waves of neuronal migration (B, arrows).

After a short introduction about normal embryology of the cerebral cortex, we will discuss the various malformations of cerebral cortical formation. We will classify them into three groups: (1) malformations secondary to abnormal stem cell proliferation or apoptosis, (2) malformations secondary to abnormal neuronal migration, and (3) malformations secondary to abnormal late migration and cortical organization. NORMAL DEVELOPMENT OF THE CEREBRAL CORTEX. A review of normal cortical formation is useful for understanding the malformations of cortical development. The developing prosencephalon consists of two parts: (1) a thin dorsal portion (also called pallium or dorsal germinal zone) that will form the cortex and hippocampus, and (2) a thick basal portion (also called subpallium or ventral germinal zone) that will form the basal ganglia. More in detail, the basal ganglia derive from two primordia that form as bulges or eminences along the lateral ventricle: the primordium of the globus pallidus, termed the medial ganglionic eminence, and the primordium of the corpus striatum, termed the lateral ganglionic eminence. A third eminence, termed the caudal ganglionic eminence, is believed 146

to give rise to the amygdala. The cells that proliferate within the ventral germinal zone include interneurons that express the neurotransmitter γ-aminobutyric acid (GABA) and have a tangential (nonradial) migration. The cells that proliferate within the dorsal germinal zone include projection neurons that express the neurotransmitter glutamate and have a radial migration to the cerebral cortex. The traditional view of cerebral cortical formation has been termed the protomap hypothesis. According to this hypothesis, nearly all neuronal precursors migrate from the ventricular zone to the cortical plate guided by radial glial fibers (Figs. 4.15 and 4.16). From the ventricular zone of cell proliferation, known as the germinal matrix, cells begin to migrate centrifugally to form the cerebral cortex. Initial migrations begin during the eighth gestational week. A 1:1 or point-to-point correlation exists between the part of the germinal matrix in which certain neurons originate and the part or lamina of the cerebral cortex where the neurons come to rest (Fig. 4.17). This correlation is maintained largely by the presence of radially oriented glial fibers that span the hemisphere and act as scaffolding along which the neurons migrate (Fig. 4.18). After cell migration, according to the protomap hypothesis, the radial glial cells regress and form the mature glia. The understanding of cortical formation, however, has considerably evolved since the protomap hypothesis. The radial glia, for example, is now known to play a much greater role in neurogenesis and has been shown to be cortical neuronal as well as glial precursors.

FIGURE 4.16 Fetal brain, 14 weeks gestation. (A) Sagittal and(B) axial images from three-dimensional gradient-echo sequence obtained on a fetal anatomy specimen. Early neuronal condensations of future caudate and lenticular nuclei can be seen (arrows).

FIGURE 4.17 Schematic drawing illustrating the relationship of the germinal matrix to the developing cortical plate. A 1:1 correspondence exists between the site of cell proliferation in the germinal zone and its eventual resting place in the cortical plate.

The choreography of neuronal migration, moreover, has been shown to be much more complex than the traditional centrifugal pattern. Precursor neurons of the piriform cortex have been shown to originate at the cortical–striatal boundary. These precursor neurons pass from the cortical–striatal boundary in an indirect, non–point-to-point fashion along a radial glial pathway known as the lateral cortical stream. Interneurons of the olfactory bulb, for example, arise in the subventricular zone and move along a rostral path termed the rostral migratory stream that does not involve radial glia. A largescale ventral-to-dorsal tangential migration, moreover, has been shown to occur from the ganglionic eminences to the neocortex and accounts for much of the GABAergic interneurons that constitute 15% to 20% of all neocortical neurons. These migrational routes are summarized in Figure 4.19. 147

FIGURE 4.18 Drawing demonstrating the relationship of the migrating neurons to the radial glial cells. A migrating neuron is illustrated ascending the radial glial fiber. Damage to the radial glial fiber results in an arrest of cell migration.

FIGURE 4.19 Known and putative routes of tangential cell migration. (A,B) Coronal and (C) sagittal sections of the telencephalon. The known routes of migration are depicted as solid arrows; putative routes are depicted by dashed arrows. (1) Medial ganglionic eminence (MGE) to neocortex (CTX) and hippocampus, (2) medial ganglionic eminence to lateral ganglionic eminence (LGE), (3) cortical–striatal boundary to ventrolateral telencephalon (lateral cortical stream), (4) LGE to neocortex and hippocampus, (5) caudal ganglionic eminence (CGE) to dorsal telencephalon, (6) LGE to olfactory bulb (rostral migratory stream), (7) retrobulbar region to marginal zone 75, 76. HIP, hippocampus. (From Corbin J, Nery S, Fishell G. Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain. Nat Neurosci 2001;4(Suppl.):1177–1182, with permission.)

Malformations Due to Abnormal Neuronal and Glial Proliferation or Apoptosis MICROCEPHALY DEFINITION. Microcephaly is defined by a head circumference that is less than two standard deviations under the norm for age, gender, and ethnicity (10,11). Microcephaly affects about 1 in 250,000 people and may be associated with normal or short stature, normal cortex or malformations of cortical development, and high or severely impaired neurologic and cognitive function. Microcephaly is usually divided into two main groups: (1) primary microcephaly with a genetic (malformative) etiology resulting in abnormal proliferation of neuronal precursors or apoptosis, and (2) secondary microcephaly, which results from late prenatal, perinatal, or postnatal injury. In the 2012 updated classification of malformations of cortical development, Barkovich et al. (4) classify congenital microcephaly into eight different groups: 148

1. Microcephaly with severe intrauterine growth retardation and short stature. This group includes Seckel syndrome with mutations in ATR and microcephalic osteodysplastic primordial dwarfism syndrome (associated with mutations in multiple genes). 2. Microcephaly with variable short stature, moderate to severe developmental delay/intellectual disability, normal to thin cortex, simplified gyral pattern, and with/without callosal hypogenesis. This groups includes Seckel syndrome due to mutations in CENPJ and CEP152. 3. Microcephaly with mildly short stature or normal growth, mild to moderate developmental delay/intellectual disability, normal or thin cortex, and with/without simplified gyral pattern, callosal hypogenesis, and/or focal periventricular nodular heterotopia (PNH). This group includes autosomal recessive primary microcephaly due to mutations in ASPM, MCPH1, CDKRAP5, and STIL. 4. Microcephaly with mildly short stature or normal growth, severe developmental delay/intellectual disability, variable cortical development with simplified gyral pattern or cortical dysgenesis, and with/without agenesis of the corpus callosum. This group includes autosomal recessive primary microcephaly due to mutations in PNKP, WDR62 (diffuse or asymmetric PMG), NDE1, and TBR2 (PMG and callosal agenesis). 5. Microcephaly with variable anomalies and with/without simplified gyral pattern, PNH, and/or cerebellar hypoplasia. This group includes patients with ARFGEF2 mutations (PNH). 6. Microcephaly with severe developmental delay/intellectual disability and evidence of degeneration with/without mild short stature, enlarged extra-axial spaces, callosal agenesis, and/or atypical cortical dysgenesis. This group includes Amish lethal microcephaly due to SLC25A19 mutations. 7. Microcephaly with LIS. This group includes Barth and Norman–Roberts syndromes. 8. Microcephaly with tissue loss and enlarged ventricles with/without cortical dysplasia and/or callosal agenesis. This group includes FBD and FDB-like sequences and familial “microhydranencephaly” due to MHAC mutations. CLINICAL FEATURES. The clinical presentation of microcephaly is heterogeneous (12). Cognitive impairment varies from moderate to severe. In children with moderate microcephaly, behavior is the predominant feature, while in children with severe microcephaly, seizures and spasticity are the main findings. A variety of craniofacial dysmorphic features may be present. In terms of diagnosis, therapy, and prognosis, it is important to differentiate primary inherited microcephaly from progressive microcephaly due to a neurodegenerative disorder. PATHOGENESIS AND GENETICS. The pathomechanisms of microcephaly are complex and multifactorial and include genetic and acquired causes. An increasing number of genes (mentioned above) have been associated with primary microcephaly. Mutated genes may cause abnormal mitotic microtubule spindle structure, numerical and structural abnormalities of the centrosome, altered cilia function, impaired DNA repair, DNA damage response signaling and DNA replication, along with attenuated cell cycle checkpoint proficiency (10). Many of these processes are highly interconnected. NEUROPATHOLOGY AND IMAGING FINDINGS. The cardinal feature in microcephaly is a small head and reduced craniofacial ratio. In addition, a simplified gyral pattern may be seen (Figs. 4.20 and 4.21). This pattern consists of a reduced number of gyri separated by abnormally shallow sulci. Common associated abnormalities include foreshortened frontal lobes, mildly enlarged lateral ventricles, and a thin or even partially absent corpus callosum. Posterior fossa involvement in primary microcephaly was recently shown. PMG, PNH, and enlarged extra-axial spaces are less common.

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FIGURE 4.20 MR images of a 6-year-old boy with developmental delay and primary microcephaly. (A–D) Axial T2weighted and (E,F) sagittal T1-weighted images show a mildly simplified gyral pattern including too few gyri and shallow sulci, normal myelination, and a normal thickness of cerebral cortex.

FIGURE 4.21 MR images of a 5-day-old male neonate with dysmorphic features, hypoplastic right heart, optic nerve hypoplasia, and severe primary microcephaly. (A,B) Sagittal and (C,D) axial T2-weighted images show an extremely simplified gyral pattern, a very thin corpus callosum, and disproportionally large cerebellum and brainstem compared to the cerebrum.

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FOCAL CORTICAL DYSPLASIA DEFINITION. Focal cortical dysplasia (FCD) is defined by the presence of abnormal neurons and glia within localized regions of the cerebral cortex. FCD is among the most common causes of epilepsy attributable to focal cerebral dysgenesis. FCD is currently subdivided into four different groups (4): 1. Minor malformations of cortical development, which are characterized by normal cortical architecture and abundant ectopic neurons; 2. FCD type I, which are associated with architectural disturbances of the radial (type Ia) or tangential (type Ib) arrangement of cortical neurons; 3. FCD type II, which is characterized by more pronounced architectural abnormalities such as dysmorphic neurons (type IIa) and balloon cells (BCs) (type IIb); 4. FCD type III, which is associated with hippocampal sclerosis (type IIIa), glial or glioneuronal tumors (type IIIb), and vascular malformations (type IIIc). FCD type II is the most prevalent type. CLINICAL FEATURES. Patients with FCD present with seizures that may be simple partial, complex partial, or secondarily generalized. Patients with FCD type II usually have extratemporal seizures that present at a younger age and have a higher frequency compared to patients with FCD type I. Developmental delay, intellectual disability, and focal neurologic deficits are unusual and only seen in patients with extensive FCD. The majority of the cases are sporadic; no familial recurrence. PATHOGENESIS AND GENETICS. The pathogenesis of FCD is still largely unknown. An association was shown between FCD type IIb and expression of human papillomavirus 16 E6 oncoprotein in large BCs, but needs confirmation. The focal and variable nature of FCD type IIb and the pathologic similarities with tubers in tuberous sclerosis suggests that somatic mosaic mutations of genes involved in the mTOR pathway may be implicated in FCD. NEUROPATHOLOGY AND IMAGING FINDINGS. FCD typically exhibits abnormal cortical lamination, an indistinct cortical–white matter junction, and hypomyelination with astrogliosis of the adjacent white matter. Histologically, this form of FCD resembles the cortical tubers of tuberous sclerosis. In these lesions, the presence of abnormal BCs suggests abnormal cell proliferation or differentiation. In FCD, the histologic changes may be localized to the cortex and the immediate subcortical white matter but may, on occasion, extend from the pia to the ventricular surface. In some cases of FCD, the cortex is disorganized but lacks the BCs of the classic form, suggesting a postproliferation, postmigration abnormality of cortical organization. FCD is rarely seen on CT and may not be visible even with high-quality MRI (e.g., mild malformations of cortical development and FCD type I). Subtle abnormalities in gyration (70%) (Fig. 4.22), cortical thickness (70%) (Fig. 4.22), and blurring of the gray–white matter junction (80%) (Fig. 4.23) are the most common feature and are best seen using thin-slice T1-weighted images (13). The subcortical white matter may exhibit hyperintense signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR), as well as hypointense signal on T1-weighted images as compared to white matter with mature myelination (Figs. 4.22 and 4.23). The white matter signal abnormality may be due to the presence of BCs or neurons within the dysplastic white matter or to abnormal or advanced myelination secondary to frequent seizures activity (14). In FCD without BCs, the lesions may be evident only as areas of blurring of the cortical gray–white matter junction. Cortical calcifications are occasionally demonstrated by CT. On imaging, FCD may be overt or extremely subtle and may occur in any lobe.

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FIGURE 4.22 A 14-year-old boy with right parietal focal epileptic seizures and focal cortical dysplasia type II. Axial (A) T1-weighted, (B) T2-weighted, and (C) FLAIR images; and coronal (D) T1-weighted, (E) T2-weighted, and (F) FLAIR images show an abnormal gyral pattern with T2- and FLAIR-hyperintense and thickened cortex in the right parietal lobe (arrows). In addition, the subcortical white matter has a T1-hypointense and T2- and FLAIR-hyperintense signal.

Bottom-of-sulcus dysplasia refers to a malformation of a form of FCD that is characterized by cortical thickening at the bottom of a sulcus, a funnel-shaped extension of the lesion toward the ventricular surface, commonly with abnormal signal intensity, and an abnormal gyral pattern related to the bottomof-sulcus dysplasia, sometimes with a puckered appearance (15). Presurgical localization of FCD often requires advanced MRI techniques and postprocessing. Functional studies including SPECT and FDG-PET scanning are also frequently needed to maximize the likelihood of identifying and defining the boundaries of FCD lesions. The role of new MRI techniques such as high field strength (>3 T), arterial spin labeling (ASL), susceptibility-weighted imaging (SWI), and DTI is currently evaluated (16). HEMIMEGALENCEPHALY DEFINITION. Hemimegalencephaly (HME) is a rare, almost always sporadic brain malformation characterized by overgrowth limited to one cerebral hemisphere (17). CLINICAL FEATURES. Children with HME typically present in infancy or already in the neonatal period. The first neurologic symptoms/findings are usually macrocephaly without signs of increased intracranial pressure; severe, early onset, and usually intractable epileptic seizures; and global developmental delay mostly leading to cognitive impairment (17,18). Contralateral hemiparesis and ipsilateral hemianopsia have also been reported. Patients with unilateral megalencephaly usually have a large head very early in life, but, possibly as a result of the intractable seizures, the head size diminishes relative to the normal curve, and eventually the patients may be normocephalic or microcephalic. PATHOGENESIS AND GENETICS. There are three forms of HME: (1) isolated HME, which is restricted to the hypertrophic and dysplastic hemisphere; (2) associated HME, in which HME is part of neurocutaneous syndromes, particularly the epidermal nevus syndrome, but also Klippel–Trenaunay syndrome, neurofibromatosis type 1, encephalocraniocutaneous lipomatosis, Proteus syndrome, hypomelanosis of Ito, tuberous sclerosis, megalencephaly–capillary malformation, and megalencephaly– polydactylypolymicrogyria–hydrocephalus syndromes (17); and (3) total HME in which the ipsilateral cerebellar hemisphere and the brainstem are also enlarged and show abnormal foliation (17,19). Recently, somatic mutations in three PI3 K-AKT-mTOR pathway genes have been reported in patients with HME including PIK3CA, AKT3, and MTOR. Mutations of this pathway genes cause the activation of 152

the pathway, which is highly expressed in the developing brain during corticogenesis. In some cases, mutations are apparently limited to the brain. As mentioned above, HME may also occur in the setting of neurocutaneous disorders and be caused by somatic de novo mutations as part of the megalencephaly-capillary malformation and megalencephaly-polydactylypolymicrogyria-hydrocephalus syndromes. In summary, HME may be caused by mutations in brain progenitor cells, but that some of these mutations occur early enough in development to be present in many tissues, affecting cells outside the brain as well. In contrast, other mutations might be limited to the brain because they occur after the embryonic separation of brain from non-brain tissue.

FIGURE 4.23 A 12-year-old girl with left frontal focal epileptic seizures and focal cortical dysplasia type II. (A) Axial and (B) coronal T2-weighted images show a T2-hyperintense signal of the affected cortex and underlying subcortical white matter (arrows). C: High-resolution axial T1-weighted image reveals a T1-hypointense signal of the subcortical white matter as well as an indistinct gray–white matter junction (arrows).

NEUROPATHOLOGY AND IMAGING FINDINGS. On neuropathology, the affected overgrown hemisphere exhibits increased white matter volume, malformations of cortical development including pachygyria, LIS, PMG, heterotopias, leptomeningeal glioneuronal heterotopia, and, most often, ipsilateral ventricular enlargement (Fig. 4.24). Malformations may be seen in the “unaffected” hemisphere as well. Conventional neuroimaging typically shows an asymmetry between the cerebral hemispheres with moderate to marked enlargement of the affected hemisphere (Fig. 4.25) (17). The cortex of the affected hemisphere appears dysplastic with an abnormal gyral pattern including broad gyri, shallow sulci, and cortical thickening resembling LIS or pachygyria, and blurring of the cortical–white matter junction (Fig. 4.24). The affected occipital lobe may be disproportionately prominent and be displaced with the falx across the midline toward the contralateral lobe. The ipsilateral ventricle appears typically enlarged with straightening of the frontal horn and/or unilateral colpocephaly (Figs. 4.24 and 4.25). The white matter shows abnormally high T2-signal intensity due to absent or incomplete myelination (Figs. 4.24 and 4.25). Cerebral calcifications may be seen on CT. The corpus callosum is almost always asymmetric with enlargement and dysplasia of the affected side (Fig. 4.26). The ipsilateral olfactory and optic nerves may also be significantly enlarged (19). The vessels of the affected hemisphere appear also enlarged compared to the contralateral side (Fig. 4.24) (19). HME most often involves only the cerebral hemisphere; however, the brainstem and cerebellum may also be enlarged (total HME) (Fig. 4.25). 153

ADVANCED IMAGING. Advanced neuroimaging, in particular DTI, may show a complete disorganization of the ipsilateral white matter fibers with an abnormal concentric orientation around the ventricle (Fig. 4.26). The septum pellucidum maybe be wide due to aberrant, midsagittal, bandlike structures beneath the corpus callosum (Fig. 4.26) connecting the frontal, parietal, and/or occipital lobes either bilaterally or ipsilaterally. Abnormal interhemispheric fibers maybe present in HME. In the majority of the cases, the ipsilateral callosal tracts are larger compared to the contralateral side because of abnormal/missing interhemispheric connections of these fibers with a resultant increased amount of ipsilateral fibers. In a minority of cases, however, the volume of the ipsilateral callosal fibers is reduced. Finally, DTI may reveal asymmetry of other white matter tracts with thickening of the ipsilateral ones.

FIGURE 4.24 A 13-month-old boy with Klippel–Trenaunay–Weber syndrome and right hemimegalencephaly. Axial(A) T2-weighted and (B) T1-weighted images show an enlargement of the right cerebral hemisphere with polymicrogyria within the frontal, temporal, and parietal cortex, T1-hyperintense and T2-hypointense signals of the subcortical white matter, and dilatation of the right lateral ventricle. In addition, the ipsilesional meningeal vessels are enlarged.

FIGURE 4.25 A 15-month-old boy with megalencephaly–capillary malformation and left hemimegalencephaly. A: Axial T2-weighted image of the cerebellum shows enlargement of the left cerebellar hemisphere (ipsilateral to the cerebral involvement). B: Axial T2-weighted images at the level of the cerebrum reveal a moderate enlargement of the left cerebral hemisphere with cortical dysplasia and T2-hyperintense signal of the left periventricular white matter. (Reprinted with permission from Poretti A, Boltshauser E. Hemicerebellar hemimegalencephaly. In: Boltshauser E, Schmahmann JD, eds. Cerebellar Disorders in Children. London: MacKeith Press; 2012.)

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FIGURE 4.26 A 15-month-old boy with left hemimegalencephaly. A: (A) Axial and (B) coronal T1-weighted images shows enlargement of the left cerebral hemisphere. (C) Axial and (D) coronal color-coded FA maps reveal asymmetrical size of the fibers running through the anterior and posterior parts of the corpus callosum (increased size within the megalencephalic hemisphere) as well as abnormal white matter tracts within the megalencephalic hemisphere (white arrows). (Reprinted with permission from Poretti A, Meoded A, Rossi A, et al. Diffusion tensor imaging and fiber tractography in brain malformations. Pediatr Radiol 2013;43:28–54.)

Malformations Secondary to Abnormal Neuronal Migration COBBLESTONE MALFORMATION DEFINITION. Cobblestone malformation is a severe brain malformation associated with abnormal migration from the brain into the leptomeninges, and frequently with eye anomalies and congenital muscular dystrophy (CMD) (20). Cobblestone malformation occurs in CMD due to reduced Oglycosylation and rarely N-glycosylation of α-dystroglycan. Based on the severity of the findings, different phenotypes have been described in order of increasing severity: Fukuyama congenital muscular dystrophy (FCMD), muscle–eye–brain disease (MEB), and Walker–Warburg syndrome (WWS). CLINICAL FEATURES. The clinical phenotype of patients with cobblestone malformation is characterized by muscle (proximal weakness, hypotonia, and increased creatine kinase values), brain (intellectual disability, seizures, tetraspasticity, and, in some patients, macrocephaly), and eye (microophthalmia, optic nerve hypoplasia, chorioretinal coloboma, retinal dysplasia, cataract, glaucoma, or high myopia) involvement (20). GENETICS AND PATHOGENESIS. To date, mutations in 15 genes have been associated with αdystroglycanopathies. Mutations in these genes cause a reduced O-glycosylation and rarely Nglycosylation of α-dystroglycan. α-dystroglycan is a highly glycosylated peripheral membrane protein that binds many extracellular matrix proteins through attached carbohydrate groups. In αdystroglycanopathies, glycosyl groups are absent or reduced, resulting in decreased binding of ligands such as laminin-2, agrin, and perlcan in skeletal muscles and neurexin in the brain. This causes defects in the pial limiting membrane and its attachment to radial glial fibers. Mutations within the 15 individual genes are associated with a phenotypic spectrum. Mutations in the majority of the genes may cause different phenotypes and there is not a real phenotype–genotype correlation. Only patients with POMGnT1 mutations are somehow exceptional because the vast majority of them present with features of MEB (20). 155

NEUROPATHOLOGY AND IMAGING FINDINGS. The neuroimaging findings of αdystroglycanopathies are wide and range from severe changes of WWS to normal brain MRI (20). However, the majority of the patients fit into one of the phenotypes (FCMD, MEB, WWS, CMD with cerebellar hypoplasia/dysplasia, normal brain MRI).

FIGURE 4.27 A 1-day-life-old neonate with Walker–Warburg syndrome and POMT2 mutations. (A) Midsagittal and (B,C) axial T2-weighted images show a marked ventriculomegaly, a diffusely thin cerebral cortex with almost no sulcations, severe hypoplasia of the cerebellar vermis and hemispheres, and an abnormal kinking of the brainstem with elongation and thickening of the midbrain and tectum and marked pontine hypoplasia. In addition, an asymmetry in the size of the eye globes with right micro-ophthalmia was seen.

In WWS, hydrocephalus is consistently present and causes macrocephaly and prominent forehead (Fig. 4.27). The cerebral surface is undersulcated and there is usually diffuse agyria. The cerebral cortex is moderately thick, unless thinned due to hydrocephalus. The cortical–white matter junction is jagged with common vertical striations. The white matter has a very abnormal signal (T2 hyperintense and T1 hypointense). The corpus callosum is typically thin. The presence of an occipital encephaloceles is not uncommon. The brainstem and cerebellum are highly dysplastic with a pontomesencephalic kinking (21). The pons is usually hypoplastic and has a ventral midline cleft. The tectum and midbrain, however, are usually enlarged and dysplastic. The cerebellum is globally hypoplastic, but the vermis is typically more severely affected. The cerebellar foliae have a dysplastic orientation. Cerebellar cysts are uncommon in WWS. In MEB, neuroimaging findings are usually similar to WWS, but less severe (Fig. 4.28) (20). Involvement of the cerebral cortex is characterized by pachygyria with frontal predominance instead of agyria. Areas resembling PMG are seen too. In MEB, there is no brainstem kinking, and the cerebellar cysts are present in almost all patients. Malformative cerebellar cysts are characteristic, but not specific for α-dystroglycanopathies and are located particularly in the boundary between the normal and dysplastic cerebellar cortex (22). In FCMD, neuroimaging findings are less severe compared to MEB (20). Hydrocephalus is uncommon and the brainstem is usually normal. Cerebellar cysts are rather common. The prenatal diagnosis of α-dystroglycanopathies is challenging. Ventriculomegaly, if present, is nonspecific. A smooth cerebral cortex and a small cerebellum may be physiologic until 24 to 25 and 18 to 20 weeks of gestation, respectively. Cerebellar cysts develop only postnatally. The abnormal brainstem angulation seems to be the most specific prenatal imaging finding and, if associated with 156

prenatal ventriculomegaly, should raise the suspicion of α-dystroglycanopathies. LISSENCEPHALY AND SUBCORTICAL BAND HETEROTOPIA SPECTRUM DEFINITION. LIS or smooth brain and subcortical band heterotopia (SBH) are the classic malformations associated with abnormal neuronal migration (23). LIS is characterized by absent or abnormally wide gyri and an abnormally thick cortex. SBH consists of a normal or mildly simplified gyral pattern with a smooth band of gray matter in the superficial and middle portions of the white matter. CLINICAL FEATURES. Typically, children with LIS and SBH come to medical attention during the first year of life because of seizures, poor feeding, hypotonia, and developmental delay. Seizures have multiple semiologies including infantile spasms with classic hypsarrythmia, and are usually therapy resistant. Neurologic outcome is typically related to the grade of LIS or thickness of SBH. PATHOGENESIS AND GENETICS. LIS, SBH, and LIS with cerebellar hypoplasia are consistently malformative in origin. To date, mutations in 12 genes have been associated with LIS and SBH and account for up to 90% of patients (23). Deletions and mutations in LIS1 are the most common causes of LIS.

FIGURE 4.28 A 5-month-old boy with muscle-eye-brain disease and POMGnT1 mutations. (A) Midsagittal and (B,C) axial T2-weighted images show a marked ventriculomegaly, dysplastic brainstem including elongated and thickened midbrain and tectum as well as hypoplastic pons with a midline dorsal cleft, global cerebellar hypoplasia with multiple cortical/subcortical cysts within the cerebellar hemispheres and vermis, generalized polymicrogyria, diffuse T2hyperintense signal of the supratentorial white matter, and absence of the septum pellucidum. (Reprinted with permission from Poretti A, Boltshauser E, Doherty D. Cerebellar hypoplasia: differential diagnosis and diagnostic approach. Am J Med Genet C Semin Med Genet 2014;166C:211–226.)

The classic four-layered LIS is associated with a spectrum of malformations including isolated LIS, SBH, and Miller–Dieker syndrome. Miller–Dieker syndrome is characterized by severe four-layered LIS with agyria and not clear gradient (Fig. 4.29), characteristic facial dysmorphism (e.g., prominent forehead, short nose with upturned nares, and protuberant upper lip), and additional body malformations. The genotype of Miller–Dieker syndrome consists of large deletions in chromosome 17p13.3 that include LIS1, YWHAE, and all intervening genes. Isolated LIS consists of classic four-layered LIS with normal or mildly hypoplastic cerebellum. Various 157

genes have been associated with different patterns. Boys with DCX mutations have a diffuse severe agyria or a frontal predominant LIS. Children with TUBA1 A mutations have also a posterior predominant LIS. SBH is caused by heterozygous mutations in DCX and most patients are female. LIS with cerebellar hypoplasia maybe divided into two groups. The first group consists of mild frontal predominant LIS associated with severe hippocampal and cerebellar hypoplasia and dysplasia. Mutations in RELN (encodes an extracellular matrix-associated glycoprotein (reelin) that is secreted by Cajal– Retzius cells in the developing cerebral cortex and is critical for the regulation of neuronal migration during cortical and cerebellar development) and VLDLR (an essential cell-surface receptor for reelin) have been found in this group of LIS patients (24,25). The second group consists of more severe LIS with cerebellar hypoplasia as occurs in tubulinopathies (26). NEUROPATHOLOGY AND NEUROIMAGING FINDINGS. In all LIS forms, the brain surface appears smooth with areas of absent (agyria: the sylvian fissures are the only definable fissures) or abnormally wide (pachygyria) gyri, and vertically oriented sylvian fissures. The cerebral cortex is thickened (8 to 15 mm compared to 2.5 to 4 mm of the normal cortex). In SBH, the brain surface is normal and there is a smooth band of misplaced gray matter within the subcortical white matter (Fig. 4.30). The anterior to posterior gradient, gender distribution, and associated malformations are essential for recognition of the different genetic forms. Mutations of DCX, ACTB, and ACTG1 result in an anterior– posterior gradient, while mutations of LIS1, TUBA1 A, TUBG1, and DYNC1H1 have a posterior–anterior gradient (23) (Fig. 4.31). Severe LIS with agenesis of the corpus callosum in a boy is strongly suggestive of ARX mutations (Fig. 4.32). LIS with pontocerebellar hypoplasia (PCH) suggests RELN or VLDRL mutations. The vermis is typically more affected compared to the hemispheres and typically does not show almost any foliation. Pontine hypoplasia is very consistent. Neuroimaging findings are more severe in RELN mutation compared to VLDRL mutation. NEURONAL HETEROTOPIA DEFINITION. Neuronal heterotopia consists of a group of neurons in an inappropriate location. The major types include PNH that line the lateral ventricles, subcortical nodular heterotopia, that tend to form large masses of nodules beneath the cortex, and SBH. SBH is discussed with LIS because of the similar pathomechanism.

FIGURE 4.29 A 1-day-old neonate with Miller-Dieker syndrome and lissencephaly. (A) Axial and (B) coronal T2weighted images show absence of medial hemispheric sulci other than the parieto-occipital sulcus and a smooth cerebral surface with the typical cortical pattern with thin (dark) outer cortical layer, relatively thick (bright) cellsparse zone (arrows), and thick (dark) inner cortical layer. The lateral ventricles are relatively enlarged.

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FIGURE 4.30 A 7-year-old girl with intractable seizures, developmental delay, and subcortical band heterotopia due to DCX mutations. (A) Axial and (B) coronal T2-weighted images show the gray–matter intensity band separated from the cortex by a layer of partially myelinated white matter. In addition, the cortex has normal thickness, but shallow sulci, and the lateral ventricles are mildly enlarged. C: Coronal necropsy specimen shows band of heterotropic gray (arrows) between subcortical and deep white matter.

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FIGURE 4.31 A 4-month-old boy with intractable seizures, developmental delay, and lissencephaly due to LIS1 mutations. (A) Axial and (B) coronal T2-weighted images show pachygyria in the posterior lobes and a more normal gyral pattern anteriorly (posterior to anterior gradient). The posterior fossa contents are unremarkable.

PERIVENTICULAR HETEROTOPIA. PNH is the most common form of neuronal heterotopia. Anatomically, PNH consists of nodular masses of gray matter that line the ventricular walls and protrude into the lumen, resulting in an irregular outline. Seizures and learning problems are common, whereas more severe developmental problems are uncommon. The age at seizure onset is variable. Most patients have focal seizures, which can not be easily controlled or are refractory to treatment.

FIGURE 4.32 A 5-day-old male neonate with epileptic seizures, ambiguous genitalia, and lissencephaly due to ARX mutation. A: Sagittal T1-weighted image shows absence of the corpus callosum and abnormal sulcation of the medial cerebral hemisphere. B: Axial T2-weighted images reveal area of pachygyria and agyria with moderately thick cortex and almost absence of the basal ganglia.

FIGURE 4.33 A 7-year-old boy with complex partial seizures and bilateral periventricular nodular heterotopia due to FLNA mutation. (A) Axial and (B) coronal T2-weighted images show bilateral diffuse nodular heterotopia along the wall of the lateral ventricles.

The most common form of diffuse PNH is caused by mutations in the X-linked FLNA gene (27). Autosomal recessive mutations in ARFGEF2 have been reported in patients with severe congenital microcephaly and diffuse bilateral PNH. FLNA and ARFGEF2 regulate actin binding, vesicle trafficking, cell adhesion, and function of radial glia. On MRI, PNH appears as ovoid lesions within the subependymal region. They are isointense with gray matter on all imaging sequences (Figs. 4.33 and 4.34). Neither perilesional edema nor contrast enhancement is seen. PNH may include only one or two lesions or may include nodules along the length of the lateral ventricles. Patients with FLNA mutations typically have bilateral contiguous PNH that spares the temporal horns, and mild cerebellar vermis hypoplasia with mega cisterna magna (Fig. 4.33) (27). Patients with ARFGEF2 mutations and PNH can have severe congenital microcephaly and thin overlying cortex with abnormal gyri. PNH may be limited to the trigons, temporal, and occipital horns of the lateral ventricles and can be associated with overlying PMG, hippocampal and cerebellar hypoplasia, or hydrocephalus. The differential diagnosis of subependymal heterotopia is limited and includes tuberous sclerosis and ependymal metastases, especially from medulloblastoma in the pediatric population. In general, the 160

lesions of tuberous sclerosis are iso- to hypointense to white matter, and they may or may not enhance. In addition, other manifestations of tuberous sclerosis are often present. In patients with ependymal metastases, a history of the primary tumor is usually available, and enhancement is the rule, although not without exception. In cases of medulloblastoma metastases to the ependyma of the lateral and third ventricles, enhancement may be lacking. SUBCORTICAL NODULAR HETEROTOPIA. Subcortical nodular heterotopia consists of a large mass of nodules expanding a portion of one cerebral hemisphere. Subcortical nodular heterotopias occur at any location within the subcortical white matter and may be associated with ipsilateral PNH, agenesis of the corpus callosum, and hypoplasia of the cerebellar vermis (28). Malformations Secondary to Abnormal Cortical Organization and Late Migration POLYMICROGYRIA WITH OR WITHOUT SCHIZENCEPHALY DEFINITION. The term PMG describes a cerebral cortex with many excessively small convolutions, which might or might not be visible on gross inspection of the brain surface (29,30). One specific pattern of PMG occurs in schizencephaly. The presence of PMG along the cleft is part of the definition of schizencephaly. The pathogenesis of PMG is poorly understood and is most likely heterogeneous (31). CLINICAL FEATURES. Patients with PMG may have a variable clinical presentation, which depends on several factors. The occurrence of severe microcephaly, abnormal neurologic examination (particularly spasticity), widespread distribution of PMG, and additional brain malformations (especially cerebellar hypoplasia) are predictors of poor outcome, while patients with focal unilateral PMG have the best outcome (Fig. 4.35). Depending on the location, patients with unilateral PMG may present with mild hemiparesis. In addition, they may develop seizures. Bilateral PMG within the perisylvian region may cause oromotor dysfunction (suprabulbar palsy), seizures, and intellectual disability (Fig. 4.36). In patients with PMG and schizencephaly, the presence of open-lip schizencephaly is a predictor of poorer outcome (Fig. 4.37). Patients with PMG and closed-lip schizencephaly usually present with hemiparesis or motor delay (Fig. 4.38), while patients with PMG and open-lip schizencephaly usually present with hydrocephalus and seizures.

FIGURE 4.34 A 3-year-old girl with complex partial seizures and bilateral periventricular nodular heterotopia. (A) Axial T2-weighted and (B) sagittal T1-weighted images reveal bilateral nodular heterotopia along the anterior wall of the lateral ventricles and extending into the white matter lateral to the ventricular bodies.

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FIGURE 4.35 Focal polymicrogyria. A 3-year-old girl with complex partial seizures. Axial and coronal T2-weighted images show irregularity of the individual gyri over the left frontal lobe representing polymicrogyria (arrows).

GENETICS AND PATHOGENESIS. The pathogenesis of PMG is heterogeneous and includes malformative and acquired causes. Acquired causes include congenital infections (particularly cytomegalovirus, Fig. 4.39) and vascular insufficiency (especially during twin pregnancies) (32). Mutations in several genes with all types of inheritance (e.g., SRPX2, RAB3GAP1, EOMES, TUBB2B, COL18A1, KIAA1279, GPR56, and PAX6) have been associated with PMG (23,31). In addition, some copy-number variants have been associated with PMG, but only deletions in 1p36.3 and 22q11.2 are common. PMG may be part of well-defined syndrome such as Aicardi syndrome, oculocerebrocutaneous syndrome, DiGeorge syndrome, and Warburg Micro syndrome. Finally, PMG has been reported in metabolic disorders such as Zellweger syndrome (Fig. 4.40), neonatal adrenoleukodystrophy, and glutaric aciduria type 2, although the histopathology differs from classic PMG. Schizencephaly has been linked to EMX2 mutations, but this finding has never been confirmed. Recently, mutations in COL4A1 have been associated with schizencephaly (6). Dominant mutations in COL4A1 cause changes of the basal membrane of capillaries resulting in microangiopathy and, hence, prenatal hemorrhages and/or ischemias resulting in schizencephaly.

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FIGURE 4.36 Bilateral perisylvian syndrome. (A) Sagittal and (B,C) axial T1-weighted, and (D) axial T2-weighted images show bilateral anomalies of cortical development (arrows) overlying underdeveloped sylvian fissures. Note the dorsal, perirolandic extension of the sylvian fissures, typical of anomalies of perisylvian polymicrogyria. Bodies of lateral ventricles (C,D) show an inverted appearance typical of this disorder. (From Truwit C, Lempert T. Pediatric neuroimaging: a casebook approach. Denver, CO: DPS Press, 1991, with permission.)

FIGURE 4.37 Bilateral open-lip schizencephaly. (A) Axial, (B) coronal, and (C) sagittal T2-weighted images show bilateral gray matter–lined clefts and absence of the septum pellucidum. The gray matter lining of the clefts is thick and irregular, suggesting polymicrogyria. The CSF is continuous from the subarachnoid space to the ventricle (openlip). D: Lateral view of a necropsy brain specimen from a patient with a lifelong history of seizures shows a transcerebral schizencephalic cleft communicating with the lateral ventricle and dysmorphic frontal gyri.

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FIGURE 4.38 Bilateral closed-lip schizencephaly. (A) Axial T1-weighted, (B) axial proton density–weighted, (C) axial T2-weighted, and (D) coronal T2-weighted images show bilateral thickened polymicrogyric cortex of the parietal lobes without communication between the clefts and lateral ventricles. Mild global volume loss of the cerebellum with widened fissures.

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FIGURE 4.39 A 14-month-old child with confirmed congenital cytomegalovirus infection. (A) Axial and (B) coronal T2weighted images show cerebellar hypoplasia, enlarged lateral ventricles, diffuse T2-hyperintense signal of the cerebral white matter, and diffuse cortical gyral anomaly resembling polymicrogyria.

NEUROPATHOLOGY AND IMAGING FINDINGS. In PMG, the cerebral cortex can have multiple small, delicate gyri or appear thick and irregularly bumpy or be paradoxically smooth because the outer cortical (molecular) layer fuses over the microsulci (Fig. 4.41). Because of the immature myelination, in young children with PMG the cortex may not appear particularly thickened. Irregularities of the gray– white matter junction are often the most convincing evidence of PMG (Fig. 4.35) (29). PMG may occur in several locations (33). Involvement of the bilateral perisylvian region is the most common location (Fig. 4.36) and may vary from the posterior perisylvian region only, to the entire perisylvian region, to the perisylvian region with extension to other brain regions but not the poles, to most of the brain including either or both the frontal or occipital poles. Perisylvian PMG can be bilateral symmetrical, bilateral asymmetrical, or unilateral. In bilateral perisylvian PMG, the opercula are dysplastic and incomplete and the sylvian fissure is wide and underdeveloped. Sagittal images may show posterior extension of the sylvian fissure, exposure of the insula, and apparent thickening of the cortex. Other patterns are almost always bilateral and symmetrical, and include generalized, frontal, posterior (probably), mesial parieto-occipital, and rare diffuse parasagittal PMG (29,33). PMG may be associated with other malformations including corpus callosum agenesis and hypogenesis, cerebellar hypoplasia, PNH, and subcortical heterotopia (29). PMG may be associated with anomalous venous drainage and large vessels are especially common in regions where there is a large infolding of thickened cortex. In PMG, diffusely abnormal signal in white matter should suggest prenatal infection, a peroxisomal disorder or a PMG-like disorder such as cobblestone brain or GPR56 mutation.

FIGURE 4.40 Newborn with confirmed Zellweger syndrome. (A) Axial T2-weighted and (B) sagittal T1-weighted images show diffuse predominantly perisylvian polymicrogyria and a subependymal cyst just anterior to the caudate vein (arrow) in the caudothalamic groove.

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FIGURE 4.41 Polymicrogyria. A: Sagittal T1-weighted and (B) axial T2-weighted images show a markedly thickened cortex bilaterally with diagnostic irregularity at the interface of gray matter and subcortical white matter. C: The surface morphology of innumerable, abnormally small gyral contours indicative of polymicrogyria. On section (D), polymicrogyria is seen as areas of gray matter forming “pseudogyri” (arrows) that lack true sulci and therefore present as thick, nearly smooth cortical surfaces.

In schizencephaly, the gray matter lining the cleft has the imaging appearance of PMG with an irregular surface, deep infolding (the cleft), mildly thick cortex, and stippling of the interface between gray and white matter (Fig. 4.42). Schizencephaly is often bilateral but frequently asymmetrical; the contralateral hemisphere should be closely assessed for milder clefts or PMG without cleft. In bilateral schizencephaly, the septum pellucidum is typically missing (Fig. 4.37). Fetal MRI may show the schizencephalic cleft. Prenatally, most clefts are open. However, up to the half of them was found to have subsequently closed on postnatal MRI (34). TUBULINOPATHIES DEFINITION. Tubulinopathies is a recently described group of brain malformation that is caused by mutations in genes that function during the early stages of neuronal proliferation, migration, differentiation, and axonal guidance (26). The full phenotypic spectrum of tubulinopathies is not yet fully known, but is vary from severe LIS with cerebellar hypoplasia to less severe malformation such as PMG. CLINICAL FEATURES. Severe intellectual disability and intractable seizures are the most common features of tubulinopathies. Tetraspastic cerebral palsy and postnatal microcephaly are other neurologic findings. Dysmorphic features are rare and other organs are not affected. GENETICS AND PATHOGENESIS. To date, mutations in nine genes (DYNC1H1, KIF2A, KIF5C, TUBA1A, TUBA8, TUBB, TUBB2B, TUBB3, and TUBG1) have been associated with tubulinopathies. The majority of mutations in tubulin genes are sporadic and de novo, but germline mosaicism and autosomal recessive inheritance have also been observed. The tubulinopathies genes play a role in the regulation of microtubule-dependent mitotic processes in progenitor cells, and on the trafficking activities of the microtubule-dependent molecular motors KIF2A, KIF5C, and DYNC1H1 in postmitotic neuronal cells. Some degree of phenotype–genotype correlation has been shown (26). A severe LIS with agenesis of the corpus callosum and severe PCH has been associated with mutations in TUBA1A and TUBB2B. 166

IMAGING FINDINGS. The spectrum of neuroimaging findings is variable and range from severe LIS with completely absent gyri, total agenesis of the corpus callosum, and severe cerebellar hypoplasia to a PMG-like malformation with cerebellar hypoplasia (26). In less severe LIS forms, a posterior to anterior gradient is usually seen. A dysmorphic appearance of the basal ganglia (mostly putamen and caudate) with absence of the anterior limb of the internal capsule is the most characteristic and consistent finding (Fig. 4.43) (26,35). Ventriculomegaly with abnormal shape of the frontal horns, as well as agenesis/dysgenesis of the corpus callosum and anterior commissure have also been described. Posterior fossa involvement includes different degrees of PCH, cerebellar (diagonal folia across vermis in axial view) and tectal dysplasia, and asymmetric midbrain and pons.

FIGURE 4.42 Schizencephaly. A: Sagittal T1-weighted images show extensive polymicrogyria with a cleft extending toward the dimpled left lateral ventricle. Axial (B) T1-weighted and (C) T2-weighted images confirm bilateral polymicrogyria, more extensive on the left side, and schizencephalic cleft. D: Preoperative functional magnetic resonance imaging in a patient with refractory epilepsy shows activity associated with motor function in proximity to abnormal cortices.

ADVANCED IMAGING. In tubulinopathies, DTI and tractography studies showed several white matter brain malformations, raising the intriguing hypothesis that mutations in the tubulin genes superfamily cause primary generalized defects in axon guidance (36). As consistent features, in these patients DTI and tractography reveal pontine abnormalities (abnormal course of transverse pontine fibers, 4-43D), defects in commissural fiber tracts (anterior commissure and corpus callosum abnormalities/agenesis), and within the fornix confirming the key role of tubulin genes in axon tract formation. Anomalies of Ventral Prosencephalon Development The disorders that cause anomalies of ventral prosencephalon development may be divided into those that involve underexpression of ventralizing gradient genes such as HPE, those that involve overexpression of dorsalizing gradient genes such as the interhemispheric variant of HPE, and those that involve underexpression of dorsalizing gradient genes such as septo-optic dysplasia (SOD). It is of note that although traditionally SOD has been considered a mild form of HPE, according to Sarnat, SOD and the interhemispheric variant of HPE are classified separately from the other types of HPE (2). Holoprosencephaly

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FIGURE 4.43 A 23-month-old child with developmental delay and TUBB3 mutation. A: Sagittal T1-weighted image shows cerebellar vermis hypoplasia, elongated midbrain, short/small pons, loss of the normal flat dorsal surface of the brainstem, and absence of the anterior commissure. B: Axial T2-weighted image though the cerebellum shows diagonal folia across the vermis. C,D: Axial T2-weighted images reveal dysmorphic caudate heads and putamina with loss of a clear interface between these structures and the internal capsule, bilateral ventriculomegaly with abnormal configuration of the anterior horns of the lateral ventricles, and no apparent cortical migrational abnormality. D: Axial color-coded FA maps shows absence of the ventral part of the transverse pontine fibers.

DEFINITION. HPE is a complex brain malformation characterized by an incomplete cleavage of the prosencephalon (telencephalon and diencephalon) and concomitant absence or poor development of the associated midline structures like, for example, the corpus callosum, pituitary gland, and hippocampal commissure (37,38). This spectrum of malformation involves the most rostral end of the neural tube and the premaxillary segment of the face. Conceptually, the most rostral midline sections of the brain and face are not genetically induced, and, therefore, do not develop. The severity of brain and facial deformities varies widely in HPE. The clinical manifestations, in terms of normal development and neurologic function, vary with the amount of brain dysgenesis. Therefore, DeMyer divided HPE into three subcategories: alobar, semilobar, and lobar HPE. These categories are useful for classifying HPE of different severity. It should be noted, however, that there is no clear distinction among these different categories; in reality, they represent a spectrum of brain dysplasia, ranging from the most severe form of alobar to the more nearly normal forms of lobar HPE. CLINICAL FEATURES. The prevalence of HPE is believed to be approximately 1 in 250 during embryogenesis, with a live birth prevalence of 1 in 10,000 to 1 in 20,000. The female-to-male ratio is 2:1, with a rate of prevalence 4.2 times higher in infants of mothers younger than 18 years of age. The alobar form is most common (46% to 54%), followed by the semilobar (18%), lobar (10%), and unclassifiable subtypes (18%). Approximately 10% of cases have isolated intracranial abnormalities without other craniofacial defect. Craniofacial abnormalities are common and range from severe (cyclopia) to mild (single midline maxillary incisor). Eye malformations appear to be the most frequently associated (77%), followed by malformations of the nose (70%), ear (50%), and maxilla (oral clefts) (42%). Although the often-quoted remark of DeMyer that “the face predicts the brain” appears to be valid in about 80% of cases, but there are exceptions. For instance, alobar HPE may occur without craniofacial abnormality. A high rate of mortality has been reported, with survival at 1 year of 54% for isolated HPE, 14% for 168

syndromic HPE, and 25% for nonsyndromic HPE with multiple defects. Among infants with isolated HPE, those with the alobar form are most severely affected, with 1-year survival reported to be 20% to 30%. For those with isolated semilobar and lobar HPE, survival well into adulthood is not uncommon. Clinical symptoms include cognitive impairment, developmental delay, hyposmia, seizures, spasticity with poor muscle control, movement disorders, pituitary dysfunction/endocrinopathies, emotional lability with sudden mood swings, hoarse or “barking” voice, growth delay, and brainstem dysfunction, including respiratory difficulties, dysrhythmias, dysphagia, and fluctuations in temperature. PATHOGENESIS AND GENETICS. HPE is etiologically heterogeneous, and there appear to be both environmental and genetic causes. The strongest teratogenic evidence exists for maternal insulindependent diabetes mellitus as well as exposure to alcohol and retinoic acid. In addition, veratrum californicum, a plant that contains cyclopamine, a steroidal alkaloid, is believed to interfere with the cholesterol synthesis and with the molecular signaling along the so-called SHH gene pathway, which plays a key role in the pathogenesis of HPE (see below). Finally, prenatal infections such as cytomegalovirus, toxoplasma, and rubella have also been linked to the occurrence of HPE in rare cases (37). HPE is genotypically heterogeneous. Chromosomal abnormalities may be present in up to 30% to 40% of patients. HPE has a higher prevalence in trisomy 13 and 18 and triploidy. In addition, HPE may be part of Mendelian disorders with a normal karyotype such as Smith–Lemli–Opitz, Pallister–Hall, and velocardiofacial syndromes. About 25% of nonsyndromic, nonchromosomal HPE cases have been associated with mutations in at least nine genes including SHH, ZIC2, SIX3, TGIF, PATCHED-1, GLI2, DISP1, NODAL, and FOXH1 (the first four are the most prevalent). Mutations in these genes are inherited mostly with an autosomal-dominant pattern and have a penetrance of 82% to 88%. However, the majority of cases are sporadic. Despite the impressive advances in the understanding of the genetics of HPE, mutations in the known HPE genes account for less than 5% of all sporadic cases of HPE. The putative role of each of the HPE genes in brain morphogenesis is beyond the scope of this chapter. SHH provides an example of these roles, however, in that it encodes a morphogen involved in the development of the ventral neural tube. The ventral neural tube is induced from the neuroectoderm by the notochord, along the trunk region as far rostral as the mesencephalon. This notochordal–ventral neural tube induction is mediated by the morphogen produced by SHH. SHH is in fact first expressed by the notochord, which induces the neural plate to become the so-called floor plate of the neural tube. The floor plate, once formed, also expresses SHH. SHH is also believed to be involved in craniofacial development. A defect in this mechanism of induction, therefore, is believed to be at the origin of the entire subsequent cascade of events leading to the HPE phenotype. Cholesterol modification of the SHH protein, moreover, is believed to be important in the spatial restriction of SHH protein activity, and this interaction with cholesterol helps to explain the association of HPE with disorders of cholesterol metabolism such as those caused by exposure to veratrum californicum or the Smith–Lemli–Opitz syndrome, where there is an enzymatic block in cholesterol synthesis. One upshot of the molecular genetics of HPE is thus a modification of the traditional view of HPE as a failure of telencephalic and diencephalic cleavage in favor of the view of HPE as a global field defect in forebrain patterning involving the prechordal mesoderm and endoderm believed to occur within the first 4 weeks of gestation. NEUROPATHOLOGY. The evolution of the terminology used in HPE epitomizes the refinement in understanding of the neuropathology. HPE was initially termed arrhinencephaly, considering the absence of the olfactory bulbs and tracts as the hallmark feature of the disorder. The term holotelencephaly was later proposed to emphasize the involvement of the entire telencephalon. Finally, the term holoprosencephaly was suggested to summarize the involvement of the diencephalon as well as the telencephalon. The major neuropathologic and imaging findings of the various types of HPE are detailed in what follows. Certain unifying features should be kept in mind. With regard to the cerebrum, the types of HPE exhibit progressive degrees of separation of a holosphere, and with regard to the ventricles, progressive degrees of separation of a holoventricle. The olfactory bulbs and tracts are almost always absent. The hypothalamus, neurohypophysis, and adenohypophysis are usually hypoplastic and hypofunctional. The mammillary bodies may be fused. The cytoarchitecture of the cerebral cortex is a subject of debate. Although malformations of cortical development may be present, primary defects of cell migration are believed to be uncommon. Of interest, the cerebellum may show cortical dysplasia or heterotopia, particularly in cases of chromosomal HPE. There is usually an abnormal course of the 169

middle and anterior cerebral arteries (ACAs) (Fig. 4.44).

FIGURE 4.44 Axial MIP of a TOF MRA in a child with semilobar holoprosencephaly shows an azygous anterior cerebral artery.

ALOBAR HPE: PATHOLOGY AND IMAGING FINDINGS. Alobar HPE is the most severe form of HPE and is frequently associated with severe midline facial deformities resulting from absence or hypoplasia of the premaxillary segment of the face. These craniofacial abnormalities include cyclopia with fused orbits, single eyeball, fused or absent metopic suture, and forehead proboscis and cebocephaly, in which two severely hypoteloric orbits are present with a proboscis between or below the orbits. Examination of the brain reveals complete fusion of the two cerebral hemispheres such that the cerebrum is composed of a single flattened mass of tissue that usually sits adjacent to the most rostral portion of the calvarium (Fig. 4.45) (38). There is absence of the interhemispheric fissure and falx cerebri. The corpus callosum and anterior commissure are usually absent; a rudimentary callosal plate may be present. There is a large, crescent-shaped holoventricle; the septum pellucidum is absent. The basal ganglia and thalami vary from distinct right and left hemispheric structures to complete fusion. The basal ganglia are sometimes absent. There is most often a large dorsal cyst which may communicate with the monoventrile. This cyst usually occupies more than half of the volume of the calvarium. SEMILOBAR HPE: PATHOLOGY AND IMAGING FINDINGS. Semilobar HPE is a less severe anomaly than alobar HPE with lack of separation of the anterior part of the hemispheres. Patients with semilobar HPE usually have normal facies, but they occasionally have mild facial anomalies including clefts of the lip and palate. The interhemispheric fissure and falx cerebri are usually formed posteriorly, but are absent anteriorly. As a result, there is separation of the cerebral hemispheres posteriorly, but the frontal lobes are undivided across the midline (Fig. 4.46) (38). The hippocampal formations remain rudimentary and, as a result, the temporal horns of the lateral ventricles are large and incompletely formed. On sagittal images, an interhemispheric commissure that strongly resembles the posterior portions of the corpus callosum is often seen dorsal and superior to the trigones of the lateral ventricles. The anterior portions of the corpus callosum are always absent. It is debated in the developmental literature whether the “pseudosplenium” is really a corpus callosum. In HPE, it is a common thought that the normal sequence of formation of the corpus callosum does not hold true. Nowadays, we know that the corpus callosum does not develop from the front to the back, but the different components develop independently and fuse at a later embryologic stage (7). In semilobar HPE, the presence of the splenium of the corpus callosum in the absence of a genu, body, and rostrum does not imply destruction of the more anterior portions of the corpus callosum, but an abnormal (malformative) development. The septum pellucidum is always completely absent. The deep gray matter nuclei are frequently incompletely separated; the thalami are, however, usually partially separated, resulting in a small third ventricle. A dorsal cyst may or may not be present. In addition to midline anomalies, semilobar HPE is commonly associated with anomalies of cortical development and disordered neuronal migration.

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FIGURE 4.45 Alobar holoprosencephaly. A: An axial T1-weighted image shows no definable interhemispheric fissure. The falx cerebri is absent. The cerebrum is composed of a pancakelike mass of tissue situated in the rostral calvarium. A crescent-shaped holoventricle is continuous with a large dorsal cyst. B: A whole-brain necropsy specimen viewed from above shows a shallow, underdeveloped interhemispheric fissure posteriorly (arrows) and an absent interhemispheric fissure anteriorly. Note the abnormal gyral pattern, with broad and smooth gyral morphology suggestive of pachygyria. C: An axial view of a fixed specimen demonstrates monoventricle and fused thalami (T) with anterior continuation of gray and white matter and no interhemispheric fissure. Pachygyria is also present. (B,C: Courtesy of Dr. Mauricio Castillo.)

FIGURE 4.46 Semilobar holoprosencephaly. (A) Axial, (B) coronal, and (C) sagittal T2-weighted images show the fusion of the frontal lobes across the midline with an abnormal gyral pattern and global hypoplasia of the frontal lobes, incomplete separation of the thalami, presence only of the splenium of the corpus callosum, and absence of the anterior horns of the lateral ventricles.

LOBAR HPE: PATHOLOGY AND IMAGING FINDINGS. The lobar form of HPE is the most developed and least anomalous form. The cerebral hemispheres are rather well developed and separated (including thalamic nuclei) (38). The interhemispheric fissure and falx cerebri separate nearly the entire cerebrum with the exception of the most rostral and ventral frontal lobes. Careful scrutiny reveals some degree of hypoplasia of the frontal lobes. The hippocampal formations are nearly normal, and the temporal horns are well defined, appearing normal or nearly normal. The olfactory bulbs, tracts, and sulci may be normal, hypogenetic, or absent. Although there is an apparent interhemispheric fissure, cerebral cortex may be found crossing the midline along nearly the entire anteroposterior axis of the brain. The anterior 171

falx is usually dysplastic. The corpus callosum shows mild dysplasia of the genu (Fig. 4.47). The frontal horns show variable degrees of development. They may be extremely rudimentary or may appear nearly normal (Fig. 4.47). The septum pellucidum is always absent. If a dorsal cyst is present, it is usually small. FETAL IMAGING. Nowadays, in most cases, the second trimester fetal MRI allows to confirm and correctly classify HPE suspected by prenatal ultrasonography (Fig. 4.48). The typical midline anomalies are easily detected, associated cortical abnormalities may be missed on early fetal MRI due to the small size of the developing brain, or the physiologic hypogyration of the brain during gestation may prevent accurate diagnosis of cortical abnormalities.

FIGURE 4.47 Lobar holoprosencephaly. A,B: Sagittal T1-weighted images show essentially normal callosal splenium and posterior body. Anterior body, genu, and rostrum, however, are not clearly visualized. This feature should prompt diagnosis of holoprosencephaly. Note the azygos anterior cerebral artery (long arrows). (C) Axial and (D) coronal T2weighted images show abnormal gray matter in place of callosal genu (C, short arrows), complete coaptation of frontal horns, and two distinct white matter bridges of hemispheric fusion (D, short arrows). Note the azygos anterior cerebral artery (long arrows), which is far more anteriorly situated than in normal patients due to hypoplastic development of interhemispheric fissure. (From Truwit C, Lempert T. Pediatric neuroimaging: a casebook approach. Denver, CO: DPS Press, 1991, with permission.)

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FIGURE 4.48 Semilobar holoprosencephaly as detected by fetal MRI at 23 weeks of gestation. (A) Sagittal and (B,C) coronal/axial T2-weighted images at 23 weeks of gestation show a single-lobed forebrain, fused central gray matter, absent septum pellucidum, partial development of the occipital and temporal horns, and a hypoplastic posterior falx cerebri. This imaging pattern suggests a semilobar holoprosencephaly. (Reprinted with permission from Dill P, Poretti A, Boltshauser E, et al. Fetal magnetic resonance imaging in midline malformations of the central nervous system and review of the literature. J Neuroradiol 2009;36:138–146.)

ADVANCED IMAGING. Only few articles have reported on the DTI and FT findings in HPE. In a patient with semilobar HPE, large white matter tracts were shown that were not apparent on conventional MRI. These large tracts were symmetric, projected on the expected course of the frontooccipital fasciculus, and were connected across the midline in the subfrontal region. In addition, the precommissural fornix could be identified, but appeared markedly thickened and was located dorsally to the fused caudate nuclei. The appearance and location of the precommissural fornix by DTI and FT are supported by neuropathologic studies. Moreover, the superior and inferior fronto-occipital fasciculi could not be distinguished. In addition, in patients with severe forms of HPE (mostly alobar HPE), the corticospinal tract (CST) does not extend past the brain stem into the spinal cord and the medial lemniscal (ML) tracts are not separated. There is a strong correlation between qualitative evaluation of the dimensions of CST and middle cerebellar peduncles (MCP) with HPE severity and neurodevelopmental outcome. Middle Interhemispheric Variant of HPE or Syntelencephaly DEFINITION. Syntelencephaly or the middle interhemispheric variant of HPE (MIVH) is a rare, milder form of HPE first described in 1993. Unlike semilobar HPE, the interhemispheric fissure and falx cerebri are variably formed both posteriorly and anteriorly, with midline cortical continuity in the posterior frontal and parietal regions (39). CLINICAL FEATURES. The clinical findings are similar to patients with a lobar HPE. PATHOGENESIS AND GENETICS. Mutations in ZIC2, one of the HPE genes, have been found in patients with MIVH. Interestingly, ZIC2 mutations causing MIVH are milder compared to mutations causing other HPE phenotypes. This suggests a phenotype–genotype correlation. Neuropathology and Imaging Findings. In MIVH, hemispheric fusion does not occur at the rostral 173

forebrain, but across the adjacent posterior frontal and parietal regions (Figs. 4.49 and 4.50). Additional neuroanatomical characteristics of syntelencephaly include normally formed genu and splenium of the corpus callosum, but an abnormal callosal body; incomplete separation of the caudate nuclei and thalami, but normal complete separation of the hypothalamus and lentiform nuclei; nearly vertical orientation of the Sylvian fissures, which are abnormally connected across the midline over the vertex of the brain; subcortical gray matter heterotopia or cortical dysplasia in about 30% of the patients; and abnormality of the anterior cerebral vessels with an azygous ACA (39). Heterotopic gray matter may be seen “inside” the expected course of the corpus callosum (Fig. 4.49). Unlike classic HPE, the anterior third ventricle, basal forebrain, and olfactory system may be normal, as in cases of semilobar and some cases of lobar HPE (39). In the series reported by Simon et al., 19% of patients had cerebellar abnormalities (39). The face and orbits, as well as the pituitary and hypothalamus, often appear normal (39).

FIGURE 4.49 A 2-year-old girl with middle inter hemispheric variant of holoprosencephaly. (A) T1/T2-weighted images and (B) color-coded FA maps show the presence of the genu and splenium, but complete absence of the body of the corpus callosum. The anterior commissure is present (white arrows in the sagittal images). The posterior frontal lobes and part of the parietal regions are fused with continuation of both the gray and white matter across the midline as a thick bundle of red (transversely oriented) white matter fibers in the expected location of the callosal corpus (white arrows in the axial and coronal images). At this level, the falx and the interhemispheric fissure cannot be identified, and the cortex around the interhemispheric fissure appears dysplastic. Additionally, there is an abnormal band of dysplastic gray matter along the genu of the corpus callosum. Finally, the cingulum bundles are laterally displaced at the level of the fused hemispheres (white arrowheads in the coronal color-coded FA maps). (Reprinted with permission from Verschuuren S, Poretti A, Meoded A, et al. Diffusion tensor imaging and fiber tractography in syntelencephaly. Neurographics 2013;3:164–168.)

ADVANCED IMAGING. DTI data from our clinic easily confirmed the fusion of the posterior frontal and parietal lobes with display of a thick bundle of transversely oriented, red encoded on FA-maps, fibers which are crossing the midline and run from one hemisphere to the other (Fig. 4.49). Using FT, the projection of these fibers onto the hemispheric cerebral cortex delineates the fused regions well. On the other hand, the white matter fibers which originate from cortical regions located anteriorly and posteriorly to the fused region are extending into the collateral hemisphere through the respective genu and splenium of the corpus callosum (Fig. 4.49). White matter fibers from the mesial temporal lobes appeared extending through the splenium of the corpus callosum and confirmed that in syntelencephaly the temporal lobes are well separated. The normal anatomy of the temporal lobes was supported by the depiction of an intact anterior commissure and the inferior fronto-occipital fasciculus on both sides (Fig. 4.49). Finally, the CST, ML, and MCP appeared normal in size at the level of the brain stem (Fig. 4.49). Septo-Optic Dysplasia DEFINITION. SOD, as described by deMorsier in 1956, consists of optic nerve hypoplasia and abnormality of the septum pellucidum. Since that time, clinical reports have shown an association with hypothalamic–pituitary dysfunction in two-thirds of patients. SOD may now be considered a clinically heterogeneous, loosely defined triadic phenotype characterized by features of optic nerve hypoplasia extending posteriorly to the optic chiasm and beyond, pituitary hypoplasia, and midline cranial 174

abnormalities such as deficiency of the septum pellucidum or callosal malformations. CLINICAL FEATURES. Visual symptoms include nystagmus and blindness, but normal vision may be present. The diagnosis is often suspected on the basis of the ophthalmologic examination, which may reveal hypoplasia of the optic discs. When hypothalamic–pituitary dysfunction is present, it is usually manifest by growth retardation secondary to diminished growth hormone and thyroid-stimulating hormone. Hypoglycemia, micropenis, and undescended testes are other possible manifestations. Although endocrine disorders have been attributed to the pituitary gland, some studies suggest that the hypothalamus is deficient, and adenohypophyseal dysfunction is secondary. Seizures may be present. PATHOGENESIS AND GENETICS. Similar to HPE, SOD is considered a defect in forebrain patterning, classified in the Sarnat scheme, as a result of underexpression of dorsal patterning genes (2). SOD has been associated with primiparous birth and young maternal age. Environmental factors may play a role in the pathogenesis of SOD. SOD has been associated with maternal smoking, low socioeconomic status, as well as fetal exposure to alcohol, cocaine, and other drugs. Mutations in two genes have been associated with SOD: the homeobox gene HESX1 and the transcription factor gene SOX2. Mutations in these genes account for only a very small percentage of SOD patients. PATHOLOGIC AND IMAGING FINDINGS. The classic neuropathologic findings are hypoplasia of the optic nerves and hypoplasia or absence of the septum pellucidum (Fig. 4.51). The septum pellucidum may be present in up to 40% of patients. In addition, other features are only variably present. These include schizencephaly, gray matter heterotopia, olfactory agenesis or hypoplasia, and absence of the neurohypophysis.

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FIGURE 4.50 Middle hemispheric variant of holoprosencephaly. Hypoplastic rostrum and posterior splenium of the corpus callosum is identifiable on sagittal T1 image (A) along with subtle gray matter abnormally situated along superior surface of callosum in midline. Coronal (B) and axial (C) images clarify that midline gray matter communicates over the superior surface of the callosum, defining holoprosencephaly as a midline interhemispheric variant; also note the absent septum pellucidum, abnormal configuration of temporal horns owing to hypoplastic hippocampi, and interdigitation of frontal gyri due to hypoplastic falx associated with corpus callosum hypogenesis.

FIGURE 4.51 Septo-optic dysplasia. A: Coronal T2-weighted image shows absence of the septum pellucidum resulting in a “boxlike” configuration of the ventricular system. B: Coronal T2-weighted images reveal hypoplasia of the optic nerves and chiasm (arrows).

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FIGURE 4.52 Septooptic dysplasia with schizencephaly. Coronal T2-weighted image through the lateral ventricle reveals the absence of the septum pellucidum. A schizencephalic cleft is seen extending to the body of the right lateral ventricle (arrows).

CT or MRI can reveal partial or complete absence of the septum pellucidum, hypoplasia of the optic nerves, and hypoplasia of the hypothalamus (Fig. 4.6). A characteristic imaging feature is the boxlike appearance of the frontal horns of the lateral ventricles on coronal imaging (Fig. 4.51). Hypoplasia of the optic nerves and chiasm can be detected on MRI in between 50% and 80% of affected individuals (Fig. 4.51). Optic nerve hypoplasia may be more apparent on high-resolution MR with the use of fat suppression. MRI reveals concurrent schizencephaly (Fig. 4.52) in 50% of patients (40). Patients without schizencephaly commonly have diffuse white matter hypoplasia resulting in ventriculomegaly (40). Complete absence of the optic chiasm (chiasmal aplasia or achiasma) (Fig. 4.53) is a rare diagnosis that may or may not be associated with other significant CNS abnormalities including other midline anomalies, such as basal encephaloceles, as well as isolated PMG. The term nondecussating retinal fugal fiber syndrome has been used to describe isolated absence of chiasmal crossing. Its clinical features include horizontal and “see-saw” nystagmus, a characteristic visual-evoked potential pattern, absence of endocrine abnormalities, normal visual fields, and normal light reflexes. SOD should be differentiated from mild to moderate ventriculomegaly with concomitant rupture of the leaves of the septum pellucidum. The neuroimaging appearance may be similar, including small, atrophic optic nerves secondary to a chronically increased intracranial pressure. The clinical and ophthalmic findings, as well as the medical history usually allow to differentiate both entities.

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FIGURE 4.53 Agenesis of the optic chiasm in a 29-year-old man with “seesaw” nystagmus. A: Sagittal image shows abnormal optic chiasm. (B) Coronal and (C) high-resolution axial images demonstrate unambiguous failure of optic nerves to cross in an identifiable optic chiasm (hypothalamus, floor of third ventricle is clearly shown). An abnormal anterior cerebral artery is also identifiable. No other brain anomaly was identified.

FIGURE 4.54 Multiple coronal T2-weighted magnetic resonance images of a fetus with a postnatally confirmed septo-optic dysplasia. The anterior horns of the lateral ventricles are malformed; a boxlike configuration is noted on coronal images. The leaves of the septum pellucidum are missing. Mild ventriculomegaly is noted. The optic nerve hypoplasia was noted on postnatal fundoscopy, prenatal imaging did not allow to study the optic nerves in detail. (Reprinted with permission from Huisman TA, Tekes A, Poretti A. Brain alformations and fetal ventriculomegaly: What to look for? J Pediatr Neuroradiol, 2012;1:185–195.)

FETAL IMAGING. The small size of the fetal optic nerves and leaves of the septum pellucidum limit the diagnostic sensitivity and specificity of fetal MRI (Fig. 4.54). Axonal Guidance Disorders Axonal guidance disorders is a recently introduced group of brain malformations that are caused by aberrant axonal connectivity (41). Genes mutated in these disorders can encode axon growth cone ligands and receptors, downstream signaling molecules, and axon transport motors, as well as proteins without currently recognized roles in axon guidance. Diseases that result from defective axonal guidance include L1 syndrome, JS, horizontal gaze palsy with progressive scoliosis (HGPPS), Kallmann syndrome (KS), albinism, congenital fibrosis of the extraocular muscles type 1, Duane retraction syndrome, and pontine tegmental cap dysplasia (PTCD). Mirror movement synkinesis is the only clinical feature that 178

may suggest axonal guidance disorders particularly affecting the CSTs. Mirror movement synkinesis refers to the contraction of homologous hand/finger muscles bilaterally when one attempts to move only one hand. Electrophysiology and neuroimaging (particularly DTI) may confirm axonal guidance disorders. DTI and tractography studies showing abnormalities of crossing white matter tracts (e.g., CSTs, corpus callosum, and SCP) are suitable techniques to study axonal guidance disorders. Kallmann Syndrome DEFINITION. KS is genetically heterogeneous and can be inherited as an X-linked, autosomal dominant, and possibly autosomal recessive trait. KS is characterized by hypogonadotropic hypogonadism and anosmia or hyposmia (42). CLINICAL FEATURES. Patients have hypogonadism secondary to deficiency of hypothalamic gonadotropin-releasing hormone. The deficiency in olfaction may be complete or partial but may require testing because patients may not be aware of the deficit. Renal agenesis, synkinesias, pes cavus, arched palate, and cerebellar ataxia have also been reported. PATHOGENESIS AND GENETICS. KS may be divided into four genotypic types: KAL1 (X-linked) and the autosomal types KAL2, KAL3, and KAL4. These genes are coding for proteins that are important for the guidance of migrating neurons. NEUROPATHOLOGY AND IMAGING. Hypoplasia of the olfactory bulbs, tracts, and sulci is the characteristic imaging finding of KS. In addition, abnormal soft tissue may be present in the region between the upper nasal vault and the forebrain. Posterior Fossa Malformations Over the past decades, significant advances in pre- and postnatal neuroimaging techniques, neuropathology, and clinical phenotyping, the development of next-generation genetic sequencing, and an increase in animal model research have markedly improve the definition, classification, and diagnosis of posterior fossa malformations and a better understanding of their pathogenesis. Classifications of posterior fossa malformations based on neuroimaging, molecular genetic, and developmental biologic criteria have been proposed. Accurate diagnoses of these complex abnormalities are of paramount significance for three primary reasons: to determine (a) inheritance pattern and risk of recurrence, (b) involvement of other systems (e.g., kidneys and liver), and (c) prognostic implications for the child and his or her family. Neuroimaging plays a key role in the diagnosis of posterior fossa abnormalities, and the challenge for the neuroradiologist is to provide the clinician with precise and up-to-date diagnostic information. In this chapter, after a short section on the basic normal embryology of the midbrain and hindbrain, we discuss the various posterior fossa malformations making use of a simple classification scheme based on the neuroimaging-based scheme proposed by Doherty et al. (43,44). We divided the posterior fossa malformations into (1) predominantly cerebellar, (2) cerebellar and brainstem, and (3) predominantly brainstem malformations. Normal Development The cerebellum is one of the first brain structures to differentiate, but it is one of the last to achieve maturity. The cellular organization of the cerebellum continues to change for several months after birth and a high number of genes are involved. This protracted developmental process creates a special susceptibility to defects during embryogenesis that may result in different malformations. Developmental Origins of the Cerebellum During early development, the neural tube forms three primary vesicles at its anterior end, that give rise to the forebrain (or prosencephalon, which will divide into the dorsal telencephalon and ventral diencephalon), midbrain (or mesencephalon), and hindbrain (or rhombencephalon, which will divide into the rostral metencephalon and caudal myelencephalon). In the developing midbrain, neurons are generated from the ventricular zone and first migrate radially, with those on the dorsal side forming the tectum and those on the ventral side forming the substantia nigra, red nuclei, oculomotor nerve, and trochlearis nerve. The hindbrain is divided into seven segments (the so-called rhombomeres) along the 179

anterior posterior axis. The cerebellum develops from the dorsal rhombomere 1. This differentiation along the anteroposterior axis is related to the formation of the diencephalic–mesencephalic and midbrain–hindbrain boundary. The first one is the result of the interaction between the Pax6, Pax2, and En1/2 molecular markers. Changes in the expression of these markers will shift the position of the diencephalic–mesencephalic boundary caudally (more Pax6) or rostrally (more Pax2/En1). The location of the midbrain–hindbrain boundary is determined by the expression of Otx2 on the anterior side (midbrain) and Gbx2 on the posterior side (hindbrain). The interaction between Otx2 and Gbx2 determines the location of the isthimic organizer (IsO), a critical transient structure that organizes gene expression and directs specification of cell type and the normal development of the cerebellum. An increase in the expression of Otx2 or decrease in Gbx2 shifts the IsO caudally, while a decrease in expression of Otx2 or increase in Gbx2 shifts the IsO rostrally. The IsO is induced to secrete growth factors (fgf8 and fgf17) that induce further changes crucial for the formation of the midbrain and hindbrain. Several other genes including Wnt1, En1, En2, Pax2, Pax5, Irx2, Isl2, and Hoxa2 are expressed around the IsO and play a key role for the development of midbrain and hindbrain. Hoxa2 is involved in the dorsoventral patterning that occurs at the same time than the anteroposterior patterning. Along the dorsoventral axis, the midbrain is divided into the tegmentum (ventral region) and tectum (dorsal region), while the hindbrain is divided into the pons (ventral region) and cerebellum (dorsal region). The dorsoventral pattern depends on the relative amounts of dorsalizing factors such as Bmp and ventralizing factors such as SHH in combination with other genes such as Hoxa2. Neurogenesis in the Developing Cerebellum Between approximately days 21 and 28 of gestation, the neural tube undergoes three flexures: mesencephalic, cervical, and, last, the pontine flexures (weeks 4 to 5). During week 5 of gestation, there is a proliferation of cells along the rostral half of the alar portions of the first rhombomere. In conjunction with the formation of the pontine flexure, the rhombic lips are formed at the lateral walls of the fourth ventricle. The neuroepithelial zones in the roof of the fourth ventricle and the rhombic lips are the locations of the germinal matrices where the cells of the cerebellum (upper rhombic lip) and many brainstem nuclei (lower rhombic lip) are formed. Most cerebellar neurons are generated in two distinct germinal matrices: (1) the dorsal ventricular zone, which generates cerebellar GABAergic neurons (Purkinje cells and others) and (2) the dorsal-most and rostral-most portion of the (upper) rhombic lip, which generates neuronal precursors that develop into glutamatergic neurons (cerebellar granule neurons and others). The mechanisms that are crucial for the definition of these germinal zones are still widely unknown. Atho1 has been shown to play a crucial role in the rhombic lip neurogenesis. In addition, Ptf1a was shown to be necessary for the generation of all cerebellar GABAergic neurons. Migration of Cerebellar Neurons After generation in the germinal matrices, all cerebellar neurons undergo extensive migration to their final destination in the mature cerebellum. Between 9 and 13 gestational weeks, the Purkinje cells of the cerebellar cortex and other GABAergic neurons of the deep cerebellar nuclei undergo a migration along radial glial processes into the cerebellar anlage, where they form clusters of Purkinje cells under the external granular layer. Several molecules have been identified that regulate Purkinje cell glialguided migration, including those of the Reelin signaling pathway. Reelin is a glycoprotein that is secreted by the external granular layer and binds receptors present on the surface of migrating Purkinjie cells, enabling the cell clusters to elongate into long parasagittal stripes, which form the framework of the mature cerebellum. In contrast, the neurons of the granular cell layer of the cerebellar cortex and the glutamatergic deep cerebellar nuclei have more complex migration routes tangentially to form a transient external granular layer on the outside of the developing cerebellar hemisphere. Several molecules including adhesion molecules, neurotrophins, and repulsive molecules on the surface of cells or in the interstitium guide this tangential migration. The external granular layer is a secondary germinal zone, since immature granule cells undergo many cycles of mitosis (stimulated by SHH), while migrating over the enlarging cerebellum. As progenitors of the external granular layer differentiate into granule neurons, they migrate inwards between clusters of Purkinje cells with the presumed aid of glial (Bergman) fibers, to form the internal granular layer. While cells generated in the rostral rhombic lips form the cerebellum, those produced in the caudal rhombic lips form brainstem nuclei that connect to the cerebellum. Neurons of brainstem nuclei also migrate to their final location: initially, they migrate tangentially along the periphery of the brainstem, and then they migrate radially inwards. 180

Predominantly Cerebellar Malformations A malformed cerebellum may be hypoplastic (reduced cerebellar volume), dysplastic (abnormal cerebellar foliation, fissuration, and architecture of the cerebellar white matter), or hypodysplastic. Each part of the cerebellum (vermis and hemispheres) may be hypoplastic and/or dysplastic, resulting in global cerebellar involvement or predominantly vermian involvement. Predominant involvement of the cerebellar hemispheres is uncommon and is characteristic of PCH as defined by Barth (45), as well as disruptive cerebellar development in very premature newborns (46). Typically, posterior fossa malformations involve both cerebellar hemispheres equally. Hypoplasia and/or dysplasia of only one cerebellar hemisphere results most likely from a prenatal disruptive lesion such as hemorrhage (47). Cerebellar Hypoplasia Cerebellar hypoplasia (CH) refers to a cerebellum with a reduced volume, and is a common, but nonspecific neuroimaging finding (48). The etiologic spectrum of CH is wide and includes both primary (malformative) and secondary (disruptive) conditions. Primary conditions include chromosomal aberrations (e.g., trisomy 13 and 18), metabolic disorders (e.g., molybdenum cofactor deficiency, Smith–Lemli–Opitz syndrome, adenylosuccinate lyase deficiency, and mucopolysaccharidosis), genetic syndromes (e.g., Ritscher–Schinzel, Joubert, oculocerebrocutaneous, and CHARGE syndromes), and brain malformations (primary posterior fossa malformations, e.g., DWM, PTCD and RES, or global brain malformations such as tubulinopathies and α-dystroglycanopathies) (Fig. 4.55). Secondary (disruptive) conditions include prenatal infections (e.g., cytomegalovirus), exposure to teratogens, and extreme prematurity. The distinction between malformations and disruptions is important for pathogenesis and genetic counseling. Neuroimaging provides key information to categorize CH based on the pattern of involvement: unilateral CH (UCH), CH with mainly vermis involvement, global CH with involvement of both vermis and hemispheres, and PCH. The category of CH, associated neuroimaging findings, and clinical features may suggest a specific disorder or help plan further investigations and interpret their results.

FIGURE 4.55 Examples of diseases associated with global cerebellar hypoplasia. A: Coronal T2-weighted image of a child with confirmed molybdenum cofactor deficiency shows global cerebellar hypoplasia and cerebral atrophy with ulegyric pattern and marked ventriculomegaly. B: Midsagittal T1-weighted image of a 9-year-old child with mucopolysaccharidosis type II reveals cerebellar hypoplasia, enlargement of the fourth ventricle, short midbrain, ventriculomegaly, enlargement of the pituitary sella, and thickening of the diploic space. C: Axial and sagittal T2weighted images of a 6-day-old neonate with oculocerebrocutaneous syndrome show a cystic malformation of the left

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eye, global cerebellar hypoplasia, and enlargement and dysplasia of the tectum. (Reprinted with permission from Poretti A, Boltshauser E, Doherty D. Cerebellar hypoplasia: differential diagnosis and diagnostic approach. Am J Med Genet C Semin Med Genet 2014;166C:211–226.)

Dandy–Walker Malformation and Other Cystic Malformations of the Posterior Fossa The cystic malformations of the posterior fossa have been the subject of discussion since the original publication of Dandy and Blackfan in 1914 and the introduction by Benda of the term Dandy–Walker malformation (DWM) in 1954. Since the initial description of the DWM, various terms such as “Dandy– Walker variant”, “Dandy–Walker complex”, and “Dandy–Walker spectrum” have been introduced to classify posterior fossa cystic malformations that do not meet the criteria for a “true” DWM. However, these terms lack specificity and can create considerable confusion. Accordingly, these terms should not be used, and a more detailed anatomic description (e.g., inferior cerebellar vermis or global cerebellar hypoplasia) is to be preferred. However, neuroimaging diagnostic criteria usually make it possible to distinguish DWM from other cystic posterior fossa malformations including Blake’s pouch cyst (BPC), arachnoid cysts, and mega cisterna magna (MCM). DANDY–WALKER MALFORMATION DEFINITION. The DWM is a cystic malformation of the posterior fossa that is defined by following neuroimaging criteria: (1) hypoplasia (or rarely, agenesis) of the cerebellar vermis (whose inferior portion is typically affected, possibly in combination with its superior portion), which is elevated and upwardly rotated, and (2) dilatation of the cystic-appearing fourth ventricle, which consequently may fill the entire posterior fossa (Fig. 4.56). CLINICAL FEATURES. DWM is the most common posterior fossa malformation. In a populationbased survey of prenatal posterior fossa malformations, the incidence of DWM has been estimated at about 1/11,000. The prevalence of isolated DWM has been estimated at about 1/30,000 live births and a slight female predilection has been reported. DWM may occur isolated or as part of a Mendelian syndrome (e.g., Ritscher–Schinzel, PHACE(S), or Ellis–van Creveld syndromes), aneuploidies (e.g., trisomy 9,13,18), or other chromosome abnormalities. In small subsets of patients, mutations in ZIC1, ZIC4, FOXC1, FGF17, LAMC1, and NID1 have been identified. DWM occurs mostly sporadically and, overall, the recurrence risk is low (1% to 5%); however, in a given family with a specific genetic disorder, the recurrence risk may be substantially higher.

FIGURE 4.56 A 10-year-old boy with Dandy–Walker malformation after shunting in the first year of life. (A) Sagittal, (B) axial, and (C) coronal T2-weighted MRI show a hypoplastic cerebellar vermis, which is elevated and upwards rotated (arrows, A), a cystic dilatation of the fourth ventricle with posterior extension and communication with an enlarged posterior fossa, elevation of the tentorium and deep venous system including vein of Galen and straight sinus (arrowheads, A), anterolateral displacement of the cerebellar hemispheres, and ventriculoperitoneal and the cystoperitoneal shunts (arrows, C). (Reprinted with permission from Poretti A, Millen KJ, Boltshauser E. Dandy– Walker malformation. In: Boltshauser E, Schmahmann JD, eds. Cerebellar Disorders in Children. London: MacKeith Press; 2012.)

The majority of children with DWM present in the first 12 months of age signs and symptoms of increased intracranial pressure. Macrocephaly is the most common manifestation, affecting 90% to 100% of children during the first months of life. Developmental delay and muscular hypotonia are additional frequent features in infants with DWM. Exceptional patients come to clinical attention first as 182

adults, or DWM may remain asymptomatic throughout life, particularly if hydrocephalus does not develop. Nowadays, the diagnosis of DWM is made prenatally in an increasing number of patients. Although all patients with DWM have hypoplasia of the cerebellar vermis, neurologic dysfunctions secondary to cerebellar abnormalities such as truncal, limb ataxia, and nystagmus are present in about 50% of the patients and appear later during life. The information about cognitive functions in children with DWM is conflicting. Several studies show different degrees of intellectual disability, whereas other reports present a more favorable cognitive outcome. Overall, at least one-third of children with DWM patients have normal cognitive functions. Normal lobulation of the cerebellar vermis and absence of associated brain abnormalities (e.g., dysgenesis of the corpus callosum) seem to be favorable prognostic factors of normal cognitive functions (49). Mostly as part of defined syndromes, DWM may be associated with systemic anomalies in 10% to 45% of the patients. Various congenital heart diseases (e.g., atrial and ventricular septal defects), anomalies of the urogenital system (e.g., vesicoureteral reflux and hydronephrosis) and extremities (e.g., polydactyly), and craniofacial dysmorphic features (e.g., micrognathia, cleft lip and/or palate, and hypertelorism) are the most common systemic features associated with DWM. PATHOGENESIS. The function of ZIC1, ZIC4, FOXC1, FGF17, LAMC1, and NID1 shed light on the possible pathogenesis of DWM. Based largely on analysis of Foxc1 mutants, DWM may represent a complex deranged interaction between the developing posterior fossa and cerebellum. Notably, Foxc1 mutation affects all defining components of DWM. Specifically, it directly regulates posterior fossa size through its cell-autonomous regulation of meningeal and osteoblast development and indirectly controls both the fourth ventricle and cerebellar size through its nonautonomous regulation of rhombic lip, roof plate, and external granule cells development. In addition, Zic1 and Zic4 are expressed in posterior fossa mesenchyme and Zic1 is a known downstream target of Foxc1. Finally, Fgf17 is known to be expressed in the developing cerebellum and developing posterior fossa mesenchyme. IMAGING AND PATHOLOGIC FINDINGS. The pathologic and imaging findings in DWM involve the cerebellum, fourth ventricle, brainstem, dura and sinuses, supratentorial brain, and cranium (49,50). Cerebellum: The patients, the cerebellar vermis is consistently hypoplastic (Figs. 4.56 and 4.57). Hypoplasia involves mostly the inferior part of the vermis, while the superior part may be normally formed or hypoplastic. The residual vermis is consistently elevated and rotated anticlockwise (Figs. 4.56 and 4.57). Consequently, it may be typically found behind the tectum and the quadrigeminal plate, and in severe cases may become attached to the tentorium. Lobulation of the cerebellar vermis may be rudimentary (49). In about 25% of the patients, the vermis is completely absent. The cerebellar hemispheres may be normal in size and morphology or hypoplastic and/or dysplastic (Fig. 4.57). Mostly due to the enlargement of the fourth ventricle, the cerebellar hemispheres are typically displaced anterolaterally against the petrous bones. Asymmetry in size may be present. After shunting of the posterior fossa cyst, the cerebellar hemispheres frequently appose one another inferiorly beneath the vermis. Malformations of the cerebellar cortex such as heterotopias may be present. Fourth ventricle: There is a consistent cystic dilation of the fourth ventricle, which communicates widely with a retrocerebellar cystic compartment (Figs. 4.56 and 4.57). The retrocerebellar cystic component may cause enlargement of the posterior fossa and elevation of the tentorium, torcula, and transverse sinuses. Enlargement of the posterior fossa and upward displacement of the tentorium are common, but are not consistent in all DWM cases (Figs. 4.56 and 4.57). Therefore, they are not included in the diagnostic criteria of DWM. The cyst wall connects anteriorly with the residual vermis, laterally to the hemispheres, and inferiorly with the medulla, and superiorly the cyst may bulge above the superior vermis into the quadrigeminal plate cistern. Histologically, the wall of the DWM cyst is composed of three layers: an inner ependymal layer in contiguity with the ependyma of the fourth ventricle, a middle layer of neuroglial tissue, and an outer pial layer that is contiguous with the pia of the hemispheres. Calcification of the middle layer has been reported at 7%. The choroid plexus may be absent (40% of patients) or displaced laterally into the lateral recesses or along the caudal insertion of the cyst wall. Lack of patency of the foramen of Magendie is usual, but not consistent, whereas the foramina of Luschka may be patent unilaterally or bilaterally. This variability in the foraminal patency may account for the different prevalence and degree of communicating hydrocephalus, which is present in about 80% to 95% of patients in neurosurgical series. The flow pattern of the CSF may be studied by CSF flow MRI. In DWM, aqueductal flow is 183

present and typically directed into the posterior fossa cyst. In patients with hydrocephalus, the aqueductal flow is usually hyperdynamic (CSF flow through the Sylvian aqueduct into the cyst produces turbulent flow within the cyst and the turbulent flow is characterized by irregular movements of the fluid with high velocity), whereas in patients without hydrocephalus it may be hyperdynamic or diminished. A pulsatile signal of the CSF flow may be seen within the cyst.

FIGURE 4.57 A 2-year-old child with Dandy–Walker malformation. (A) Sagittal and (B) axial T2-weighted MR images show a severe hypoplasia, elevation, and upwardly rotation of the cerebellar vermis (arrows, A), asymmetric hypoplasia of the cerebellar hemispheres (arrows, B), marked elevation of the tentorium (arrowheads, A), marked enlargement of the posterior fossa, pontine hypoplasia, and agenesis of the corpus callosum. (Reprinted with permission from Poretti A, Millen KJ, Boltshauser E. Dandy–Walker malformation. In: Boltshauser E, Schmahmann JD, eds. Cerebellar Disorders in Children. London; MacKeith Press; 2012.)

Brainstem: The brainstem generally appears thin, mostly due to pontine hypoplasia (Fig. 4.57). Subtotal aplasia of the medullary olives, other nuclear dysplasias, and heterotopias of the inferior olivary nuclei have been described. Dura and sinuses: The tentorium, transverse and straight sinuses, and torcular are high riding in the most severe cases. The angle subtended between the superior sagittal sinus and the straight sinus may be increased from the normal 50 to 75 degrees to 90 to 150 degrees. The incisura is widened. The falx cerebelli is absent. Cranium: Macrocephaly with dolicocephaly, thinning and protuberance of the occiput, widening of the lambdoid sutures, and scalloping of the inner table of the occipital bone and the petrous pyramids is common (Figs. 4.56 and 4.57). Supratentorial brain: Hydrocephalus is present in upto 80% to 95% of the patients. Additional brain malformations are associated with DWM in about 30% to 50% of patients. Dysgenesis of the corpus callosum is seen in 10% to 20% of patients (Fig. 4.57). PMG or gray matter heterotopias are seen in approximately 10% of patients, and occipital encephaloceles can be seen in 3% to 5%. The cerebral aqueduct may be narrowed or occluded. Recent advances in fetal imaging have significantly improved the prenatal diagnosis of DWM (51). The neuroimaging criteria leading to a prenatal or a postnatal diagnosis are the same (Fig. 4.58) (52). In light of the prenatal diagnosis of DWM, it is important to know that an enlarged fourth ventricle may be a transient phenomenon between the 14th and 16th weeks of gestation. Therefore, a prenatal diagnosis of DWM is usually possible toward 20 weeks of gestation. Additionally, the tentorium has its definitive orientation from the 20th gestational week. If the prenatal diagnosis of DWM is made or suspected, hydrocephalus and associated supratentorial malformations have to be carefully sought for, as their presence represents a risk of poor cognitive outcome. DWM should be differentiated from hypoplasia of the inferior part of the cerebellar vermis (IVH). IVH is defined by partial absence of the inferior portion of the cerebellar vermis with normal- or near– normal-shaped cerebellar hemispheres, a normal-sized posterior fossa without cystic lesions, and normal supratentorial structures. In the literature, however, the diagnostic entity of IVH remains inconsistently used. Some authors believe that IVH may represent a normal variant. Other authors report this anatomical entity as “Dandy–Walker variant” leading to confusion. The term IVH itself is not correct. “Hypoplasia” means a small but complete anatomical structure with a congenital volume diminution. IVH, however, represents an arrested, incomplete downward growth of the cerebellar vermis and the term “inferior vermian agenesis” would be more adequate (51). “Agenesis” is defined, as either complete or partial absence of an anatomical structure. Due to the craniocaudal development of the 184

vermis, partial agenesis involves the inferior (caudal) part as occurs in IVH. Postnatally, the diagnosis of IVH is made best on midsagittal images and confirmed on axial and coronal imaging. Prenatally, IVH may be reliably diagnosed when caudal growth of the inferior vermis over the fourth ventricle remained incomplete after 18 to 20 weeks of gestation. The entire vermis is generally closed by the end of the 15th week of gestation, but its posterior–inferior aspect may remain open in about 4% of the fetuses until 17.5 weeks.

FIGURE 4.58 Sagittal, coronal, and axial T2-weighted fetal MRI of a fetus with a Dandy–Walker malformation. The fourth ventricle is widened, the small hypoplastic vermis rotated upward, the posterior fossa is enlarged with high insertion of the tentorium and torcular. On axial imaging, the significantly widened fourth ventricle is noted as well as the high-grade supratentorial ventriculomegaly. The germinal matrix is seen as a T2-hypointnese band along the lateral ventricles. (Reprinted with permission from Huisman TA, Tekes A, Poretti A. Brain alformations and fetal ventriculomegaly: What to look for? J Pediatr Neuroradiol 2012;1:185–195.)

Blake’s Pouch Cyst The Blake’s pouch (BP) is a physiologic, transient structure during the embryology of the posterior fossa (50). It is a midline protrusion of the intact roof of the fourth ventricle. BP extends posteriorly and inferiorly to the cerebellum and initially does not communicate with the surrounding subarachnoid space. The subsequent fenestration of the BP results in the foramina of Magendie. Failure of the BP’s perforation and its postnatal persistence is believed to cause the BPC (50). Hydrocephalus and macrocephaly are the most common presenting features in the neonatal or infant age. BPC may also present later in life without hydrocephalus. In these patients, the normal function of the foramen of Luschka may help to maintain a normal CSF flow between the fourth ventricle and subarachnoid space avoiding the development of hydrocephalus.

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FIGURE 4.59 A 7-month-old child with Blake’s pouch cyst. Sagittal and axial T2-weighted images show a tetraventricular hydrocephalus with marked enlargement of the fourth ventricle that communicates with an infravermian cystic formation representing Blake’s pouch cyst (BP). The cerebellar vermis is normally formed and not rotated, the size of the posterior fossa is normal. The medial part of the cerebellar hemispheres are winged outwards by the cyst. (Reprinted with permission from Poretti A, Scheer I, Boltshauser E. Posterior fossa cysts and cyst-like malformations. In: Boltshauser E and Schmahmann JD, eds. Cerebellar Disorders in Children. London: MacKeith Press; 2012.)

FIGURE 4.60 A 10-year-old girl with retrocerebellar asymmetrical arachnoid cyst after ventriculoperitoneal shunting in the first year of life. Sagittal and axial T2-weighted images reveal a retrocerebellar arachnoid cyst that compresses and distorts the cerebellum. A defect of the corpus callosum after shunting is noted. (Reprinted with permission from Poretti A, Scheer I, Boltshauser E. Posterior fossa cysts and cyst-like malformations. In: Boltshauser E, Schmahmann JD, eds. Cerebellar Disorders in Children. London: MacKeith Press; 2012.)

BPC may be located purely infracerebellar or infraretrocerebellar. The fourth ventricle as well as the other ventricles are usually enlarged, while there is no communication with the subarachnoid spaces (Fig. 4.59). The degree of the enlargement of the fourth ventricle is variable. If the BPC has a retrocerebellar extension, the posterior fossa may be enlarged and the tentorium displaced upwards. The choroid plexus may be displaced to the superior wall of the cyst inferiorly to the cerebellar vermis (50). Mass effect may cause a mild impression of the lower vermis, but the size of the vermis is consistently normal and there is no vermian rotation. This helps to differentiate BPC from DWM. In practice, the membranous outline of BPC is not consistently demonstrable by MRI. Posterior Fossa Arachnoid Cysts Arachnoid cysts are CSF-filled lesions of the arachnoid membrane that do not communicate with the surrounding subarachnoid space and ventricular system. The posterior fossa represents the second common location and accounts for about 10% to 25%. In the posterior fossa, arachnoid cysts are usually large (>5 cm) and may be located inferior or posterior to the vermis in a midsagittal location (retrocerebellar), cranial to the vermis in the tentorial hiatus (supravermian), lateral to the cerebellar hemispheres, anterior to the brainstem, or anterolaterally in the cerebellopontine angle cistern. Based on the location and size, posterior fossa arachnoid cysts may become symptomatic in early infancy or remain asymptomatic. Macrocephaly, signs of increased intracranial pressure, and developmental delay are common presenting features. 186

Neuroimaging typically shows a well-circumscribed extra-axial fluid collection or cyst that is isointense relative to CSF with all sequences. The presence of proteinaceous content may lead to lack of complete signal suppression with FLAIR. Posterior fossa arachnoid cysts may cause mass effect on the cerebellum, which may result in obstruction of the fourth ventricle, hydrocephalus, and/or remodeling or thinning of the overlying occipital bone (Fig. 4.60). Otherwise, the cerebellum has a normal size and morphology. The normal size or compression of the fourth ventricle differentiates posterior fossa arachnoid cysts from DWM and BPC.

FIGURE 4.61 Mega cisterna magna as incidental finding in a 4-year-old child who has been investigated for focal seizures. Sagittal and axial T2-weighted MRI show retrovermian- and supravermian extension of the mega cisterna magna (arrows). The size and shape of the cerebellar vermis and hemispheres are normal. (Reprinted with permission from Poretti A, Scheer I, Boltshauser E. Posterior fossa cysts and cyst-like malformations, In: Boltshauser E, Schmahmann JD, eds. Cerebellar Disorders in Children. London: MacKeith Press; 2012.)

FIGURE 4.62 Rhombencephalosynapsis. (A) Axial, (B) coronal, and (C) sagittal T2-weighted images show continuity of the cerebellar hemispheres with an abnormal transverse orientation of the cerebellar foliae. In addition, there is continuity of the dentate nuclei and superior cerebellar peduncles without an intervening vermis.

Mega Cisterna Magna An MCM is defined as a cystic posterior fossa malformation characterized by an intact vermis, an enlarged cisterna magna (≥10 mm on midsagittal images), and absence of hydrocephalus. MCM is a common, benign imaging finding representing about 50% of all cystic abnormalities of the posterior 187

fossa. MCM is believed to result from a late fenestration of the BP. The pouch persists and expands posterior to the cerebellum and the vermis resulting in free communication between the “cyst” (= MCM) and the fourth ventricle (Fig. 4.61) (50). The free communication between MCM, fourth ventricle, and spinal subarachnoid spaces results in consistent absence of hydrocephalus in MCM. The extend of MCM is variable: It may be purely infravermian, extends laterally, posteriorly, and superiorly, and sometime reaches the quadrigeminal plate cistern or may extend into a focal dehiscence of the falcotentorial junction. The posterior fossa may be enlarged. The cerebellum and the brainstem are consistently normal. The absence of hydrocephalus helps to differentiate MCM from DWM and BPC. A normal cerebellum favors the diagnosis of MCM compared to a posterior fossa arachnoid cyst. Rhombencephalosynapsis DEFINITION. RES is defined by the absence of the cerebellar vermis and continuity of the cerebellar hemispheres, dentate nuclei, and SCP (Fig. 4.62) (53). RES was first described by Obersteiner in 1916 in a 28-year-old man, who was employed as a clerical assistant and committed suicide. With the advent of MRI, RES has been increasingly recognized pre- and postnatally. CLINICAL FEATURES. RES occurs sporadically and has a very low recurrence risk. Children with RES may present with truncal and limb ataxia, hypotonia, abnormal eye movements such as strabismus and nystagmus, and delayed motor development in the first years of life. About 85% of patients have headshaking stereotypies (repetitive figure-8 or side-to-side swinging motion) that may represent a response to deficits in central vestibular processing. In some patients, the diagnosis of RES is made during the neonatal period because of the association with hydrocephalus. Long-term cognitive outcome varies between normal functions and severe intellectual disability. Some degree of intellectual disability is present in the majority of patients. In addition, behavioral problems such as attention deficits may be present. Systemic involvement is uncommon. In children with RES, neuroimaging findings correlate with the neurologic outcome. A poor neurodevelopmental outcome is associated with the severity of RES (children with complete agenesis of the vermis had a poorer outcome compared to children with partial agenesis), severity of ventriculomegaly, and presence of aqueductal stenosis, fused colliculi, abnormal temporal cortex, and HPE (53). In the majority of patients, RES occurs as an isolated disease. RES, however, may be part of the Gómez–López–Hernández syndrome, which is defined by the presence of RES, bilateral parietal alopecia, and, in some patients, trigeminal anesthesia causing corneal opacities, and craniofacial dysmorphisms such as midface hypoplasia, low-set posteriorly rotated ears, brachycephaly, and hypertelorism. In addition, features of VACTERL association (Vertebral anomalies, Anal atresia, Cardiovascular anomalies, Trachea–Esophageal fistula, Renal anomalies, Limb defects) are seen in a few patients with RES. PATHOGENESIS. The pathogenesis of RES is unknown and no genetic causes have been identified. Disruption of dorsal–ventral patterning is a proposed mechanism underlying RES, but no animal model has been identified, limiting the understanding of underlying mechanisms. IMAGING AND PATHOLOGIC FINDINGS Cerebellum: The cerebellar vermis is completely or partially absent (Figs. 4.62 and 4.63). There is continuity of the cerebellar hemispheres, SCP, and dentate nuclei, which arch in a horseshoe shape across the midline, resulting in a keyhole-shaped fourth ventricle (53). The posterior coronal sections are crucial to evaluate the horizontal cerebellar folial pattern (Figs. 4.62 and 4.63). On the midsagittal images, the dentate nuclei are seen rather than the vermis (if normal anatomy is present, the vermis separates the dentate nuclei in the midline; Fig. 4.62). Only in the most severe cases, the entire cerebellar volume is reduced. Neuropathologic studies confirmed that nodulus and flocculi are spared in RES. Brainstem: RES is often associated with midbrain abnormalities such as midline fusion of the colliculi (Fig. 4.63) (53).

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FIGURE 4.63 A 3-day-old neonate with congenital hydrocephalus and rhombencephalosynapsis. (A) Axial, (B) coronal, and (C) sagittal T2-weighted images reveal a small posterior fossa and midline continuity of the cerebellar hemispheres, dentate nuclei, and superior cerebellar peduncles without an intervening vermis. The quadrigeminal plate is dysplastic. A severe hydrocephalus and absence of the septum pellucidum are noted. (Reprinted with permission from Poretti A, Boltshauser E. Rhombencephalosynapsis. In: Boltshauser E, Schmahmann JD, eds. Cerebellar Disorders in Children. London: MacKeith Press; 2012.)

Supratentorial findings: Hydrocephalus is present in about 50% of the patients and aqueductal stenosis is the most common cause of hydrocephalus in RES (about 60% of RES with hydrocephalus) (Fig. 4.63) (53,54). Supratentorial malformations may be associated with RES including dysgenesis of the corpus callosum, absence of the septum pellucidum, hippocampal hypoplasia, absent olfactory bulbs and tracts, abnormal dysplastic temporal cortex, fusion of fornices and thalami, absent posterior pituitary gland, and, in rare patients, HPE (53). In RES, DTI showed the absence of the transversely oriented fibers in the midsection of the cerebellum (absence of the vermis), a vertical orientation of the fibers in the midportion of the fused cerebellum, and a medial displacement of the dentate nuclei. Prenatal diagnosis of RES has been reported at the earliest at 21 weeks of gestation. Fetal ventriculomegaly is the common indication for prenatal MRI in fetuses with RES. Cerebellar Dysplasia Cerebellar dysplasia is defined by abnormal cerebellar foliation, white matter arborization, and gray– white matter junction (Fig. 4.64). Cerebellar dysplasia has been reported in a few posterior fossa malformations including Chudley–McCullough syndrome, α-dystroglycanopathies, GPR56-related PMG, and Poretti–Boltshauser syndrome. In addition, diagonal folia across the vermis on axial images have been reported in tubulinopathies. For specific diagnosis, it is important to determine the pattern of dysplasia and the presence of cerebellar cysts and correlate them with clinical information. Diagnosing cerebellar dysplasia is important because most of the genetic causes are autosomal recessive with 25% recurrence risk. In the majority of the patients, the diagnosis of the underlying disease remains unknown. In this subchapter, we will discuss Chudley–McCullough syndrome, GPR56-related PMG, and Poretti–Boltshauser syndrome, while α-dystroglycanopathies have been discussed earlier in this chapter. Chudley–McCullough Syndrome Chudley–McCullough syndrome is an autosomal recessive disorder caused by mutations in GPSM2, 189

which encodes a GTPase regulator needed for correct orientation of stem cell division (55). Children with Chudley–McCullough syndrome present typically with sensorineural hearing loss and mild global developmental delay. Seizures are uncommon. Neuroimaging findings are distinct and include dysplasia of the inferior cerebellar hemispheres without cysts, partial agenesis of the corpus callosum, frontal PMG, and medial frontal heterotopia. Poretti–Boltshauser Syndrome Poretti–Boltshauser syndrome is an autosomal recessive disorder caused by mutations in LAMA1, which play a key role for the correct formation of the basement membrane (56). Mutations in LAMA1 cause basement membrane defects that result in abnormal neuronal migration. Children with Poretti– Boltshauser syndrome typically present with ataxia, ocular motor apraxia, and developmental delay. Some of the patients may have high myopia and abnormal retinal development. The neuroimaging findings include dysplasia of the cerebellar vermis and hemispheres and cerebellar cysts located mostly in the anterior and superior parts of the vermis as well as in the posterior and superior regions of both cerebellar hemispheres (Fig. 4.65). The SCP are typically elevated and splayed. The fourth ventricle is enlarged and has an abnormal, squarelike shape. A brainstem involvement including mild pontine hypoplasia and/or mild elongation of the midbrain and patchy T2-hyperintense signal of the periventricular white matter have been reported in a few patients.

FIGURE 4.64 Cerebellar dysplasia. (A) Axial and (B) coronal T2-weighted images show abnormal cerebellar foliation and fissuration with loss of the normal white matter architecture in the inferior aspect of the cerebellar hemispheres.

GPR56-Related Polymicrogyria GPR56-related PMG is an autosomal recessive disorder. GPR56 has been shown to play an important role in regulating pial basement membrane during cortical development and mutations in GPR56 cause neuronal ectopia, neuronal overmigration, and a cobblestone-like malformation. Children with GPR56related PMG typically present with severe motor and cognitive impairment and epileptic seizures (57). Neuroimaging findings include PMG (frontoparietal or generalized with and anterior to posterior gradient), patchy to diffuse T2-hyperintense signal of the supratentorial white matter, cerebellar dysplasia, and cerebellar cysts with a subpial and cortical location (Fig. 4.66) (57). The brainstem is usually normal.

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FIGURE 4.65 A 3.8-year-old boy with Poretti–Boltshauser syndrome and LAMA1 mutations. (A) Sagittal, (B) axial, and (C) coronal T2-weighted images show diffuse cerebellar dysplasia with multiple cortical/subcortical cysts in the cerebellar vermis (anterior and superior parts) and both cerebellar hemispheres (posterior and superior parts). In addition, hypoplasia of the inferior vermis, an enlarged fourth ventricle with a peculiar elongated and squared shape, an elongated midbrain, and a short pons are noted. (Reprinted with permission from Boltshauser E, Scheer I, Huisman TA, et al. Cerebellar cysts in children: a pattern recognition approach. Cerebellum 2014;14(3):308–316.)

FIGURE 4.66 A 3.5-year-old boy with GPR56 mutations. (A) Sagittal and (B,C) axial T2-weighted images show multiple cysts and dysplasia of the cerebellar vermis and hemispheres. In addition, bilateral migration abnormality, T2-

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hyperintense signal of the periventricular white matter, and mild ventriculomegaly are noted. (Reprinted with permission from Boltshauser E, Scheer I, Huisman TA, et al. Cerebellar cysts in children: a pattern recognition approach. Cerebellum 2014;14(3):308–316.)

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Cerebellar Hyperplasia or Macrocerebellum DEFINITION. Cerebellar hyperplasia or macrocerebellum is an extremely rare condition that is characterized by an abnormally large cerebellum with preservation of its overall shape (Fig. 4.67) (58). CLINICAL FEATURES. Macrocerebellum may be isolated (nonsyndromic) or part of well-defined syndromes (e.g., Costello, Sotos, Proteus, and megalencephaly syndromes) or neurometabolic diseases (e.g., fucosidosis, Alexander disease, and mucopolysaccharidosis types I and II) (58). The recurrence risk of macrocerebellum depends on the underlying disorder. In patients with isolated macrocerebellum, the recurrence risk is low. The clinical presentation of patients with macrocerebellum is highly heterogeneous and depends mostly on the underlying disease. Ataxia, hypotonia, intellectual disability, and ocular movement disorders are common in patients with isolated macrocerebellum. PATHOGENESIS. The pathogenesis is highly different between the disorders associated with macrocerebellum. This difference suggests that macrocerebellum may not be a nosologic entity, but instead represents the structural manifestation of a deeper, more basic biologic disturbance common to heterogeneous diseases. IMAGING FINDINGS. The key neuroimaging finding of macrocerebellum is disproportionate cerebellar enlargement with preserved architecture and shape, which is best seen on sagittal or axial images (Fig. 4.67) (58). The cerebellar hemispheres are more affected than the vermis and may expand into adjacent anatomic regions by wrapping around the brainstem or herniating upward or downward. Supratentorial findings such as ventriculomegaly or white matter signal abnormalities may be present depending on the underlying disease. Cerebellar and Brainstem Malformations Pontocerebellar Hypoplasia DEFINITION. In clinical practice, the use of the term PCH is not uniform. It is often used in a descriptive manner to imply that the volume of the cerebellum and the pons are reduced, generally in a nonspecific way (Fig. 4.68). On the other hand, it is used in the context of the so-called PCH, as previously conceptualized by Peter Barth (59). However, in the last sense, PCHs are a heterogeneous group of disorders with different course (some an early (prenatal) onset degenerative disorders, others are nonprogressive diseases), clinical phenotype, and genetic background. In this subchapter, we will discuss the 10 subtypes of PCH as well as PCH related to CASK mutation. An imaging phenotype of PCH, however, may be seen as posterior fossa involvement in some cortical malformations (e.g., primary microcephaly, LIS due to RELN mutations, tubulinopathies, and VLDRL mutations), congenital disorders of glycosylation (mostly type 1a, but also type 1q), α-dystroglycanopathies (e.g., WWS and MEB disease), and as a sequela of disruptive lesions (e.g., cerebellar injury secondary to prematurity) (48). Posterior fossa involvement in cortical malformations has been discussed in the subchapters on LIS, PMG, and α-dystroglycanopathies (cobblestone brain). CLINICAL FEATURES. Patients with PCH present prenatally with polyhydramnios, microcephaly, ventriculomegaly, posterior fossa fluid collection, or in the newborn period with abnormal tone, poor feeding, or seizures (59). Many patients have severe neurodevelopmental disability, with a few notable exceptions. Congenital or, more commonly, postnatally developing progressive microcephaly is common. Anterior horn cell involvement with weakness, hypotonia, areflexia, respiratory insufficiency, and congenital contractures is characteristic for PCH1. Extrapyramidal dyskinesias and dystonia are the major features of PCH2, while pure spasticity is reported in a minority. Short stature, seizures, hypotonia, optic atrophy, and a nonprogressive course suggest PCH3. Patients with PCH4 have a very severe perinatal course with excessive, prolonged general clonus, congenital contractures, polyhydramnios, and primary hypoventilation. Fetal onset of seizurelike activity and a lethal neonatal course are features of PCH5. Infantile encephalopathy, dysphagia, seizures, progressive microcephaly, and generalized hypotonia followed by spasticity are typically seen in PCH6. In addition, increased CSF lactate has been reported in PCH6. Involvement of the genital organs (e.g., micropenis with impalpable testes) is characteristic of PCH7. A nonprogressive impairment in motor, speech, and cognitive functions and joint contractures has been reported in all children with PCH8. The clinical phenotype of PCH9 is nonspecific and includes profound microcephaly and global developmental delay as well as spasticity. 193

The clinical phenotypes of PCH10 and PCH9 are similar, but some patients with PCH10 have an axonal sensorimotor neuropathy. Although PCH related to CASK mutations is inherited with an X-linked pattern, it occurs mostly in girls, because it is most likely lethal in boys (60). Developmental delay, severe intellectual disability, progressive microcephaly, dystonia, sensorineural hearing loss, and seizures are common features of PCH related to CASK mutations.

FIGURE 4.67 A 7-month-old boy with macrocerebellum.(A) Sagittal, (B) coronal, and (C) axial T2-weighted images show macrocerebellum with marked thickening of the cerebellar gray matter and mild volume decrease of the cerebellar white matter. In addition, mild cerebellar dysplasia involving the posterior part of the hemispheres, an elongated and thickened mesencephalon, a short pons, a wide prepontine cistern, and a moderate ventriculomegaly are noted. (Reprinted with permission from Poretti A, Mall V, Smitka M, et al. Macrocerebellum: significance and pathogenic considerations. Cerebellum 2012;11:1026–1036.)

FIGURE 4.68 A 1-year-old boy with PCH2 and TSEN54 mutations. (A) Sagittal T1-weighted and (B) coronal T2weighted images show hypoplasia of the pons and cerebellar vermis. The reduction in the size of the cerebellar hemispheres with relative preservation of the midline vermis results in a characteristic dragonfly appearance. In addition, reduced cerebral volume and secondary ventriculomegaly are noted. (Reprinted with permission from Bosemani T, Orman G, Boltshauser E, et al. Congenital abnormalities of the posterior fossa. Radiographics 2015;35:200–220.)

PATHOGENESIS. The pathogenesis of the various PCH subtypes is heterogeneous and mutations in 194

several genes have been reported. Several genes have been associated with one PCH phenotype and the same gene has been reported in children with different PCH subtypes. Interestingly, several genes involved in PCH are involved in essential processes in protein synthesis in general and tRNA processing in particular (59). CASK is a member of the membrane-associated guanylate kinase family involved in synapse formation and in the regulation of gene expression, including Reelin, which is critical in brain development. PATHOLOGY AND IMAGING FINDINGS. Hypoplasia and/or atrophy of the cerebellum and pons, progressive microcephaly, and variable cerebral involvement are common neuroimaging features of all PCH subtypes (59). The increasing number of neuroimaging reports in PCH revealed that the classic dragonfly type on coronal images (flattened, severely involved cerebellar hemispheres with relative sparing/prominence of the vermis) is present only in a group of patients, particularly children with mutations in the TSEN54 gene (PCH types 2 and 4; Fig. 4.67), but also patients with PCH1 and mutations in EXOSC3. In children with TSEN54 mutations, the ventral pons is flattened, myelination is delayed, the corpus callosum is completely formed, but thin, and in most patients there is some degree of ventriculomegaly resulting from tissue loss (45). The cerebral cortex shows a variable degree of atrophy. Atrophy of the cerebral cortex is not unique of PCH2 and TSEN54 mutations, but may be also seen in PCH3 and PCH6. In PCH4, however, lack of growth in the insular area may result in wide-open Sylvian fissures and suggests a delayed neocortical maturation rather than atrophy. Neuropathology showed that the cerebellar cortical development proceed normally until the start of foliation, but subsequent growth by the formation of folia stalls, resulting in short folia and diminished lateral branching. Cerebellar degeneration is partly diffuse, but the main focus of degeneration is found in the bottom region between folia and dentate nuclei. The ventral pons is affected by severe neuronal loss.

FIGURE 4.69 CASK mutation. (A) Sagittal and (B) coronal T2-weighted images show hypoplasia of the pons and cerebellum. The reduction in the size of the cerebellar vermis and hemispheres is proportional. In addition, the size of the corpus callosum is reduced.

FIGURE 4.70 Cerebellar agenesis. (A) Sagittal and (B) axial T2-weighted images show near-complete absence of cerebellar structures except for a rudimentary remnant of the anterior vermis, an enlarged posterior fossa, and marked hypoplasia of the pons. (Reprinted with permission from Poretti A, Prayer D, Boltshauser E. Morphologic spectrum of prenatal cerebellar disruptions. Eur J Paediatr Neurol 2009;13:397–407.)

In some PCH patients, however, involvement of cerebellar vermis and hemispheres is similar, 195

resulting in a small, but normally proportioned cerebellum (butterfly type). The butterfly type has been reported in patients with PCH3 (PCLO mutations) and PCH6 (RARS2 mutations). Severe, symmetric involvement of cerebellar vermis and hemispheres is also a feature of PCH8. A postnatal atrophylike pattern with a preserved ventral pons and cerebellar hemispheres that are reaching the margins of the posterior fossa (not hypoplastic), but have enlarged interfolial spaces (atrophy), has been also reported in PCH1 and VRK1 or EXOSC3 mutations. Finally, in PCH5 the cerebellar vermis is more affected compared to the hemispheres. Complete or partial agenesis of the corpus callosum is exceptional in PCH and suggests PCH9. Cerebellar cysts of destructive origin have been reported in the lateral aspects of the cerebellar hemispheres of a few children with PCH1 (EXOSC3 mutations), PCH2 (TSEN54 mutations), and PCH6 (RARS2 mutations) (22). In PCH related to CASK mutations, hypoplasia of the brainstem and cerebellum is consistently present, but may have a variable degree of severity (Fig. 4.69) (60). The brainstem hypoplasia usually involves mostly the inferior part. Cerebellar hypoplasia involves similarly the vermis and hemispheres, which are usually symmetric, and may cause a secondary enlargement of the fourth ventricle. There is typically a correlation between the degree of cerebellar and brainstem hypoplasia. In a small number of patients, a simplified gyration of the cerebral cortex has been reported. The corpus callosum is typically normally formed. DTI studies in single patients with PCH showed that pontine hypoplasia is mostly due to a severe reduction in size of the transverse pontine fibers (61). Cerebellar Agenesis DEFINITION. Cerebellar agenesis is defined by the near complete absence of cerebellar tissue. The definition of cerebellar agenesis is based on the morphologic pattern and does not suggest the pathogenesis (47). CLINICAL FEATURES. All patients with cerebellar agenesis are symptomatic. Patients who survive infancy have variable degrees of cerebellar dysfunction (truncal and limb ataxia, dysarthria) as well as cognitive impairment (47). Neonates with cerebellar agenesis should be evaluated for diabetes mellitus, since this association is suggestive of a mutation in PTF1A (62). PATHOGENESIS. Cerebellar agenesis may represent a malformation resulting from a genetically mediated pathomechanism (e.g., mutations in PTF1A) (62) or a disruption (e.g., hemorrhage that occurs during gestation or in the perinatal period or vascular insufficiency in Chiari II malformation and cerebellar herniation) (47). IMAGING FINDINGS. Near-complete absence of cerebellar structures with only remnants of the anterior vermis, floccules, and/or MCP are the diagnostic findings of cerebellar agenesis (Fig. 4.70). A secondary pontine hypoplasia and a normal or enlarged posterior fossa may be seen. Supratentorial involvement such as sequelae of germinal matrix hemorrhage or periventricular leukomalacia may be seen in cerebellar agenesis of disruptive origin. Joubert Syndrome DEFINITION. JS was first described in 1969 and is now defined by the presence of the “molar tooth sign” (MTS) on neuroimaging (Fig. 4.71). The MTS was identified in 1997 and consists of elongated, thickened, and horizontally oriented SCP. CLINICAL FEATURES. JS is a rare midbrain–hindbrain malformation with an estimated prevalence between 1:80,000 and 1:100,000 live births. In almost all patients, JS is inherited with an autosomal recessive pattern and has a 25% recurrence risk in the affected families. Only mutations in OFD1 are exceptional and inherited with an X-linked pattern. About 30% to 40% of children with JS present during the neonatal period because of irregular breathing pattern, which include phases of apnea and tachypnea. Later in life, children with JS present with muscular hypotonia, cerebellar ataxia, and ocular motor apraxia (63). Cognitive functions are impaired in almost all patients, but the degree of impairment ranges between profound and mild. Systemic involvement may be present and includes renal (nephronophthisis 25%), eye (retinal dystrophy 30% and colobomas 20%), liver (congenital hepatic fibrosis 15%), and skeletal (different forms of polydactyly 20%) abnormalities (63). Renal and liver involvement may cause high morbidity and mortality and needs appropriate workup and regular follow-up. Based on the systemic involvement, 196

six phenotypes have been described: (1) pure JS (purely neurologic involvement), (2) JS with eye involvement, (3) JS with kidney involvement, (4) JS with involvement of eyes and kidneys, (5) JS with liver involvement, and (6) JS with oral–facial–digital involvement or the oral–facial–digital syndrome type VI (OFDVI) (63). The presence of tongue hamartoma, additional frenula, upper lip notch, mesoaxial polydactyly of one or more hands or feet, and/or hypothalamic hamartoma differentiates OFDVI from the other phenotypes. Some degree of correlation between these clinical phenotypes and the genotype has been shown. The strongest correlation is between mutations in TMEM67 and liver involvement.

FIGURE 4.71 A 5-year-old boy with Joubert syndrome. A: Sagittal T2-weighted image shows hypoplasia and dysplasia of the vermis, enlargement of the fourth ventricle with upward and posterior displacement of the fastigium, and a narrow pontomesencephalic isthmus. B: Axial T2-weighted images reveals elongated, thickened, and horizontally oriented superior cerebellar peduncles and a deepened interpeduncular fossa, resulting in the characteristic molar tooth sign.

In the past, the term “Joubert syndrome and related disorders” (JSRD) has been coined to describe overlapping diseases sharing the MTS such as Dekaban–Arima or Senior–Löken syndromes. Nowadays, we know that the variable clinical phenotypes associated with the MTS do not comprise distinct clinical syndromes, but are part of the wide phenotypic range that is characteristic of JS. For these reasons, we favor the term JS, instead of JSRD or the names of the distinct diseases sharing the MTS. PATHOGENESIS. Mutations in more than 30 genes have been associated with JS so far (63). All genes encode for proteins that localize to primary nonmotile cilia and its basal body which play a key role in the development and functioning of the brain, retina, kidney, liver, and other organs. Primary cilia mediate various signaling processes and brain malformations in JS may result from defects in midline fusion of the developing vermis or defects in SHH-mediated granule cell proliferation. In addition, cilia have been shown to have a repressing role onto the Wnt signaling by maintaining a discrete range of Wnt responsiveness. Both Wnt and SHH signaling have been linked to axonal guidance. PATHOLOGIC FINDINGS. Few reports on neuropathology studies in JS are available. These studies showed cerebellar abnormalities including hypoplasia of the cerebellar vermis, neuronal loss and gliosis of the Purkinje cell layer, and fragmentation of the dentate nucleus. In addition, neuropathology studies revealed extensive involvement of the brainstem including elongation of the locus coeruleus, dysplasia of the inferior olivary nuclei, anomalies of the dorsal column nuclei, solitary and trigeminal tracts, and absence of decussation of the SCP in the pontomesencephalic junction and CST in the lower brainstem, respectively. Absence of decussation of the SCP and CST was reproduced in a mouse model of JS and showed in patients with JS using DTI and FT (64). The lack of SCP and CST decussation led to the inclusion of JS into the group of axonal guidance disorders (41). IMAGING FINDINGS. In JS, the spectrum of neuroimaging findings extends beyond the MTS confirming the heterogeneity of JS not only from the clinical and genetic, but also from the neuroimaging point of view (65). As discussed below, with the exception of hypothalamic hamartoma, no correlation between the imaging phenotype and (1) clinical phenotype including cognitive functions and (2) genotype has been found. In addition, neuroimaging findings may vary between siblings in the same family (intrafamilial heterogeneity). Cerebellum: In all patients, the cerebellar vermis is hypoplastic and dysplastic (incomplete 197

development or abnormal orientation of the vermian fissures) (Fig. 4.71). The range of hypoplasia is variable. There is incomplete fusion of the halves of the vermis, resulting in an abnormal vermian cleft, which runs in the anteroposterior dimension. The size of the cerebellar hemispheres is variable. In the majority of the patients, it is normal, while 12% of the patients have hypoplastic and 5% of the patients enlarged cerebellar hemispheres, respectively (65). An abnormal cerebellar foliation, white matter arborization, and gray–white matter junction has been reported in up to 35% of the patients (Fig. 4.72) (65). Due to the hypoplasia of the cerebellar vermis, a cleft between the cerebellar hemispheres is usually seen. Based on the size of the cerebellar hemispheres, the shape and size of the interhemispheric cleft may vary. The dentate nuclei are typically lateralized.

FIGURE 4.72 Variety of infratentorial findings in Joubert syndrome. A: Axial images show a variable orientation of the superior cerebellar peduncles. B: Axial T2-weighted image reveals a diffusely abnormal foliation and fissuration of both cerebellar hemispheres. C: Axial and sagittal T2-weighted images reveal a posterior fossa encephalocele. D: Sagittal T2-weighted image shows midbrain elongation and dysplasia and tectal dysplasia. (Partially reprinted with permission from Poretti A, Huisman TA, Scheer I, et al. Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AJNR Am J Neuroradiol 2011;32:1459–1463.)

Fourth ventricle: The fourth ventricle is consistently enlarged and distorted due to the vermian hypoplasia and the fastigium is rostrally displaced (Fig. 4.71). On axial images, the rostral fourth ventricle is often bat-shaped. SCP: As part of the MTS, the SCP are typically thickened, elongated, and horizontally orientated. The SCP are usually symmetric in size and shape, while different forms of the MTS have been reported (Fig. 4.72). The interpeduncular fossa (cistern) is typically deepened. Brainstem: Brainstem abnormalities (other than deepening of the interpeduncular fossa and secondary pseudoelongation of the midbrain) are common in JS and have been reported in up to 30% of the patients (Fig. 4.72) (65). Dysplasia of the quadrigeminal plate and midbrain (e.g., presence of interpeduncular heterotopia or ventral enlargement of the midbrain) is more common compared to anomalies of the pons or lower brainstem. Interpeduncular heterotopia is characterized by nodular brain-isointense tissue located between and in direct contact with the cerebral peduncles. Posterior fossa: The size of the posterior fossa is enlarged in up to 45% of the patients and marked retrocerebellar CSF collection is present in about 5% of the patients. In these patients, JS may be (initially) misdiagnosed with DWM.

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FIGURE 4.73 Variety of supratentorial findings in Joubert syndrome. A: Sagittal T2-weighted image shows hypoplasia and dysplasia of the cerebellar vermis, enlargement of the fourth ventricle with upwards displacement of the fastigium, and agenesis of the corpus callosum. B: Sagittal T2-weighted image shows hypoplasia and dysplasia of the cerebellar vermis, an enlarged fourth ventricle, a posterior fossa with marked retrocerebellar CSF collection, a hypothalamic hamartoma, elongation of the midbrain, reduction in size of the pons, dorsal heterotopia at the level of the craniocervical junction, and a thin corpus callosum. C: Axial T2-weighted image reveals extensive bilateral polymicrogyria. (Partially reprinted with permission from Poretti A, Huisman TA, Scheer I, et al. Joubert syndrome and related disorders: spectrum of neuroimaging findings in 75 patients. AJNR Am J Neuroradiol 2011;32:1459–1463.)

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FIGURE 4.74 Joubert syndrome. A: Axial color-coded FA maps at the level of the pontomesencephalic junction show a “red dot” (arrow) representing the decussation of the superior cerebellar peduncles in a healthy subject, whereas in a patient with Joubert syndrome the “red dot” is missing representing absence of decussation of the superior cerebellar peduncles. B: Axial color-coded FA maps at the level of the lower brainstem reveal a “red dot” (arrow) representing the decussation of the corticospinal tracts in a healthy subject, whereas in a patient with Joubert syndrome the “red dot” is missing representing absence of decussation of the corticospinal tracts. C: Fiber tractography displays the course of the pyramidal tracts (blue encoded) in a coronal projection. In a patient with Joubert syndrome (left), no crossing fibers could be identified, and the pyramidal tracts show a parallel course within the caudal medulla. An anatomic axial section is projected within the display for orientation purposes. In a healthy subject (right), the normal course of the pyramidal tracts (blue encoded) is shown in a coronal projection. A partially red-encoded pyramidal decussation is seen at the level of the caudal medulla (large arrows). The red-encoded decussation of the superior cerebellar peduncles is seen at the level of the mesencephalon (arrowheads). In addition, multiple red-encoded crossing fibers are seen at the level of the pons (small arrows). (Reprinted with permission from Poretti A, Boltshauser E, Loenneker T, et al. Diffusion tensor imaging in Joubert syndrome. AJNR Am J Neuroradiol 2007;28:1929–1933.)

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FIGURE 4.75 Fetal MRI in Joubert syndrome (29 weeks of gestation). A: Axial T2-weighted image shows a molar tooth sign and a hypothalamic hamartoma. B: Sagittal T2-weighted image reveals severe hypoplasia of the cerebellar vermis, enlargement of the fourth ventricle and posterior fossa, elongation of the midbrain, a hypothalamic hamartoma, and a thin corpus callosum. (Reprinted with permission from Poretti A, Brehmer U, Scheer I, et al., Prenatal and neonatal MR imaging findings in oral-facial-digital syndrome type VI. AJNR Am J Neuroradiol 2008;29:1090–1091.)

Cephaloceles: Two forms and locations of cephaloceles have been reported in JS: (1) occipital and atretic cephaloceles in up to 10% of the patients (Fig. 4.72) and (2) small cephaloceles in the occipital bone at the level of the foramen magnum. These cephaloceles present as a diverticular meningeal protrusion filled with CSF. Supratentorial findings: In JS, supratentorial findings occur in about 30% of the patients and may include dysgenesis of the corpus callosum (callosal agenesis is rare and occurs only in about 1% of JS patients), migrational disorders including PMG, PNHs and FCD, hippocampal malrotation, and ventriculomegaly (Fig. 4.73) (65). Ventriculomegaly is usually mild, while marked hydrocephalus is highly uncommon in JS. Hypothalamic hamartoma is uncommon and specific for the OFDVI phenotype. In JS, DTI and FT show absence of decussation of both the SCP and CST at the level of the pontomesencephalic junction and lower brainstem, respectively (Fig. 4.74) (64). In pregnancies at risk for JS, it is possible to diagnose JS before 24 weeks of gestation (Fig. 4.75). A monitoring protocol was proposed to include serial ultrasounds combined with fetal MRI at 20 to 22 weeks of gestation. In selected fetuses, the MTS has been shown by fetal MRI as early as 17 to 18 weeks of gestation. As discussed in the section on DWM, however, a prenatal diagnosis of JS before 20 weeks of gestation might result in a high rate of false positive and should be confirmed after 20 weeks of gestation. Pontine Tegmental Cap Dysplasia DEFINITION. PTCD is a recently described, rare brainstem malformation that is defined by the distinct neuroimaging findings (66). CLINICAL FEATURES. PTCD occurs sporadically and no familial recurrence risk has been reported. The clinical presentation is characterized by multiple cranial nerve involvement. The most commonly affected cranial nerves are the vestibulocochlear, facial, trigeminal, and glossopharyngeal nerves with resultant bilateral sensory deafness, bilateral trigeminal anesthesia causing corneal ulcers, bilateral facial paralysis, and difficulty in swallowing needing gastrostomy in some children (66,67). In addition, ocular movement disorders such as nystagmus and cerebellar signs such as truncal and limb ataxia and dysarthria are common in PTCD. Finally, global developmental delay and intellectual disability are features of almost all children with PTCD and range between mild cognitive delay and severe intellectual disability. The degree of developmental disability seems to correlate with neuroimaging findings: mildly affected patients tend to have a rounded bump (the so-called cap) and those who are more severely affected tend to have a more angular brainstem kink (a so-called beak) (43). Systemic involvement with vertebral segmentation anomalies, rib malformations, and congenital heart defects has been observed in several patients.

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FIGURE 4.76 A 3-year-old girl with pontine tegmental cap dysplasia, sensorineural hearing loss, and global developmental delay. A: Axial T2-weighted images show hypoplasia of the inferior olivary nuclei and middle cerebellar peduncles, and slightly elongated and horizontally orientated SCP remotely reminiscent of a “molar tooth like” appearance. B: Sagittal T1-weighted image reveals a flattened ventral pons, an abnormal curved structure (the so called “cap”) covering the middle third of the pontine tegmentum and projecting into the fourth ventricle, and hypoplasia and dysplasia of the cerebellar vermis. C: Coronal T1-weighted image reveals absence of the inferior cerebellar peduncles. (Partially reprinted with permission Poretti A, Boltshauser E, Doherty D. Cerebellar hypoplasia: differential diagnosis and diagnostic approach. Am J Med Genet C Semin Med Genet 2014;166 C:211–226.)

FIGURE 4.77 A 3-year-old girl with pontine tegmental cap dysplasia, sensorineural hearing loss, and global developmental delay. A: Sagittal color-coded FA maps reveals absence of the transverse pontine fibers in the ventral and middle pons and an ectopic band of fibers (arrow, red, horizontal orientation) dorsal to the pons. B: Axial colorcoded FA maps shows absence of the transverse pontine fibers, presence of an abnormal bundle of ectopic, transverse fibers at the level of the “cap” in the dorsal pons (arrow), and lack fo the midline “red dot” at the level fo the posntomesencephalic junction representing absence of the SCP decussation. In addition, the middle cerebellar peduncles (green) are hypoplastic. (Partially reprinted with permission from Poretti A, Boltshauser E, Doherty D. Cerebellar hypoplasia: differential diagnosis and diagnostic approach. Am J Med Genet C Semin Med Genet 2014;166 C:211–226.)

PATHOGENESIS. The (presumed genetic) cause of PTCD is unknown, and the lack of familial recurrence supports de novo dominant or complex causes. The absent transverse pontine fibers and SCP 202

decussation, ectopic transverse fibers on the dorsal pons, and ectopic prepontine arcuate fibers are highly suggestive of an underlying axonal guidance defect (41,67). IMAGING FINDINGS. PTCD has a distinct neuroimaging pattern including a flattened ventral pons, an abnormal curved structure (the so-called “cap”) covering the middle third of the pontine tegmentum and projecting into the fourth ventricle, hypoplasia, and dysplasia of the cerebellar vermis, slightly elongated and horizontally orientated SCP remotely reminiscent of a “molar-tooth like” appearance, thin to almost absent MCP, absence of the inferior cerebellar peduncles (ICP), a short pontomesencephalic isthmus, an altered shape of the lower brainstem due to hypoplasia or agenesis of the inferior olivary nuclei, and a slightly enlarged fourth ventricle (Fig. 4.76) (66,67). Additional neuroimaging findings include hypoplastic or absent facial and cochlear nerves, duplicated internal auditory canals, and, in few patients, supratentorial abnormalities such as dysgenesis of the corpus callosum and mild ventriculomegaly. DTI showed the absence of the transverse pontine fibers and presence of an abnormal bundle of ectopic, transverse fibers at the level of the “cap” in the dorsal pons (Fig. 4.77) (66,67). In addition, DTI revealed absence of the decussation of the SCP at the pontomesencephalic junction (67). Finally, extraaxial arcuate tracts connecting the basal pons to the cerebellar hemispheres and bypassing the MCP have been recently reported. Both semi-arcs fused in a single midline trunk, caudally connecting to the region of the internal arcuate fibers in the medulla oblongata. Predominantly Brainstem Malformations Brainstem Disconnection DEFINITION. Brainstem disconnection (BD) is defined by nearly complete absence of a brainstem segment with intact rostral and caudal portions connected only by a thin cord of tissue (Fig. 4.78). CLINICAL FEATURES. All children are symptomatic at birth, with absent or weak suck and swallowing, central respiratory insufficiency, increased or decreased muscle tone, and reduced visual fixation. Seizures and unstable body temperature may also occur. The majority of children dies before 2 months of age and do not achieve any developmental milestones (68). Extracerebral involvement (congenital cardiac abnormalities, hydronephrosis, and vertebral body anomalies) may occur. PATHOMECHANISM. The pathogenesis pathomechanisms have been proposed.

is

unknown.

Both

malformative

and

disruptive

IMAGING FINDINGS. Discontinuation of the brainstem with absence of the pons (best evaluated on sagittal sections) represents the neuroimaging hallmark of BD (Fig. 4.78). The absent segment of the brainstem can variably extend rostrally to the midbrain or caudally to the medulla oblongata. A thin strand of tissue connects the rostral and caudal portions of the brainstem. In the majority of patients, BD is associated with hypoplasia of the cerebellar vermis and hemispheres (Fig. 4.78). In several patients, MRI and magnetic resonance angiography (MRA) did not show the basilar artery (Fig. 4.78) (68). Supratentorial abnormalities are unusual. Horizontal Gaze Palsy with Progressive Scoliosis HGPPS is a rare autosomal recessive disorder caused by mutations in ROBO3, which encodes a receptor required for axonal guidance. Children with HGPPS typically present with congenital absence of horizontal eye movements (the vertical gaze and convergence are preserved) and progressive development of scoliosis. Neuroimaging findings are distinct and include a butterfly-shaped medulla due to the missing prominence of the gracile and cuneate nuclei, as well as prominent inferior olivary nuclei with respect to the medullary pyramids (69). The pons is hypoplastic and has a dorsal midline cleft with absence of the bulging contour of facial colliculi. DTI typically shows absence of decussation of the CST, pontine sensory tracts, and SCP. L1 Syndrome Due to Mutations in L1CAM L1 syndrome is a highly variable X-linked neurologic disorder resulting from mutations in the L1CAM gene on chromosome Xq28. The clinical presentation includes a combination of macrocephaly due to severe hydrocephalus, cognitive impairment, aphasia, spastic paraparesis, and thumb adduction deformities. The neuroimaging findings of L1 syndrome include severe congenital hydrocephalus, hypoplasia of the corpus callosum, large massa intermedia, and enlarged quadrigeminal plate. 203

Other Disorders with Predominantly Brainstem Involvement Athabascan brainstem dysgenesis syndrome (ABDS) and Bosley–Salih–Alorainy syndrome (BSAS) are brainstem patterning disorders caused by loss of HOXA1 function. In mouse models, HOXA1 is needed for correct specification of hindbrain rhombomeres 4 and 5, as well as inner ear and heart development. ABDS and BSAS share the same phenotype including cranial nerve palsies, sensorineural hearing loss, and cardiac outflow tract defects. Neuroimaging may show aplasia of inner ear structures and abnormal intracranial blood vessels. CHN1-related Duane retraction syndrome, SALL4-related Duane radial ray syndrome, and congenital fibrosis of the extraocular muscles (CFEM) types 1 to 3 caused by mutations in KIF21A, PHOX2A, TUBB3, and TUBB2B are other cranial dysinnervation disorders characterized by abnormal eye movements. In Duane syndrome, neuroimaging may reveal hypoplasia of the abducens and oculomotor nerves as well as oculomotor innervated muscles, and aberrant innervation of the lateral rectus muscle. In CFEM, neuroimaging may show absence of the superior division of the oculomotor nerve, marked hypoplasia of the oculomotor innervated muscle, and misinnervation of the lateral rectus muscle by an oculomotor nerve branch.

FIGURE 4.78 A 3-week-old neonate with brainstem disconnection. A: Midsagittal T2-weighted image shows absence of the middle and lower pons with only two thin strands of tissue connecting anteriorly and posteriorly the upper pons and the medulla. The cerebellar vermis and hemispheres are globally hypoplastic. B: Coronal FLAIR image reveals global cerebellar hypoplasia. C: Axial T2-weighted images show an abnormal shape of the medulla and absence of the pons. D: TOF MRA did not show the basilary artery. (Reprinted with permission from Poretti A, Denecke J, Miller DC, et al. Brainstem disconnection: two additional patients and expansion of the phenotype. Neuropediatrics 2015;46:139–144.)

Moebius syndrome is mostly sporadic and defined by the combination of congenital nonprogressive abducens and facial nerve palsies. It is a heterogeneous disorder presumably caused by malformative and disruptive etiologies and has been associated with prenatal exposure to misoprostil. Neuroimaging findings may be normal or include pontine calcifications and pontine malformations with absence of the facial colliculi (70). Anomalies of the Craniocervical Junction: The Chiari Malformations In 1891, Hans Chiari described three malformations of the hindbrain associated with hydrocephalus. Five years later, he published a further study on hindbrain deformities in which he revised the second type of malformation and described a new, fourth type of malformation. Despite countless 204

modifications, the essence of Chiari’s reports remains. Since Chiari’s initial descriptions, however, significant contributions have been made in the descriptions of the associated anomalies that are present in these disorders. In addition, numerous etiologic theories have been proposed over the last century, although the definitive mechanisms are the subject of debate. Chiari Type I Malformation DEFINITION. The Chiari type I malformation (C1M) can be simply defined as inferior displacement of the cerebellar tonsils and, sometimes, the inferior vermis through the foramen magnum into the rostral cervical spinal canal (Fig. 4.79). Chiari originally described a hindbrain malformation in association with hydrocephalus; however, it became apparent that hydrocephalus is not mandatory for the diagnosis of C1M.

FIGURE 4.79 Chiari type I malformation. Sagittal T1-weighted image shows herniation of the cerebellar tonsils more than 5 mm below the line connecting the basion and the opisthion (white line).

CLINICAL FEATURES. C1M tends to present in the second or third decade of life, but presentation within the first years of life has been also reported. The clinical presentation may include a variety of symptoms ranging from headache to severe myelopathy and brainstem dysfunction (71). Headache affects approximately 80% of patients, and is usually occipital in location and induced or exacerbated by Valsalva maneuvers. Other common symptoms include neck pain, weakness, numbness, and loss of temperature sensation. Ocular (e.g., downbeat nystagmus) and otoneurologic (e.g., dizziness, dysequilibrium, and tinnitus) signs and symptoms are reported in ∼70% of patients. Lower cranial nerve dysfunction (e.g., dysphagia and stridor) is typical in children thoracic) spinal cord atrophy may also be seen and associated with a progressive clinical course and greater disability (116,117).

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FIGURE 6.30 Multiple sclerosis in the cervical spinal cord with enhancement. A,B: Sagittal T2-weighted magnetic resonance (MR) image. C,D: Sagittal T1-weighted MR image after gadolinium. Focal intramedullary lesions (A) show partial enhancement (B) in this multiple sclerosis patient with new symptoms.

FIGURE 6.31 Sagittal views of the cervical spinal cord in two patients with relapsing–remitting multiple sclerosis (A,B and C,D). Cord lesions (red arrows) are seen as hypointensities on 3D T1-weighted (A, C) and hyperintensities on STIR (B,D) sequences at 3-T MRI. Typically, multiple sclerosis spinal lesions extend less than three longitudinal segments and involve only partially the cross-sectional cord area (preferentially the posterior cord columns).

T2-weighted spin-echo or fast spin-echo (FSE) and fast short-TI inversion recovery (STIR) sequences have been accepted as a clinical standard in the search for spinal cord MS lesions (Fig. 6.31). Despite the high sensitivity for detecting lesions in the brain, fast FLAIR images have been shown to be unreliable in the detection of MS lesions in the spinal cord (118), particularly in chronic lesions that may have relaxation values similar to those of the adjacent cord parenchyma and lose conspicuity within the cord. DTI studies have shown significantly increased mean diffusivity and decreased fractional anisotropy (FA), more prominent in the lateral and posterior regions of the cord (119–121). 1H MR spectroscopy of normal-appearing cervical cord in MS patients also shows evidence of decreased NAA when compared with healthy controls (122,123). OPTIC NERVE IMAGING IN MS. Optic neuritis is the initial manifestation of MS in about 25% of 314

cases and occurs during the course of the disease in 70% of cases (124). It is also estimated that 35% to 75% of patients with isolated optic neuritis go on to develop MS at some point during the next 15 years. The clinical conversion to MS is highly dependent on the co-presence of brain/spinal cord lesions suggestive of MS. In patients with clinically diagnosed optic neuritis, the roles of MR are the differential diagnosis, the detection of other brain and spinal cord lesions, and the related stratification of the risk of conversion to MS. MRI of the optic nerve is challenging. Optic nerve involvement in MS is quite common clinically and at autopsy (56), but routine spin-echo sequences often fail to detect optic nerve involvement in clinically affected individuals. Other pulse sequences, including STIR and fat-suppressed fast spin echo, high-resolution T2-weighted fast spin-echo MR with fat suppression, and high-resolution postcontrast enhanced T1-weighted images, have been proposed to this attempt. With these techniques, optic neuritis appears as abnormal high signal intensity within the affected nerves (Fig. 6.32). DTI techniques showed increased mean diffusivity and decreased anisotropy values in the affected optic nerves (125). Optical coherence tomography (OCT) is a promising technique for evaluation and monitoring the retinal nerve fiber layer thinning in eyes affected and not affected by optic neuritis (126). VARIANTS. Less common variants of MS are occasionally seen and differ from classic MS in their clinical presentation, course, and histopathologic findings (127) (Table 6.1).

FIGURE 6.32 Multiple sclerosis with optic neuritis. A: Coronal T2-weighted image (with fat suppression) through the optic nerves shows mild enlargement and high signal intensity within the left optic nerve (arrow). Postcontrast T1weighted images (with fat suppression) demonstrate abnormal enhancement of the left optic nerve in the (B) coronal plane (arrow) and in the (C) axial plane.

Acute MS (Marburg type) occurs as an infrequent variety of MS, most commonly in younger patients. It is often preceded by fever and typically has inexorable rapid progression to death within months. This fulminant form of MS has also been seen as a terminal event in classic MS. Pathologic findings of extensive myelin destruction, severe axonal loss, and early edema are seen. The typical MRI features of this variant include multiple, large, and often confluent lesions, which can involve the brainstem. Lesions can enhance and show perilesional edema. It is not rare to detect simultaneously a mixture of acute, subacute, and chronic lesions. Treatment is directed at reducing the inflammation. Although acute fulminant MS is associated with high morbidity and mortality, it may respond to aggressive immunosuppressive therapy (128). Schilder type, or myelinoclastic diffuse sclerosis (Fig. 6.33), refers to an entity consisting of extensive, confluent, asymmetric demyelination of both cerebral hemispheres with involvement of the brainstem and cerebellum. It is usually seen in children presenting with seizures, signs of pyramidal 315

tract involvement, ataxia, and psychiatric symptomatology. Adult cases have also been described (129). Typically, there is a rapid progression of disease over the course of 1 to 2 years, but the demyelinating process may be fulminant. Late in the disease, Wallerian degeneration and cavitation can be seen. The following criteria (130) have been proposed for the diagnosis: (a) a subacute or chronic myelinoclastic disorder with one or two roughly symmetrical lesions at least 2 cm × 3 cm in two of three dimensions; (b) involvement of the centrum semiovale; (c) these being the only lesions based on clinical, paraclinical, or imaging findings; (d) adrenoleukodystrophy must be excluded. In some cases, small MSlike lesions have been described in addition to large areas of demyelination. Concentric sclerosis (Balò type) is a rare type of demyelinating disease in which large regions with alternating zones of demyelinated and myelinated WM are found (131). The unique pattern of demyelination has been, recently, ascribed to a hypoxia-like type of tissue injury (132). The upregulation of stress proteins (preconditioning) is thought to be responsible for the sparing of the thin external ring of myelinated WM (132). When encountered, Balò concentric sclerosis has a pathognomonic appearance on both pathology and MRI (42). These lesions appear as concentric rings of hyperintensity alternating with isointense WM on T2-weighted sequences and alternating rings of varying degrees of hypointensity on T1-weighted images (Fig. 6.34). 1H MRS has shown metabolic abnormalities similar to those seen in very large MS lesions (increased cho/Cr, decreased NAA/Cr, and increased lactate) (133), which tend to normalize on follow-up scans. Restricted diffusion along the surfaces of some Balò concentric sclerosis lesions may occur. These findings may normalize or become regions with increased diffusivity (134). Neuromyelitis Optica and NMO Spectrum Diseases CLINICAL FEATURES. NMO or Devic’s disease is a severe relapsing disease that has a peculiar predilection for the optic nerve and spinal cord (Fig. 6.35). This condition has a different pathogenesis from MS since tissue injury is antibody dependent (aquaporin-4 antibody, AQP4Ab) and complement mediated. Patients experience acute relapses with poor recovery, leading early to major disabilities (quadriplegia and bilateral blindness) and death. Relapses are treated with IV steroids, while long-term treatments include anti-CD20 monoclonal antibody (rituximab) and other immunosuppressants (135). The current NMO diagnostic criteria (136) require one attack of optic neuritis and transverse myelitis plus two of the three supporting criteria: a spinal cord lesion on MRI involving three or more cord segments, a brain MRI not meeting MS diagnostic criteria or AQP4Ab seropositive status. Recently, the seropositivity for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies has been detected in a small percentage of patients with clinical NMO and AQP4Ab seronegative, supporting the notion that NMO is a spectrum of diseases (137).

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FIGURE 6.33 Schilder disease. A 13-year-old girl with a 10-day history of fever and worsening hemiparesis. A1,A2: Axial fluid-attenuated inversion recovery image demonstrates heterogeneous signal abnormality primarily within the right parietal lobe extending into and across the posterior corpus callosum. B1,B2: Note the peripheral low signal intensity that enhances on postcontrast T1-weighted images. This pattern of ill-defined peripheral enhancement (at the edge of a lesion) is frequently found in demyelination. C: Coronal postcontrast T1-weighted image demonstrates peripheral ill-defined enhancement in the same region. A follow-up magnetic resonance image (not shown) demonstrates dramatic regression of findings after the administration of steroids. (Courtesy of Dr. Gary L. Hedlund, Salt Lake City, UT.)

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FIGURE 6.34 Balò concentric sclerosis in a 40-year-old woman. These 3-T images using T1 (A) and fluid-attenuated inversion recovery (B) clearly demonstrate spiral morphology of the right frontal lesion, the hallmark of Balò concentric sclerosis. (Courtesy of R. Mendonca, Sao Paulo.)

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FIGURE 6.35 Devic disease; symptoms of transverse myelitis with optic neuritis. Coronal T2 (A) shows right optic nerve hyperintensity with enhancement (B) in a patient with optic neuritis. Cervical and thoracic spinal cord lesions (C) show patchy enhancement (D).

PATHOLOGIC FEATURES. AQP4 is a water channel mainly expressed by astrocytes and ependymal cells. In the spinal cord and optic nerves, early pathological changes are related to complement deposition and extensive granulocyte infiltration. Lesions are then characterized by pronounced loss of AQP4 positive astrocytes, demyelination, and severe axonal loss (138). IMAGING FINDINGS. Brain and spinal cord MRI are always required to diagnose NMO. Differently from spinal cord MS lesions, the longitudinally extensive transverse myelitis involves usually three or more contiguous cord segments, both WM and GM are typically affected, and there is no predilection for the cervical cord. The acute myelitis is usually characterized by an inhomogeneous enhancement. Extensive optic nerve lesions may involve also the chiasm. While small T2 WM lesions are the most common brain MRI finding in NMO, they are not specific. However, other brain abnormalities have been identified that are highly characteristic for NMO. These include lesions around the third and fourth ventricles in the hypothalamus and area postrema and surrounding the aqueduct of Sylvius; these areas are rich in AQP4. Lesions in the area postrema at the floor of the fourth ventricle are thought to be responsible for the characteristic prodrome of vomiting and hiccups that occurs in around 10% of NMO patients at first presentation. However, such lesions in AQP4-rich regions only occur in between 5 and 10% of patients. Other brain abnormalities seen in NMO include brainstem lesions, particularly of the centrodorsal medulla and the pons, and large, even tumefactive, hemispheric lesions. At 7 T, NMO brain lesions are not perivenular on T2*-weighted scans and cortical lesions are absent. Using DTI, initial evidences suggest that the normal-appearing WM is spared from a diffuse pathological process (139). Cervical cord damage, quantified using MT MRI, is similar in NMO and MS patients (140), whereas a DT MRI study disclosed more severe cervical cord damage in NMO than in MS patients (141). Inflammatory Demyelinating Pseudotumor CLINICAL FEATURES. Demyelinating diseases occasionally present as solitary, focal, or ill-defined space-occupying lesions in the brain that closely mimic a neoplasm both clinically and radiologically 319

(142,143) (Fig. 6.36). These lesions have been called inflammatory pseudotumors, focal tumor–like demyelinating lesions, or inflammatory myelinoclastic diffuse sclerosis, terminology that is more pathologic jargon than actual entities with distinct pathologic features (144). These lesions can be found in all age groups, but over half of them are seen in the third to fifth decades. Clinical manifestations are varied but strongly influenced by the anatomic location of the lesions, and respond to IV steroid administration. In a study by Kepes (144), most patients did not have any additional lesions during their follow-up period, but 1/10 of patients developed additional lesions consistent with the diagnosis of MS. In addition, none of these patients had a recent infection. A brain biopsy may be performed to establish the diagnosis because these lesions appear similar to neoplasms on imaging. If the diagnosis of demyelination is considered, biopsy can perhaps be delayed and patients can be imaged after treatment with steroids to look for regression of MR findings.

FIGURE 6.36 Inflammatory demyelinating pseudotumor. Axial fluid-attenuated inversion recovery images demonstrate ill-defined high signal intensity within the right frontoparietal white matter (A) and effacement of adjacent gyri and extension along the length of the corticospinal tract, (B) the posterior limb of the internal capsule, and (C) the cerebral peduncle. Postcontrast axial T1-weighted image (D) shows ill-defined minimal enhancement. These findings mimic the appearance of a large infiltrative neoplasm. Biopsy confirmed the presence of demyelination.

PATHOLOGIC FEATURES. The biopsy material usually yields a histopathologic picture of acute demyelinating disease. Demonstration of demyelination and relative preservation of axons is mandatory before a diagnosis of demyelinating disease is made (Fig. 6.18). Typically, there is focal lymphocytic infiltration accompanied by macrophages. The ratio between lymphocytes and macrophages is very variable, depending on the timing of biopsy. There are also reactive astrocytes (145). IMAGING FINDINGS. The imaging findings include large focal or ill-defined areas of hypodensity on CT, and MR shows these areas to be high in signal intensity on T2-weighted images. There may be a significant amount of swelling in the affected region of the brain, with mass effect on adjacent structures. The location of these lesions is typically in the hemispheric WM (Fig. 6.36) and occasionally in the cerebellar WM (144). In contrast to classic MS, there is no predilection for the periventricular WM, optic nerves, or brainstem. Follow-up imaging after steroids usually shows partial or complete resolution of these lesions. Disorders with Secondary Demyelination and/or Destruction of White Matter 320

There is a spectrum of WM diseases having varying degrees of secondary demyelination or destruction of the WM and known etiologies. The pathologic changes are quite varied and may include pure demyelination, as in central pontine myelinolysis (CPM), or necrosis and demyelination, as in PML (see Table 6.2). White Matter Diseases Associated with Viral Agents Viral infections of the nervous system produce a spectrum of abnormalities based on the specific site affected (i.e., meninges, peripheral nervous system, or CNS) and the rate of progression of disease. These factors in turn determine the clinical presentation and the underlying pathologic changes. Demyelination may occur in association with viral agents by several potential mechanisms: (a) direct infection of oligodendrocytes (e.g., JC virus), (b) immune-mediated oligodendrocyte or myelin destruction by immune reactions against viral antigens, (c) secondary damage from immune complex formation, and (d) antimyelin autoimmune reactions. The glial and neuronal cells may be directly infected or destroyed, as seen in acute infective encephalitis and encephalomyelitis (see Chapters 14 and 24), or there may be an immune-mediated demyelination (acute disseminated encephalomyelitis [ADEM]) in which a virus is not isolated from the brain. Acute Disseminated Encephalomyelitis (Perivenous Encephalomyelitis, Postinfectious Encephalomyelitis, Postvaccinal Encephalomyelitis, Acute Perivascular Myelinoclasis) CLINICAL FEATURES. ADEM is an inflammatory/demyelinating condition that is frequently seen in children, but individuals of all ages can be affected (146,147). It usually presents as a monophasic selflimited illness within weeks after a nonspecific respiratory infection, a specific viral illness (measles, rubella, mumps, chickenpox, Epstein–Barr virus, pertussis influenza, mycoplasma, Coxsackie B), or vaccination (rabies, diphtheria, smallpox, tetanus, or typhoid), or it can be seen spontaneously (146). Clinical manifestations commonly present days to several weeks after the inciting event with fever, headaches, meningeal signs that may progress to seizures, and focal neurologic deficits, including ataxia, cranial nerve palsies, choreoathetosis, stupor, and coma. There is usually a favorable response to intravenous glucocorticoids; however, in more severe cases glucocorticoids combined with plasmapheresis or intravenously administered immunoglobulin have been effective (148). The neurologic deficits usually resolve spontaneously within 1 month. Permanent neurologic sequelae occur in 10% to 20% of cases (149,150), and the residual complications are most commonly related to frequent seizures. Occasionally, there is a progressive downhill course, with severe paresis, neurologic dysfunction, and death. PATHOLOGIC FINDINGS. The CSF may be normal or show a pleocytosis of 1,000 or more cells/mm3, predominately neutrophils or mononuclear cells, a slight elevation of protein, and occasional oligoclonal IgG bands. The histologic appearance of ADEM is similar to that of experimental allergic encephalomyelitis (particularly the chronic form), supporting the hypothesis that ADEM results from an autoimmune response to a CNS antigen triggered by viral infections. The prominent histopathologic features of ADEM are lymphocytic infiltration of the meninges and perivascular spaces; perivascular infiltrates consisting of lymphocytes, reactive microglia, and foamy macrophages; numerous demyelinating foci scattered throughout the brain and spinal cord; vasculitis; and perivascular necrosis. Demyelination is largely limited to areas with inflammatory cell infiltration (147). Macroscopically, the brain is edematous, and herniation may be present. MRI FINDINGS. ADEM diagnosis is challenging. Some features make the MR appearance of ADEM partially distinguishable from that of MS, even if some patients initially diagnosed as ADEM go on to develop exacerbations of their neurologic symptoms and are reclassified as MS. Typically, lesions appear at the same time and concomitantly with clinical presentation. The brain involvement is bilateral (rarely unilateral) with asymmetric or symmetric multifocal lesions. The WM is more frequently involved than GM (deep GM nuclei and cortex), but usually both are affected. Within the WM, deep and juxtacortical WM is more involved than the periventricular one and the corpus callosum is rarely affected. Lesions occur usually both supratentorially and infratentorially (less commonly either/or) (147,151) (Figs. 6.37–6.39). Lesions may be large and masslike but characteristically show only mild mass effect (Fig. 6.38). The contrast enhancement is variable, between 33% and 100%, thus the absence of enhancement does not lessen the likelihood of the diagnosis (151). Similar to MS, optic neuritis is common, and involvement of the spinal cord may be seen (Fig. 6.39). Follow-up MR commonly demonstrates marked decrease in the size and number of the lesions, and complete resolution of disease 321

may be seen in response to steroids in conjunction with clinical improvement (Fig. 6.38). A large effort has been devoted to define those MRI parameters capable to differentiate MS from ADEM in pediatric populations. A recent investigation has shown that the presence of either at least one T1-hypointense lesion or one or more periventricular lesions is associated with an increased likelihood of MS (152). Using MT MRI and DT MRI, no abnormalities of the normal-appearing brain tissue and spinal cord have been detected in ADEM patients after the acute phase of the disease (153), whereas mild DT MRI abnormalities of the basal ganglia have been described (154). 1H MR spectroscopy studies provided conflicting results in ADEM: some authors found no metabolic abnormalities in the acute stage of the disease, and others described a transient decrease of NAA in regions corresponding to T2 lesions on the 1H MR spectroscopy obtained during the acute phase which normalized after clinical recovery (155,156).

FIGURE 6.37 Acute disseminated encephalomyelitis as multiple masses (biopsy proven). A–C: T2-weighted MR image. D–F: T1-weighted MR image after gadolinium. A child after viral illness presented with ataxia. Focal lesions with some mass effect (A–C) involve both gray (B) and white matter (A, C). Significant irregular enhancement (D–F) is also seen.

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FIGURE 6.38 Acute disseminated encephalomyelitis with enhancement; 32-year-old man with a seizure 4 weeks after viral illness, initial and follow-up. A large lesion confined to white matter on initial T2 (top row, A) images shows irregular enhancement (bottom row, A). Four weeks later (B1), T2 and fluid-attenuated inversion recovery images show significant resolution of the lesion with residual enhancement (B2).

FIGURE 6.39 Acute disseminated encephalomyelitis (ADEM) with brain and spinal cord lesions. Multiple focal white matter lesions (A,B) in association with extensive spinal cord abnormality (C) with questionable enhancement (D) were due to ADEM in this case.

Acute Hemorrhagic Leukoencephalitis CLINICAL FEATURES. Acute hemorrhagic leukoencephalitis (Hurst disease) is considered a 323

hyperacute or fulminant form of ADEM (147). This entity is typically seen in young patients who have an abrupt onset of fever, neck stiffness, and progressive neurologic deficits often leading to coma and death within 1 to 5 days. It has been reported after viral respiratory infections. The CSF findings include lymphocytosis, neutrofilia, and red cells (147). There are case reports in the literature of prolonged clinical course after the administration of high-dose steroids (157,158). The brain is edematous, and the high fatality is due to respiratory paralysis secondary to tonsillar and transtentorial herniation (159). PATHOLOGIC FINDINGS. Postmortem examination of the brain usually shows multifocal areas of acute perivascular demyelination and hemorrhage confined to the cerebral WM (especially in the central part of the centrum semiovale, internal capsule, and convolutional WM of the cingulate gyrus) with strict sparing of the subcortical U fibers. Microscopically, a necrotizing angiitis is seen with petechiae and perivascular ring and ball hemorrhages (160) (Fig. 6.40). The hemorrhages can also appear as confluent hematomas. The perivenous chronic inflammatory cell infiltrate is composed of lipid-laden macrophages and CD4+ and CD8+ T lymphocytes with microglial and astrocytic activation. MRI FINDINGS. Multifocal asymmetric areas of high signal intensity are seen on the T2-weighted images primarily within the WM with hemorrhages (Fig. 6.41). Subacute Sclerosing Panencephalitis Subacute sclerosis panencephalitis (SSPE) results from a slow infection reactivated after an episode of measles. Immunization programs make SSPE a very uncommon disease. A latency of several years after the infection may be present, with age at onset between 3 and 20 years. Clinical features include behavioral changes with progressive myoclonus, ataxia, and seizures. MR and CT findings are of edematous periventricular WM lesions with significant mass effect, initially compressing the ventricles, followed by an end-stage appearance of marked cerebral atrophy (Fig. 6.42). SSPE usually progresses to death in 6 months to 6 years. Progressive Rubella Panencephalitis Progressive rubella panencephalitis is pathologically characterized by widespread demyelinating changes in the brain with extensive involvement in the basal ganglia and brainstem. There is also widespread neuronal destruction with perivascular lymphocytic infiltration and vasculitis. Progressive Multifocal Leukoencephalopathy CLINICAL FEATURES. Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of a latent infection by a papovavirus (JC virus) in a new permissive environment. It is a severe opportunistic infection of the CNS and has been associated to three main medical conditions: (1) lymphoproliferative disorders (lymphoma, leukemia), (2) HIV and acquired immunodeficiency syndrome (AIDS), and, more recently, (3) drug-induced immunosuppression (Tysabri [natalizumab]) in disimmune disorders such as MS, Crohn’s disease, and psoriasis (161). In the last 10 years, ∼450 cases of Tysabri (natalizumab)-induced PML have been reported. The stratification of the risk in drug-induced PML is assuming a major role in patient management and decision-making; MS patients are at high risk for PML if they are JC virus seropositive, if they have already been treated with immunosuppressants, and if the duration of natalizumab administration is prolonged for more than 2 years (161). The clinical onset is often insidious and mistaken for other neurological conditions (MS relapse, stroke). Cognitive impairment, motor weakness, language disturbance, and visual loss are the more common clinical presentation. Seizures may be seen, which is believed to reflect involvement of the cortex by the JC virus (162). The diagnosis is made by a combination of MR findings and detection of JC virus on CSF analysis (163). The prognosis is largely dependent on the predisposing condition (worse in neoplastic and AIDS than in MS patients). The initiation of antiretroviral therapy or the discontinuation of Tysabri (natalizumab) contributes significantly to prolonged survival; however, the rapid restoration of the immunity within the CNS may be associated to a, sometimes transient, paradoxical worsening of the clinical picture, called immune reconstitution inflammatory syndrome (IRIS) (164).

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FIGURE 6.40 Acute hemorrhagic leukoencephalitis. A: Coronal gross specimen with extensive white matter hemorrhages. B: Microscopic section demonstrates the characteristic ball and ring hemorrhages. Hematoxylin and eosin, ×200. (Courtesy of Dr. Mark A. Edgar, New York.)

FIGURE 6.41 Acute hemorrhagic leukoencephalitis. Computed tomography (CT) and magnetic resonance images in a 32-year-old man with rapidly progressive deterioration who died within 4 d. Axial CT scans show low density within the (A) occipital periventricular white matter and (B) parietal periventricular white matter with swelling and low density within the splenium of the corpus callosum. Axial (C) proton density-weighted and (D) T2-weighted images show high signal intensity and swelling within the splenium of the corpus callosum and high signal intensity within the occipital and parietal periventricular white matter. E: Axial T2-weighted image shows involvement of the body of the corpus callosum. F: Gross specimen showing multiple small hemorrhagic foci (arrows) in the white matter. The corpus callosum was cut to facilitate fixation.

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FIGURE 6.42 Subacute Sclerosing Panencephalitis. Young woman presenting with confusion, dizziness, and vomiting. She had measles at 4 months of age. Axial FLAIR images show extensive and progressive hyperintense areas in the supra- and infratentorial cerebral white matter, including the corpus callosum (A) and cerebellar peduncles (B) on FLAIR images.

PATHOLOGIC FINDINGS. Within the CNS, JC virus is known to infect preferentially oligodendrocytes and astrocytes (165). PML is characterized pathologically by focal or confluent areas of demyelination, mainly distributed throughout the cerebral WM. Cerebellar peduncles and brainstem may be involved as well. The GM involvement is prominent and has been neglected for a long time (Fig. 6.43); however, the subpial cortical layer is spared (166). Microscopically, there are multiple confluent foci of demyelination. The salient pathologic features are atypical oligodendrocytes containing large, swollen nuclei with basophilic or eosinophilic inclusion bodies (Fig. 6.43) accompanied by reactive astrocytes that may be enlarged, abnormal, and atypical; there is also a variable amount of perivascular inflammatory cell infiltration (163,165,167,168). MRI FINDINGS. The classic MRI appearance of PML is multifocal areas of ill-defined high signal intensity on the T2-weighted sequences within the subcortical WM (Fig. 6.44). The parietal WM is more frequently involved; however, any WM region may be affected (169,170). Up to 50% of patients may have some GM involvement. The posterior fossa can be involved (Fig. 6.45) and when present should prompt consideration of this disease (171). Optic nerve involvement does not commonly occur with PML, and spinal cord involvement is extremely rare. The lesion expansion follows the main WM tracts, and thus contralateral lesions may be seen (166). Up to 50% of cases of natalizumab-induced PML have been reported to demonstrate gadolinium enhancement. IRIS, when present, is generally associated to new areas of punctate enhancement (166,170). Marked focal or global atrophy is a long-term sequel of PML lesions.

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FIGURE 6.43 Progressive multifocal leukoencephalopathy, two cases. A: Typical oligodendroglial inclusion in a patient with progressive multifocal leukoencephalopathy. Hematoxylin and eosin, ×400. B: Oligodendroglial nucleus containing the papovavirus in progressive multifocal leukoencephalopathy. Electron micrograph. ×10,000. C: Atypical reactive astrocytes in a focus of demyelination in progressive multifocal leukoencephalopathy. Hematoxylin and eosin, ×1,000. D: Progressive multifocal leukoencephalopathy. Top: The transition from the severely affected area (left) to the less affected area (right). At this magnification, there are numerous reactive astrocytes. Perivascular chronic inflammatory cell infiltration is also noted. Bottom: In addition to atypical oligodendrocytes, atypical astrocytes are also present (middle). Cells infected by JC virus are best demonstrated by in situ hybridization (inset). Hematoxylin–eosin stain.

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FIGURE 6.44 Progressive multifocal leukoencephalopathy in patient with acquired immunodeficiency syndrome. A, B: White matter lesions seen on T2-weighted image (4,000/80), with predilection for subcortical white matter. C: Postcontrast T1-weighted images demonstrate slight peripheral enhancement.

In patients with AIDS, many other disease processes may affect the WM and mimic PML. These include diseases with multifocal involvement predominantly of the WM, most notably encephalitides, including cytomegalovirus, toxoplasmosis, or HIV-1 encephalopathy (see Chapter 14 for a complete discussion). Human Immunodeficiency Virus Encephalopathy CLINICAL FEATURES. Neurologic manifestations are the initial manifestations of AIDS in 7% to 20% of patients (172). Neuropathologic changes can be caused by HIV itself or by other infectious agents. Opportunistic infections such as cytomegalovirus, toxoplasmosis, and JC virus that cause PML, fungi, and other opportunistic infections are common (172) (also see Chapter 14). HIV-related neurologic complications include aseptic meningitis, HIV encephalopathy, vacuolar myelopathy, polyneuropathy, and myopathy (172). In this chapter, we limit our discussion to HIV-associated neurocognitive disorders (HAND) (173,174) that include (1) asymptomatic neurocognitive impairment, (2) mild neurocognitive disorder, and (3) HIV–dementia (also known as HIV encephalopathy, AIDS dementia complex, and HIVassociated dementia complex). HIV infects the brain and CSF early in the disease, and as the disease progresses the CSF viral load is strongly predictive of increased dementia risk (175). Despite the use of antiretroviral therapy, ∼50% of HIV patients present different degrees of cognitive impairment, likely due to the poor distribution of some drugs into the CNS and related CSF viral escape (176). In this context, it is very important for the neuroradiologist to rule out HAND from other dementing diseases. Most patients develop an insidious onset of disturbed intellect, progressive psychomotor slowing, and memory impairment (Table 6.10). In rare instances, this disorder may develop abruptly and have rapid progression. CNS IRIS can be seen in a subset of patients with AIDS or immunosuppression, in which highly active antiretroviral therapy (HAART) is initiated and the syndrome is characterized by a paradoxical worsening of a previously acquired opportunistic infection with an exaggerated inflammatory response that makes the symptoms of the infection worse. CNS IRIS can be seen with organisms (varicella zoster, cytomegalovirus, HIV, Candida, Mycobacterium Tuberculosis, Toxoplasma gondii), or without organisms. MRI can show restricted diffusion in cases of infarcts, leptomeningeal enhancement, and high signal intensity in the WM on FLAIR/T2-weighted images reflecting demyelination or vasculitis (Fig. 6.46) (177). 328

PATHOLOGIC FINDINGS. Only mild cerebral atrophy is seen in most cases of HAND that are not complicated by other diseases such as toxoplasmosis and lymphoma. Microscopic abnormalities are variable and may be widely distributed. The central cerebral WM and deep GM are preferentially affected, whereas the cortex is relatively spared. Histologically, the myelin is diffusely pale in both the cerebral hemispheres and cerebellum. The WM may reveal vacuolation or loss of myelin and axonal loss with frank necrosis. A low grade of chronic inflammation may be present. These lesions are associated with infiltration by macrophages, increase in number of microglia, and reactive astrocytes. The microglial cell infiltrates may form well-defined microglial nodules. Multinucleated giant cells, often associated with microglial nodules, are the most distinctive microscopic feature of HIV encephalopathy. Most commonly, they are found in the cerebral WM, basal ganglia, and thalamus.

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FIGURE 6.45 Progressive multifocal leukoencephalopathy involving the posterior fossa with change in enhancement over several months. A: Axial T2-weighted images (4,000/80) show high signal intensity throughout the pons, bilateral middle cerebellar peduncle, and right cerebellar hemisphere white matter with a small amount of swelling. B1,B2: Postcontrast T1-weighted axial images (600/20). C: Coronal images show ill-defined peripheral enhancement. Several months after therapy, (D) the signal intensity on the T2-weighted images is not as extensive, and (E) postcontrast T1-weighted images show that the enhancement has significantly decreased.

FIGURE 6.46 Immune reconstitution inflammatory syndrome (IRIS). Middle-aged woman with history of HIV infection presenting with worsening confusion and cognitive dysfunction after starting antiretroviral therapy. Axial FLAIR images show extensive signal abnormalities in the (A) bilateral cerebral white matter, (B) corpus callosum, (C) periventricular, deep, and subcortical white matter, and (D) posterior fossa.

TABLE 6.10 Differentiation of Human Immunodeficiency Virus (HIV) Dementia from Progressive 330

Multifocal Leukoencephalopathy (PML)

MRI FINDINGS. The most common finding on imaging is atrophy of the brain. In early stages of the disease, small areas of high signal intensity are seen on the T2-weighted sequences in the periventricular WM that lack mass effect or edema (178). Studies have shown increased detection of small lesions, particularly in subcortical and cortical locations, using fast FLAIR sequences (178). Progression of disease typically demonstrates multifocal confluent lesions or diffuse symmetric high signal intensity in the periventricular and deep WM (Fig. 6.47). Bilateral symmetric increased signal intensity on the T2weighted sequences has been described in the basal ganglia (Fig. 6.48) (caudate and putamen) and thalamus, and may also involve the brainstem (179). A range of decreased MT ratios in areas of high signal intensity and in the normal-appearing WM has been reported in HIV patients (180). 1H MR spectroscopy studies have shown decreased NAA/Cr, increased levels of choline, and the presence of lactate in normal-appearing WM and regions of WM with signal abnormality (181). White Matter Diseases Associated with Nutritional and Vitamin Deficiency Central Pontine and Extrapontine Myelinolysis (Osmotic Demyelination) CLINICAL FEATURES. CPM describes demyelination usually isolated to the central pons; however, extrapontine sites of demyelination are not uncommon. It is commonly found in association with alcoholism, chronic nutritional deficiency, and many other systemic disorders with electrolyte abnormalities (182,183), including chronic pulmonary disease, liver and kidney diseases, diabetes mellitus, liver transplant, and neoplasia. The term “osmotic demyelination syndrome” has been proposed (184) because of the common association with rapidly corrected hyponatremia. The symptoms of CPM include spastic quadriparesis, pseudobulbar palsy, changing levels of consciousness, and coma (185). A significant proportion of patient’s progress to death, which may be preceded by a state of pseudocoma (locked-in syndrome). The clinical outcome does not necessarily depend on the severity of the neurologic deficits during the acute phase or on the degree of hyponatremia (186). Due to improved detection of the disease with MRI and intensive medical care, many more patients are surviving with varying degrees of residual neurologic deficits and in some cases complete neurologic recovery (186).

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FIGURE 6.47 Human immunodeficiency virus encephalopathy in a patient with acquired immunodeficiency syndrome showing diffuse white matter involvement. A–D: Fluid-attenuated inversion recovery images progressing inferiorly to superiorly demonstrate diffuse white matter signal abnormality.

FIGURE 6.48 Human immunodeficiency virus encephalopathy with characteristic involvement of the basal ganglia. A: Axial fluid-attenuated inversion recovery image demonstrates bilateral symmetric increased signal intensity within the basal ganglia and external capsules. B: Axial postcontrast T1-weighted image demonstrates no evidence of enhancement.

PATHOLOGIC FINDINGS. On gross examination, the classic pontine demyelinating lesions appear as triangular or butterflylike areas of symmetric gray discoloration along the midline of the basis pontis. A rim of normal WM typically surrounds the area of demyelination, and the tegmentum is usually not involved. Histologically, the area of myelin breakdown is sharply demarcated and displays extensive loss of oligodendrocytes, infiltration with foamy macrophages, and reactive astrocytosis. Neurons and axons are typically spared (187). MRI FINDINGS. The regions of demyelination within the brain demonstrate high signal intensity on the T2-weighted sequences, most prominently seen in the upper and middle pons (182–185). The pontine lesion is central, with characteristic sparing of the peripheral pial and ventricular surface (Fig. 6.49). Gadolinium contrast enhancement is only occasionally seen, and when present is in the periphery of the signal abnormality (Fig. 6.50). Extrapontine sites of myelinolysis may occur even without 332

significant pontine abnormality and characteristically involve the deep WM (particularly the external capsules) and the deep GM (Fig. 6.50) in a relatively symmetric pattern. The signal abnormality in the pons may improve slightly, and only rarely do the MR findings completely resolve (186,188,189). The clinical diagnosis of CPM can often be difficult to ascertain, and so the recognition of the pattern of abnormalities by the astute radiologist often prompts a thorough search of the electrolyte results. The key is recognition of characteristic sparing of corticospinal tracts and perfect symmetry in osmotic demyelination. A general differential diagnosis, if one does not realize the classic neuroanatomic distribution of the entity, should probably include ischemia, MS, encephalitis, toxic exposures, and radiation therapy effects, particularly when extrapontine lesions are seen. One key distinction on MRI is that acute osmotic demyelination is commonly associated with restricted diffusion, a finding not commonly found in other demyelinating diseases (Fig. 6.51). Marchiafava–Bignami Disease CLINICAL FEATURES. Marchiafava–Bignami disease is a rare condition in which demyelination and necrosis primarily affect the corpus callosum and sometimes also involve extracallosal regions (95,190,191). It was originally described in 1903 by the Italian pathologists Amico Bignami and Ettore Marchiafava in an Italian Chianti drinker. It has been subsequently seen predominantly in male alcoholics and, in more recent years, in poorly nourished nondrinkers (192). The acute clinical presentation consists of sudden onset of a symptom complex including altered consciousness, seizures, dysarthria, ataxia, diffuse hypertonia, pyramidal signs, and frontal liberation reflexes (95). Subacute and chronic clinical forms present over several months to years and appear as progressive dementia with occasional clouding of consciousness, signs of interhemispheric disconnection, and pyramidal and cerebellar dysfunction eventually leading to death. A better clinical outcome is seen after thiamine substitution and normal nutrition (191).

FIGURE 6.49 Central pontine myelinolysis. A: T2-weighted axial image shows characteristic high signal intensity within the midpons, with a surrounding rim of normal-appearing pontine parenchyma and sparing of the corticospinal tracts. B: Sagittal T1-weighted image demonstrates a low-signal lesion within the pons.

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FIGURE 6.50 Central pontine and extrapontine myelinolysis. A: T2-weighted axial image shows high signal intensity within the midpons, with a surrounding rim of normal-appearing pontine parenchyma and sparing of the corticospinal tracts. B: Contrast-enhanced T1-weighted image (600/26) demonstrates faint enhancement at the margins of the pontine lesion. C: T2-weighted axial images show high signal abnormality particularly in basal ganglia, thalami, and external capsules. D: Foci of high signal intensity are also seen in deep and subcortical white matter and bodies of the caudate nuclei.

PATHOLOGIC FINDINGS. On gross examination, Marchiafava–Bignami disease is characterized by necrotizing cystic lesions predominating in the genu and body of the corpus callosum. Lesions may also be seen within the optic chiasm, anterior commissure, centrum semiovale, and middle cerebellar peduncles. Microscopically, there is demyelination with relative sparing of the axons. The central fibers of the corpus callosum are mainly affected, with preservation of the upper and lower edges. Oligodendrocytes are markedly reduced in numbers, with an abundance of lipid-laden macrophages. Astrocytes generally show mild reactive changes. Vessels in and around the necrotizing lesions may show proliferation and hyalinization of their walls. The pathogenesis of Marchiafava–Bignami disease is poorly understood. Of interest, similar lesions have been described after experimental cyanide and carbon monoxide intoxication.

FIGURE 6.51 Central pontine myelinolysis with restricted diffusion. Note classic morphology of pontine lesion on FLAIR (A) and T2 (B) with sparing of periphery. DWI (C) shows markedly restricted diffusion.

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FIGURE 6.52 Marchiafava–Bignami syndrome with cavitary lesions of the corpus callosum (CC). Sagittal T1weighted image (A) demonstrates small areas of low signal intensity in the genu, body, and splenium of the CC. Axial T2-weighted image (B) demonstrates a focal area of high signal intensity within the splenium of the CC and remains isointense to cerebrospinal fluid on the (C) fluid-attenuated inversion recovery axial image.

MRI FINDINGS. In the acute stage of the disease, the corpus callosum demonstrates diffuse swelling and high signal intensity on the T2-weighted images (190). In the chronic stage, diffuse atrophy of the corpus callosum and focal necrosis may be seen in the genu, body, or splenium of the central portion of the corpus callosum (Fig. 6.52). Focal hypointensity on the T2-weighted images within the corpus callosum has been described which has been speculated to represent either hemosiderin deposits or lipid-laden macrophages. Confluent areas of high signal intensity on the T2-weighted images may be seen within the subcortical and periventricular WM, likely related to edema rather than demyelination (95). Subacute Combined Degeneration of the Spinal Cord CLINICAL FEATURES. Subacute combined degeneration (SCD) refers to vitamin B12 (cobalamin) deficiency with demyelination and vacuolation found in the posterior and lateral columns of the spinal cord. One of the most common causes of vitamin B12 deficiency is pernicious anemia as a result of autoimmune gastritis in which intrinsic factor is not produced. Other common causes include gastric surgery and various malabsorption syndromes. Dietary lack of vitamin B12 is rare but may be seen in vegetarians. Symptoms of SCD include generalized weakness, paresthesias consisting of tingling, or “pins and needles” involving the hands and feet. As the disease progresses, unsteady gait, limb weakness, and stiffness develop that may evolve to ataxic paraplegia with spasticity and contractures. Clinical signs typically include loss of position and loss of vibration, most pronounced in the legs. Treatment involves lifetime monthly B12 intramuscular injections. The duration of symptoms appears to be the most important factor influencing the response to treatment. PATHOLOGIC FINDINGS. SCD is primarily a myelinopathy, but axonal degeneration is always seen in longstanding cases. The brain appears macroscopically normal, but the spinal cord is shrunken. The posterior and lateral columns of the spinal cord appear gray–white in color with an almost translucent appearance. Early lesions contain swollen myelin sheaths with little change in the axons. Foamy macrophages are present in areas where there is myelin breakdown, and some perivascular lymphocytic infiltration is present. Lesions begin as small foci and then become confluent. In full-blown cases, the 335

spinal cord has multifocal vacuolated and demyelinated lesions affecting the dorsal and lateral columns, and sometimes the anterior columns may be affected. Axonal degeneration is found in areas with increased vacuolation and demyelination. The midthoracic cord is usually the most severely affected. Small areas of perivascular demyelination may also be found in the brain. MRI FINDINGS. MRI findings in SCD of the spinal cord include increased signal intensity on the T2weighted sequences of the dorsal columns of the cervical and thoracic cord (Fig. 6.53). Mild expansion of the cord may be seen and mild contrast enhancement has been described. There is typically a continuous long segment of signal abnormality confined to the dorsal columns, which may help to distinguish this entity from other demyelinating lesions found in the cord that appear patchier in distribution (193,194). Vacuolar myelopathy seen in patients with AIDS may appear similar on imaging, and therefore, the clinical history plays an important role in distinguishing these entities. MR findings in the brain in patients with vitamin B12 deficiency may reveal areas of high signal intensity on the T2weighted images in the cerebral WM (195). Imaging findings in SCD may resolve after treatment with vitamin B12 (194).

FIGURE 6.53 Subacute combined degeneration of the spinal cord (B12 deficiency). A: Sagittal T2-weighted image demonstrates a long segment of high signal intensity within the dorsal aspect of the cervical spinal cord. B: Axial T2weighted image shows high signal intensity within the dorsal columns. (Courtesy of Dr. Laurie A. Loevner, Philadelphia, PA.)

White Matter Diseases Associated with Physical/Chemical Agents or Therapeutic Procedures Specific toxins tend to affect specific vulnerable regions of the brain. This concept of specific vulnerability is explained by the principle of functionally related systems (a functional chain of neurons and tracts), regions having similar characteristics (i.e., oxygen requirements, chemical compositions, and neurotransmitters), or regions developing at the time of the insult. For example, certain toxins such as carbon monoxide tend to selectively affect the GM (globus pallidus); however, the WM may also be affected (196) (Fig. 6.54). Many different physical, pharmacologic, and environmental agents and abuse substances can produce WM abnormalities. Some of the most common are listed in Table 6.11. Radiation and Chemotherapy Effects Radiation therapy and chemotherapy may result in transient abnormalities in the brain (i.e., edema) but typically cause small-vessel injury (arteritis and secondary ischemia). Symptoms of radiation- or chemotherapy-induced arteritis are similar to those of an intracranial mass: seizures, headaches, confusion, and focal neurologic deficits. MRI can be of great value in differentiating primary from secondary neurologic dysfunction. Most recurrent or residual tumors appear as focal areas of enhancement with surrounding edema. Radiation-induced injury to the CNS has been classified into acute, early-delayed, and late-delayed effects (197). The initial (acute) changes occur during radiation therapy and they are believed to reflect edema from damage to the capillary endothelium and may be transient and of little clinical consequence. These acute changes present on MRI as high signal intensity on the T2-weighted images, which may demonstrate mass effect but usually do not enhance. The early-delayed effects occur several 336

weeks to months (up to approximately 6 months) after radiation therapy and are presumably due to demyelination that may be reversible. MRI typically shows diffuse increased signal intensity on the T2weighted images within the WM. The subcortical U fibers may be affected, but the corpus callosum is usually spared. Late-delayed effects occur months to years later and present as either diffuse WM injury or focal radiation necrosis. This is due to ischemia from endothelial proliferation in the microvasculature (198). Areas of radiation necrosis can be focal or disseminated within the WM (199). The typical appearance is high signal intensity on the T2-weighted images, with a variable amount of gadolinium enhancement on T1-weighted images. Mass effect and edema are common findings, and the lesion may be indistinguishable from neoplasm. Although radiation necrosis is generally confined to the WM, a recent study evaluating patients receiving radiation therapy for nasopharyngeal carcinoma found that radiation necrosis in the brain frequently involved both WM and GM. GM involvement was detected in 88% of their patients (200) and, this high prevalence has been speculated to be due to the higher radiation doses to focused regions of the brain as may be seen in other head and neck cancers (Fig. 6.55).

FIGURE 6.54 Carbon monoxide intoxication. Axial T2-weighted images (A,B) show typical abnormal high signal intensity within the globus pallidus and also with extensive periventricular white matter involvement.

TABLE 6.11 Toxic Leukoencephalopathy: Causative Agents

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Chronic changes in the brain can be marked, with devastating clinical sequelae, including widespread leukomalacia, calcifying microangiopathy, and atrophy (198). Focal atrophy of any portion of the CNS can occur, including the optic nerves, resulting in optic atrophy, and the pituitary gland, resulting in panhypopituitarism. The age of the patient is particularly important in determining the extent of injury. Younger age at the time of radiation therapy seems to correlate with a worse prognosis. Children receiving radiation are also more likely to develop capillary telangiectasias and large-vessel vasculopathy. Intimal proliferation develops with eventual thrombosis that may result in a moyamoyalike collateral circulation (201). The effects of radiation are usually more severe in combination with chemotherapy (Fig. 6.56). A subacute leukoencephalopathy can be seen as a consequence of the combination of intrathecal methotrexate and irradiation of the CNS (202). Various chemotherapeutic agents, including methotrexate, cytarabine, carmustine, cyclophosphamide, cisplatin, and fludarabine (Fig. 6.57, 203), have been reported to cause signal abnormality within the WM (204). WM hyperintensity on T2weighted images may be focal, multifocal, or diffuse in association with chemotherapeutic agents. Lasparaginase, an enzyme used in treating acute leukemia, can cause WM signal abnormality and intracranial sinus thrombosis (1% to 2% of children) (205) and may result in hemorrhagic infarcts. Bone marrow transplantation is another source of treatment-related changes in the WM. In one series, 59% of pediatric bone marrow recipients developed neurologic complications, including cerebral infarction, meningitis, and meningoencephalitis (206). High-dose chemotherapy in association with hematopoietic progenitor cell support is another commonly used therapy for advanced breast carcinoma (207). A longitudinal study by Brown et al. (207) showed signal abnormality in the WM starting at 2 months, with a rapid progression of up to 6 months that appeared to stabilize up to 1 year.

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FIGURE 6.55 Radiation injury involving cortex and subcortical white matter. The patient received radiation therapy for ethmoid sinus carcinoma 9 months before this scan. A: Axial fluid-attenuated inversion recovery image demonstrates high signal intensity within the bilateral anterior temporal lobes (primarily within the subcortical white matter), left greater than right. B: Axial T1-weighted image postcontrast shows solid parenchymal enhancement of the left medial temporal cortex and subcortical white matter.

Drugs of Abuse Abuse substances are an increasingly recognized cause of leukoencephalopathy, parallel to the rising prevalence of their consumption. Chronic intentional inhalation and exposure to fumes from spray paints and glues containing toluene may produce dementia, ataxia, and additional neurologic symptoms related to a direct myelotoxic effect of this highly lipophilic compound (208). MRI of individuals with toluene toxicity shows extensive WM hyperintensities typically proportional to the degree of cognitive dysfunction (208). Chronic alcohol consumption has also been associated with WM abnormalities, with T2 hyperintensities on MRI and DTI, particularly in the frontal WM. Additional manifestations of the myelotoxic properties of alcohol exposure include Marchiafava–Bignami disease (see earlier discussion) and fetal alcohol syndrome in pregnant females (with evidence of abnormal fetal myelination) (208). Cocaine, MDMA (3,4-methylenedioxy-N-methylamphetamine or “ecstasy”), heroin (intravenous and inhaled forms), and psilocybin can also produce variable WM abnormalities (208). The inhalation of heroin pyrolysate (obtained after heating the drug on aluminum foil; also called “chasing the dragon”) produces a particular leukoencephalopathy with spongiform changes and characteristic involvement of the cerebellar WM and posterior limb of the internal capsule, sparing the anterior limb and subcortical WM (208) (Fig. 6.58). Vascular Hypertensive Encephalopathy (Reversible Posterior Leukoencephalopathy) CLINICAL FEATURES. Hypertensive encephalopathy is a clinical entity that it is important to recognize early because the clinical and imaging findings are usually reversible. It refers to vascularly mediated phenomena with characteristic neurologic and imaging findings due to elevated blood pressure that exceeds the autoregulatory capacity of the brain vasculature (209). The clinical findings make up a recognizable syndrome, referred to as reversible posterior leukoencephalopathy, characterized by headaches, decreased alertness, altered mental functioning, seizures, and visual loss, including cortical blindness (209). Acute elevation of blood pressure (several hours to days before the onset of symptoms) is the most common precipitant. The blood pressure may even be in the normal range but is elevated compared with the individual’s baseline (210). The syndrome can also be seen with renal decompensation, preeclampsia/eclampsia, fluid retention, and treatment with immunosuppressive drugs (209,211). Cyclosporine is the most commonly implicated immunosuppressive drug; however, the syndrome has also been reported in association with numerous other immunosuppressants (after organ transplantation) and chemotherapeutic agents, including tacrolimus, FK506, l-asparaginase, cisplatin, and mouse monoclonal antibody (OKT3) (212–217). The mechanism underlying the syndrome is likely a brain–capillary leak syndrome with regions of vasodilation and vasoconstriction, particularly in arterial boundary zones. Sympathetic innervation to the vasculature has been shown to initiate vasoconstrictive protection to the brain from marked increases in blood pressure (210). Because the anterior circulation is better supplied with sympathetic innervation than the posterior circulation, it is theorized to be better protected during elevation of 339

systemic blood pressure. The clinical signs and findings on MRI are characteristic. The syndrome is uncommon in children and is usually seen in association with systemic disease and after organ transplantation (218). Because the syndrome is reversible, prompt diagnosis is essential so that treatment can be directed at controlling the blood pressure and discontinuing or decreasing the dose of the immunosuppressive or chemotherapeutic agent (209).

FIGURE 6.56 Arteritis in patient with both radiation therapy and experimental chemotherapy for breast cancer. A: Marked bilateral occipital lesions are present on this T2-weighted sequence (2,000/80), involving both gray and white matters. B: After cessation of chemotherapy and administration of steroids, the lesions are largely resolved.

FIGURE 6.57 Fludarabine-induced toxicity. 40 year male patient with history of Crohn’s disease and stage IV lymphoma—s/p reduced intensity haploidentical combined BM–kidney transplant, presenting with altered mental status. Axial FLAIR (A,B) images show characteristic abnormal hyperintense signal in the posterior corpus callosum, posterior periventricular white matter and post-chiasmatic optic pathways corresponding diffusion-weighted images (C,D) show abnormal restricted diffusion. (Crombe A, Alberti N, Gilles M, et al. Extensive acute toxic leukoencephalopathy induced by Fludarabine: two months follow-up on brain MRI. J Neuroradiol. 2015 Apr;42(2):127–30.)

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FIGURE 6.58 Heroin inhalation–induced leukoencephalopathy (“chasing the dragon”). A 26-year-old man with a history of heroin inhalation presenting with impaired motor function, speech disturbances, and cognitive dysfunction. Axial T2-weighted MR images demonstrate symmetric increased signal in the posterior cerebral white matter and splenium of the corpus callosum (A), brainstem (B), and cerebellar (C) white matter. The cortex, basal ganglia, and thalami are spared. (From Chang WC, Lo CP, Kao HW, et al. MRI features of spongiform leukoencephalopathy following heroin inhalation. Neurology 2006;67(3):504, with permission.)

FIGURE 6.59 Hypertensive encephalopathy. FK506 toxicity in a child after liver transplant with seizures. Axial fluidattenuated inversion recovery images. A: Typical bilateral symmetric high signal intensity is seen within the occipital white matter with mild swelling of the overlying cortex. B: Symmetric high signal intensity within the subcortical frontal and parietal subcortical white matter with localized swelling and signal abnormality within the adjacent cortices.

MRI FINDINGS. Confluent areas of signal abnormality are typically seen in a bilateral symmetric pattern that may be limited to the subcortical WM but frequently also involves the overlying cortex (Fig. 6.59). High signal intensity is seen on the T2-weighted sequences usually in regions supplied by the posterior circulation (occipital, parietal, and posterior temporal lobes, posterior fossa) but may also involve the frontal lobes and corpus callosum (210) (Fig. 6.60). Mild mass effect with sulcal effacement is usually seen. Hemorrhagic foci can be found, particularly in patients with thrombocytopenia, and are best depicted on gradient-echo images as focal areas of hypointensity (219). Contrast enhancement may also be seen in the regions of signal abnormality. Typically, the clinical and imaging findings are reversible after the control of blood pressure, and the clinical and imaging findings establish the diagnosis without the need for biopsy. However, in cases documented in the literature in which the diagnosis was uncertain and biopsy was performed, these WM abnormalities seen on imaging have been shown to be correlated with WM edema on pathology (220). DW sequences may be normal or may demonstrate increased diffusion in these regions, supporting the concept of increased interstitial fluid in the WM and not ischemia (221). However, in cases with prolonged seizures or hypertension, frank ischemia or infarction may result. Preliminary reports of perfusion MRI have shown preserved or increased perfusion to affected regions of the brain (218,222), whereas acute ischemia is generally associated with decreased perfusion. 1H MR spectroscopy findings in patients with eclampsia have shown a decrease in NAA persisting for weeks after reversal of imaging findings and absence of lactate (223). Lactate was detected in cases in which the imaging findings were persistent, suggesting infarction. Because the history of hypertension or seizures may not always be present, the characteristic imaging findings should allow the radiologist to suggest the diagnosis, and follow-up imaging in 1 to 2 weeks will usually show resolution of findings. 341

Ischemia and Arteritis Small areas of hyperintensity on T2-weighted images in the WM are common in the elderly and may not be correlated with neurologic deficits (224). The underlying pathology of these lesions is believed to represent gliosis, loss of myelinated axons, and small areas of ischemia (225). Small-vessel ischemia is seen as part of normal aging (see Chapter 15 for a full discussion) and may be even more severe in patients with hypertension and/or diabetes. These lesions are typically patchy, multifocal (226), and most commonly seen in the periventricular and deep WM of the centrum semiovale and optic radiations. Focal areas of hyperintensity in the basal ganglia are also commonly seen in association with WM lesions and may help to differentiate ischemia from MS. When the signal abnormality is extensive, there does appear to be some correlation between WM ischemic disease and dementia. Clinical correlation is always necessary, however, to make the diagnosis of Binswanger encephalopathy or subcortical arterial sclerotic encephalopathy. Causes of ischemia in younger patients include embolic disease, hypoxia, dissection, arteritis, and migraine. Patients with complicated migraine have small areas of high signal intensity on the T2-weighted images within the WM that may be potentially reversible. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited vasculopathy manifesting as subcortical dementia of the Binswanger type (227,228). Patients are typically younger than individuals with subcortical arterial sclerotic encephalopathy and may present with recurrent transient ischemic attacks, strokes, or migraine headaches (229). The genetic defect is located on chromosome 19q12 and is identified by the notch 3 gene (227,228). The onset of symptoms usually occurs in the fourth to fifth decades. Typically, there is no history of hypertension or other risk factors for cerebrovascular disease. The underlying pathology is believed to be due to a characteristic angiopathy of small- and middle-sized arteries. The characteristic MRI findings include symmetric and confluent areas of high signal intensity on the T2-weighted images in the subcortical and periventricular WM (Fig. 6.61) (230) of frontal, temporal, and insular lobes, as well as variable involvement of the external and internal capsules, basal ganglia, thalamus, and brainstem (230). Microbleeds (smaller than 5 mm) are frequently detected on T2*-weighted images (31% to 73% of cases) (231).

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FIGURE 6.60 Hypertensive encephalopathy, supratentorial and infratentorial involvement. Cyclosporine toxicity with involvement of the posterior fossa on fluid-attenuated inversion recovery (FLAIR) (A) and T2-weighted images (B) also involves supratentorial white matter on FLAIR (C) and T2-weighted images (D). Note the unusual and extensive linear enhancement (E) and absence of restricted diffusion (F).

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FIGURE 6.61 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), two different patients. A: Axial fluid-attenuated inversion recovery image shows the typical pattern of bilateral symmetric high signal intensity within the external capsules, subcortical, and periventricular white matter in a 40-year-old patient. B, C: Axial T2-weighted images from a different patient show multifocal areas of high signal intensity within the bilateral thalami, posterior limbs of the internal capsules, external capsules, and periventricular subcortical white matter, with associated atrophy.

CNS vasculitis encompasses a heterogeneous group of inflammatory disorders that primarily affect the small leptomeningeal and parenchymal blood vessels of the brain. Multiple factors can cause CNS vasculitis, including infection, cocaine ingestion, ionizing radiation, malignancy, and autoimmune disease. The most common autoimmune conditions associated with CNS vasculitis include primary angiitis of the CNS, systemic lupus erythematosus (SLE), polyarteritis nodosa, giant cell arteritis, and Sjögren syndrome. The typical MRI findings in CNS vasculitis include multiple small areas of high signal intensity on the T2-weighted images, frequently found in the deep WM and the subcortical WM (Fig. 6.62), even though the subcortical WM has extensive collateral circulation (232). Lesions may also be seen in the GM and may be hemorrhagic (Fig. 6.63). Overt cortical infarctions may also be seen. The MRI findings seen in CNS vasculitis may appear virtually identical to that of MS (232). Steroids are the mainstay in therapy for CNS vasculitis, and regions of swelling and signal abnormality can regress after therapy.

FIGURE 6.62 Lupus vasculopathy. A: Axial fluid-attenuated inversion recovery images show cortical swelling and signal hyperintensity and small focal areas of high signal within the pons. B: Characteristic findings of central

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nervous system vasculitis. Small focal areas of high signal intensity within the deep gray and subcortical white matter are seen. C, D: Note the involvement of a long segment of the spinal cord as well with mainly gray matter disease.

FIGURE 6.63 Central nervous system vasculitis with focal hemorrhage. T1-weighted image (A) shows a focal cavitary infarct in the periventricular white matter with a small amount of high signal presumably representing focal subacute hemorrhage. Fluid-attenuated inversion recovery images demonstrate (B) high signal intensity surrounding the focal infarct and (C) diffuse high signal intensity within the periventricular and deep white matter.

Susac’s syndrome (retinocochleocerebral vasculopathy) is a microangiopathy of unknown etiology (although thought to be autoimmune), presenting with encephalopathy, retinal arterial involvement, and hearing loss. The entity was first described by Dr. John Susac in 1979 in Florida (233) and has a female predominance of 3:1, age range extending from 16 to 58 years. The cerebral involvement is characterized by vasculitic lesions in the corpus callosum, deep GM, and microinfarcts of the cortex; leptomeningeal enhancement has also been seen. On MRI, Susac’s syndrome has been described as showing central callosal “holes” (microinfarcts) (234) which are thought to develop as the acute callosal changes resolve. Small areas of restricted diffusion can be seen on DWI in the central corpus callosum (Fig. 6.64). Miscellaneous Sarcoidosis CLINICAL FEATURES. Sarcoidosis is a systemic noncaseating granulomatous disease with neurologic involvement in up to 10% of cases (235). The etiology is unknown, and the disease has a slight predilection for females and blacks. Most patients are affected between the ages of 20 and 40 years. The clinical diagnosis may be characteristic if the patient has hilar adenopathy, anergy, hypercalcemia, and uveitis. Some patients with neurosarcoidosis may have no systemic manifestations of the disease. The prognosis is variable, with some patients dying within several weeks and others demonstrating a chronic course. Treatment initially includes high doses of corticosteroids, and then immunosuppressive agents and/or immunomodulatory monoclonal antibodies, such as infliximab (anti-TNF alfa) (235). MRI FINDINGS. The primary intracranial findings in neurosarcoidosis include granulomatous infiltration, with a dense adhesive arachnoiditis causing cranial nerve deficits and inflammation of the meninges and perivascular involvement resulting in vasculopathy. Disruption of the leptomeningeal blood—brain barrier allows the granulomatous infiltrate to involve the brain parenchyma along the perivascular spaces (236). Postcontrast T1-weighted images typically demonstrate nodular enhancement of the leptomeninges, most commonly involving the basal meninges and basal midline structures (hypothalamus, infundibulum, pituitary gland, and floor of the third ventricle) (Fig. 6.65). Granulomatous lesions may coalesce and present as a focal mass lesion with edema in the adjacent brain. Multifocal parenchymal lesions may be seen in the cortex and subcortical WM that demonstrate high signal intensity on the T2-weighted sequences. These lesions may appear very similar to the findings seen in MS and vasculitis (236) and are believed to represent areas of granulomatous infiltration, gliosis, and edema. Abnormal enhancement has also been described in the subependyma, periaqueductal region, and pineal gland (237). Sarcoid may also involve the spinal cord or parenchyma and/or leptomeninges. The cervical or upper thoracic cord is most commonly involved, and there may be mild expansion of the cord with patchy multifocal parenchymal and linear leptomeningeal enhancement (238).

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FIGURE 6.64 Susac’s syndrome. Middle-aged woman with history of melanoma and thyroid cancer presenting with headache, visual scotomas, sensorineural hearing loss, and vertigo. The patient was recently diagnosed with branch retinal artery occlusion. Sagittal FLAIR (A), axial FLAIR (B) and axial DWI (C) images demonstrate multiple hyperintense foci in the cerebral white matter (including the central corpus callosum). Some of these foci demonstrate abnormal restricted diffusion.

FIGURE 6.65 Sarcoidosis with white matter abnormality. A: Axial T2-weighted image shows high intensity bilaterally in the gyrus rectus with a focal granulomatous lesion (arrow). B: Gadolinium-enhanced T1-weighted image shows nodular enhancement of the parenchyma, optic chiasm, optic nerves, and infundibulum. C: Axial T2-weighted image demonstrates swelling and high signal intensity within the bifrontal subcortical white matter. D: Axial postcontrast T1weighted image shows nodular enhancement along the falx and parenchyma with thick linear dural enhancement along the frontal lobe.

Lyme Disease CLINICAL FEATURES. Lyme disease is a multisystem infectious disease found in discrete geographic regions in North America. Borrelia burgdorferi is a spirochete that causes Lyme neuroborreliosis and affects the peripheral nervous system (10% to 15% of patients) far more often than the CNS (239). In cases of CNS involvement, clinical symptoms may be absent or include photophobia, headache, and meningismus (240). CSF analysis demonstrates the findings of aseptic meningitis with mild elevation of protein, moderate lymphocytic pleocytosis, and normal or minimally decreased CSF glucose. Encephalomyelitis occurs in approximately 0.1% of infected untreated patients and may involve the parenchyma of the brain or spinal cord (240). B. burgdorferi is also known to penetrate the blood–brain 346

barrier and to induce a vasculitis (241). Several weeks of antibiotic treatment are usually effective, although there are cases of patients developing persistent or relapsing symptoms. MRI FINDINGS. MRI of the brain in neuroborreliosis may be normal or include diffuse leptomeningeal enhancement with or without parenchymal lesions (239) (Fig. 6.66). Multifocal areas of high signal intensity have been reported in the cerebral WM, brainstem, and cerebellum on the T2weighted images (242,243). Parenchymal ring-enhancing lesions may be seen and appear identical to those lesions seen in ADEM or MS (244). Abnormal enhancement of cranial nerves may be seen, and acute transverse myelitis has also been described (245).

FIGURE 6.66 Lyme disease. A,B: Axial fluid-attenuated inversion recovery (FLAIR) images show scattered areas of high signal intensity within the bilateral thalami, basal ganglia, and external capsules and hyperintensity within sulci. C: Axial FLAIR image demonstrates abnormal high signal along the leptomeningeal (ventral surface) and parenchyma of the medulla. D: Axial postcontrast T1-weighted image shows leptomeningeal enhancement along the medulla. E: Sagittal postcontrast T1-weighted image depicts abnormal leptomeningeal enhancement along the ventral surface of the brainstem.

INHERITED METABOLIC DISORDERS Enormous progress has been achieved in recent years in identifying and understanding the biochemical 347

defects that underlie the vast number of inherited metabolic disorders. In most of these genetic disorders, the responsible genes have been isolated. Complex genetic heterogeneity has been shown even among patients with the same clinical manifestations, biochemistry, and enzymatic defects (246). Although these entities are rare, MRI plays a critical role in the early identification of these disorders (247). In this section, we discuss dysmyelinating diseases (abnormal development or maintenance of myelin), encompassing not only dysmyelinating diseases, but also disorders in which the abnormal accumulation of a biochemical or absence of a specific enzyme primarily affects GM structures (and are not considered primary diseases of the WM). The clinical and histopathologic criteria for a leukodystrophy include metabolic disorders in which there is an inherited defect affecting the oligodendroglial cells or myelin that causes progressive neurologic deterioration. Of interest, several of these disorders (e.g., adrenoleukodystrophy, metachromatic leukodystrophy [MLD], and Krabbe disease) demonstrate evidence of both demyelination and dysmyelination on pathology that cannot be distinguished by MRI. Most metabolic disorders present in early childhood, and only a few present in early infancy or adulthood. Inheritance is typically by an autosomal recessive pattern, although there are exceptions (Table 6.3). Specific enzyme replacement, stem cell transplantation, and gene therapy are emerging therapies for these conditions (246). TABLE 6.12 Discriminating Features of Common Leukoencephalopathies

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TABLE 6.13 Characteristic 1H Magnetic Resonance Spectroscopy Findings in Metabolic Disorders

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One of the most common nonspecific MRI findings in many of the metabolic disorders is a delay in the normal myelination in the infant. In the older child, progressive WM lesions are typically seen, resulting in diffuse cerebral atrophy. Although the MRI findings are similar for most of these disorders in the later stages, there are some distinguishing features early in the disease course (247) (Table 6.12). The most common findings on 1H MR spectroscopy in metabolic disorders is a nonspecific pattern of decreased NAA with or without a lactate peak (Table 6.13). Although practically most metabolic disorders demonstrate a decrease in the NAA, Canavan disease is the only metabolic disorder characterized by an increase in the NAA peak, providing a specific diagnosis. This section discusses these groups of inherited disorders based on pathology of the subcellular organelles (lysosomes, peroxisomes, and mitochondria) and nonorganelle (i.e., amino or organic acid)-based pathology (Tables 6.14 and 6.15). Lysosomal Disorders In lysosomal disorders, specific catabolic enzymes are deficient, resulting in the accumulation of products (such as lipid, carbohydrate, or mucopolysaccharide) that interfere with cell function and eventually lead to cell death. This group of genetic disorders is classified by the nature of the material that accumulates abnormally (sphingolipidoses, mucopolysaccharidoses, and the mucolipidoses; Table 6.16). They often have a relentless progressive course and vary only in the rate of intellectual and visual deterioration. In many cases, there are no abnormalities on MRI until late in the course. Sphingolipidoses METACHROMATIC LEUKODYSTROPHY CLINICAL FEATURES. MLD is the most common lysosomal disorder and is characterized by a deficiency of the lysosomal enzyme arylsulfatase A (cerebroside sulfatase). It is inherited in an autosomal recessive pattern, encoded on chromosome 22q, and primarily affects the CNS and peripheral nervous system (248). Cerebroside sulfate (galactosyl sulfatide) abnormally accumulates within the WM (resulting in breakdown of the membrane of the myelin sheath), kidneys, gallbladder, and other viscera (249). The diagnosis of MLD is based on the finding of abnormally low levels of arylsulfatase A in the urine and peripheral leukocytes. Additional tests may include measurement of urinary sulfatide, assessment of fibroblast sulfatide catabolism, and sural nerve biopsy. The four principal forms of the disease are congenital, late-infantile (presenting between 6 months and 3 years of age), juvenile (presenting at 4 to 6 years), and the adult variant. In one family only one variant of MLD occurs. The congenital form is rare, presents with seizures at birth, and is followed by death within a few days or weeks. The late-infantile form comprises most cases (approximately 80%). The clinical presentation is marked by gait difficulties, with frequent falls in the second and third years of life. The disease progresses quickly, with poor speech, mental deterioration, seizures, and hypertonia, and evolves to decerebrate and decorticate posturing within 3 to 6 months. In the less common juvenile form, symptoms usually do not develop until 4 years. The clinical picture is similar to the late-infantile form, except that the child is old enough to manifest behavioral disturbances as well. TABLE 6.14 Common Metabolic Disorders (Organelle-Based Pathology)

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TABLE 6.15 Common Metabolic Disorders (Non–organelle–Based Pathology)

PATHOLOGIC FINDINGS. The hallmark of the disease is metachromatic granules (20 to 30 mm in diameter), presumably derivatives of cerebroside sulfate, which are found in the brain, liver, kidney, peripheral nerves, and other organs. The demyelinated areas are infiltrated by macrophages that contain these metachromatic granules, and gliosis may be seen. In areas where myelin is preserved, metachromatic granules may be found within oligodendrocytes. Although axons are relatively spared, some of them are fragmented. Oligodendroglia are absent in areas of demyelination and are reduced in number even in areas where the myelin is still intact. There are no inflammatory cells within areas of demyelination. TABLE 6.16 Lysosomal Disorders

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MRI FINDINGS. The characteristic MRI features of MLD include symmetric confluent areas of high signal intensity on the T2-weighted images within the periventricular (butterfly configuration) and cerebellar WM, with sparing of the subcortical U fibers until late in the disease (250) (Fig. 6.67). In late-onset cases (juvenile and adult forms), there is predominant involvement of the frontal WM (Fig. 6.68). The signal abnormality progresses from the anterior to the posterior direction. In the lateinfantile form of MLD (251), the most common type, a posterior (occipital) predominance of signal abnormality has been reported with dorsofrontal progression of disease. Involvement of the corticospinal tracts, although typically ascribed to X-linked adrenoleukodystrophy, may also be seen in the late-infantile form of MLD. As the disease progresses, the signal abnormality becomes more extensive and confluent with associated atrophy. The corpus callosum is invariably affected, and hypointensity within the thalami on T2-weighted images may be seen. Lesions in the deep GM are rarely seen, and if present appear as subtle signal abnormalities. The so-called tigroid and “leopard skin” pattern of demyelination (alternating areas of normal WM within areas of demyelination, suggestive of perivascular WM sparing) (252) in the periventricular WM and centrum semiovale has been typically described in Pelizaeus–Merzbacher disease but has also been noted in the late-infantile form of MLD. Distinguishing features of MLD include absence of contrast enhancement, frequent involvement of 352

cerebellar WM, and lack of involvement of deep GM. DWI shows evidence of increased signal within the WM abnormalities, with occasional demonstration of the “tigroid” pattern, with decreased signal on the ADC map, likely secondary to myelin edema, or without changes in the ADC map, likely from T2 shine through (253,254). In advanced and more chronic cases, the demyelinating lesions are hypointense on DWI (253,254). 1H MR spectroscopy frequently demonstrates abnormality in the metabolic peaks (decreased NAA, elevated myo-inositol, and, occasionally, elevated lactate) before conventional MRI.

FIGURE 6.67 Metachromatic leukodystrophy. A: Extensive disease throughout white matter on T2-weighted image (2000/80). Note the partial preservation of the subcortical U fibers. B: Cerebellar involvement is common, as seen on axial T2-weighted sequence (2,000/80).

FIGURE 6.68 Metachromatic leukodystrophy, juvenile form. A 14-year-old girl with characteristic involvement of the frontal white matter in the late-onset or juvenile form. A,B: Axial fluid-attenuated inversion recovery images demonstrate increased signal intensity within the periventricular white matter (frontal white matter is more severely affected than the occipital and parietal). Note abnormal signal intensity within the splenium of the corpus callosum. C: T2-weighted image demonstrates white matter involvement along with abnormal iron deposition in basal ganglia. D: Sagittal T1-weighted image shows severe atrophy of the corpus callosum. E: Single-voxel 1H magnetic spectroscopy (point-resolved spectroscopy, 2,000/288) performed in the right frontal periventricular white matter demonstrates a decrease in the N-acetylaspartate/creatine ratio and prominent choline peak. (Courtesy of Dr. Gary L. Hedlund, Salt Lake City, UT.)

Krabbe Disease 353

Clinical Features Krabbe disease, or globoid cell leukodystrophy (GLD), is an autosomal recessive inherited disorder in which the deficiency of the lysosomal enzyme galactocerebroside β-galactosidase (255,256) (chromosome 14) results in the accumulation of galactocerebroside in macrophages. Because galactocerebroside is an important component of mature myelin, symptoms generally begin during the period of active myelin synthesis. Several clinical types have been distinguished based on the age at onset and disease course (256). The early-infantile form of the disease is the most common clinical form and has three distinct clinical stages. By 6 months of age, the infant presents with spasticity, irritability, and fever, without signs of infection (irritable-hypertonic presentation). Development fails to progress, and the infant regresses neurologically. The second phase is characterized by rapid deterioration in motor function, with chronic opisthotonos and myoclonic jerking, accompanied by hyperpyrexia, hypersalivation, and hypersecretion from the lungs. In the third phase, the child appears decerebrate and has flaccid paralysis that culminates in death by 2 years of age. The later-onset forms have a more variable clinical presentation with a slower progression of disease. Enzyme replacement, stem cell transplantation (257), and gene therapy are new available treatments for Krabbe disease (246,257). Pathologic Findings The pathologic hallmark is a massive accumulation of large multinucleated cells containing periodic acid-Schiff–positive material (globoid cells). In contrast to other demyelinating diseases, lipid-laden macrophages are uncommon. Demyelination and dysmyelination are seen. MRI Findings Characteristic MRI patterns in GLD have been described based on the age at the onset of clinical symptoms (258). The most characteristic MRI finding in both the infantile and late-onset forms of GLD is high signal intensity on the T2-weighted images found along the lengths of the corticospinal tracts (250). Additional findings in the early-onset form include abnormal signal intensity within the cerebellar WM and deep GM nuclei, with progressive involvement of the parieto-occipital WM and posterior portion of the corpus callosum. In the late-onset form, in addition to corticospinal tract involvement, there is predominant involvement of the posterior portion of the corpus callosum and bilateral symmetric parieto-occipital WM (Fig. 6.69). The cerebellar WM and deep GM nuclei are not involved in the late-onset form. Classically, the subcortical U fibers are spared until late in the disease. Optic nerve atrophy and rarely bilateral symmetric optic nerve hypertrophy have been described (259). The CT findings of hyperdense thalami, caudate nuclei, and corona radiata are characteristic but not specific for the disease and correspond to fine calcifications at autopsy (260). Atrophy is common late in the course due to progressive loss of WM. Late-onset cases of GLD with primary involvement of the parietal periventricular WM, splenium of the corpus callosum, and corticospinal tracts may appear similar on imaging to adrenoleukodystrophy. However, auditory pathway involvement is characteristic of adrenoleukodystrophy and is not seen in GLD (258). The 1H MR spectra of the WM lesions in patients with the infantile form typically show highly elevated levels of inositol and choline, with moderate increase of the total creatine (tCr) (creatine and phosphocreatine) and decreased total NAA (tNAA) (NAA plus N-acetyl-aspartylglutamate [NAAG] peaks), with occasional accumulation of lactate (261), compatible with a combination of astrocytosis and neuronal degeneration (262). Patients with the juvenile form show milder elevations of inositol with variable levels of choline and normal or mildly elevated tNAA (261), producing increased inositol/NAA ratios with relatively normal choline/NAA, reflecting a predominantly astrocytic response without neuronal damage (262). These spectroscopy abnormalities typically become even milder, closer to normal, in the adult/late-onset cases (261,263).

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FIGURE 6.69 Krabbe disease. Axial T2-weighted image shows symmetric areas of increased signal intensity within the periventricular white matter and corpus callosum with relative sparing of the subcortical U fibers (2,000/80). In the late-onset form of Krabbe, there is predominant involvement of the parieto-occipital white matter (as seen in this case). Corticospinal tract involvement (not shown) is characteristic of the disease.

DWI typically demonstrates increased signal along the “progression line” of active dysmyelination/demyelination during the early stage, likely related to myelin edema, with eventual normalization and decreased signal with advancing demyelination/dysmyelination (indicating more advanced myelin loss) (254). Preliminary data suggest that anisotropy maps offer a higher sensitivity for WM abnormalities than conventional T2-weighted images and may be used as a marker of therapeutic response (264,265). McGraw et al. (266) reported a significant difference in the mean FA ratios between patients transplanted at an early age (less than 1 month old) and patients transplanted at 5 to 8 months, with the early group showing higher baseline FA ratios (suggesting relatively normal WM in the first postnatal month) and significantly higher FA ratios after transplantation, indicating modification of the underlying dysmyelinogenesis (266), with good correlation with neurodevelopmental scores (267).

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GM1 and GM2 Gangliosidoses Clinical Features GM1 gangliosidosis is a rare lysosomal storage disorder that occurs as a result of deficiency of the lysosomal enzyme β-galactosidase (268). The extent of ganglioside accumulation dictates when the disease presents. GM2 gangliosidosis occurs secondary to a deficiency of hexosaminidase activity. Tay– Sachs disease is a form that is found mainly in Jewish children of Eastern European descent and is due to a deficiency in the β-N-acetylhexosaminidase-A isozyme. Infants present within the first few weeks or months with hyperacusis, irritability, psychomotor retardation, progressive weakness, hypotonia, seizures, blindness by 1 year, and cherry-red spots in the macula. Juvenile and adult-onset forms also exist and have a slower progressive course, including dementia, seizures, spasticity, cerebellar ataxia, proximal muscle atrophy, and dystonia. Sandhoff disease (deficiency of A and B isozymes of hexosaminidase) has a clinical course similar to Tay–Sachs but also has visceral involvement (268).

FIGURE 6.70 Tay–Sachs disease, two patients: a 28-year-old man (A,B) with characteristic cerebellar atrophy on sagittal and coronal T2-weighted images, showing severe atrophy of the cerebellum without signal abnormality, and a 3-year-old child (C,D) with extensive supratentorial and infratentorial white matter disease and severe posterior fossa atrophy.

MRI Findings MRI findings in GM1 gangliosidoses differ depending on the age of presentation and thereby reflect the extent of underlying ganglioside accumulation. In infancy, there is extensive demyelination and gliosis in the WM, resulting in diffuse high signal intensity on the T2-weighted images. In the childhood form, diffuse generalized cerebral and cerebellar atrophy has been described. When the disease presents in young adults, cerebral atrophy and high signal intensity on T2-weighted images can be found in the bilateral caudate nucleus and putamen. Early in the disease course of GM2 gangliosidoses, MRI demonstrates high signal intensity within the bilateral basal ganglia on the T2-weighted images. Calcification is frequently seen in the basal ganglia on CT, which presents on MRI as high signal intensity on the T1-weighted images and low signal intensity on the T2-weighted images. Enlargement of the caudate nuclei has also been described. Diffuse atrophy may be seen early. As the disease progresses, diffuse high signal intensity is seen within the WM, reflecting gliosis; demyelination and cavitation may be seen. Severe generalized atrophy is most prominent in the cerebellum (Fig. 6.70) and brainstem. 1H MR spectroscopy in patients with infantile GM1 gangliosidosis shows decreased NAA/Cr and 356

increased choline/Cr ratios (269) (Fig. 6.71). Tay–Sachs disease demonstrates increase in myoinositol/Cr and choline/Cr ratios, with a decrease in the NAA/Cr ratio, supporting the presence of demyelination, gliosis, and neuronal loss. Decreased levels of NAA in normal-appearing GM and WM have also been described in patients with late-onset GM2 gangliosidoses (270). Fabry Disease Clinical Features Fabry disease is an X-linked recessive disorder due to a deficiency of the lysosomal enzyme βgalactosidase A, which results in the accumulation of glycosphingolipids in the vascular endothelium, smooth muscles, and neurons. It typically presents late in childhood but occasionally is not recognized until the third or fourth decade of life. Early manifestations include a punctate telangiectatic skin and mucous membrane lesion (angiokeratoma corporis diffusum), followed by fever, weight loss, and pain in the extremities and abdomen (271). Retinal, corneal, and conjunctival abnormalities are present early in the disease. Cardiac disease develops with age and is typically worsened by systemic hypertension secondary to renal vascular disease. Patients may eventually present with transient ischemic attacks or strokes secondary to small-vessel ischemia and focal infarcts. Patients are treated early with recombinant β-galactosidase A (enzyme replacement therapy) (271).

FIGURE 6.71 Tay–Sachs disease. A 1H magnetic resonance spectrum obtained using single-voxel spectroscopic techniques at 1.5 T from the right cerebellar hemisphere of a patient with Tay–Sachs disease. Cerebellar volume loss is evident on the reference images. The spectrum demonstrates a decrease in N-acetylaspartate and an increase in choline.

FIGURE 6.72 Fabry disease. Scattered focal areas of high signal intensity on T2-weighted images within the (A) brainstem; (B) basal ganglia, thalami, and (C) periventricular white matter. (Courtesy of Dr. Michael Sacher, New York.)

MRI Findings Early in the disease, small areas of high signal intensity are seen on long-TR sequences, most commonly in the basal ganglia (Fig. 6.72) and periventricular WM. The periventricular disease becomes more extensive and confluent with time with associated generalized cerebral volume loss. Cerebral hemorrhage has also been reported. Increased MD values (272) and decreased MT ratios (273), predominantly in the periventricular WM, are probably related to microangiopathic changes predominantly involving the long perforating arteries or reflect increased interstitial water contents in these regions. 1H MR spectroscopy showed 357

significantly lower NAA/Cr levels in patients with Fabry disease versus normal controls (273). Gaucher Disease Clinical Features Gaucher disease includes several autosomal recessive lipid storage diseases in which there is a deficiency of the lysosomal enzyme glucocerebroside. Several forms are recognized, with varying severity of the enzyme deficiency. The clinical presentation is that of splenomegaly, hepatomegaly, thrombocytopenia, lesions of the long bones, and variable neurologic signs (274,275). The adult form of Gaucher disease does not have neurologic manifestations. Neurologic symptoms include seizures, developmental regression, spasticity, mental deficiency, incoordination, and tics. The diagnosis is made by clinical criteria, by the presence of Gaucher cells in the bone marrow, and by finding reduced glucocerebroside β-glucosidase in the cultured skin, fibroblasts, or blood leukocytes. Enzyme replacement and substrate reduction therapy are the available therapeutic options (275). MRI Findings MRI and CT findings are similar to those of Fabry disease, with atrophy, infarction, and occasional hemorrhage (274) (Fig. 6.73). Mucopolysaccharidoses Clinical Features The mucopolysaccharidoses include a group of inherited metabolic disorders in which a lysosomal enzyme deficiency results in the inability to degrade the mucopolysaccharides (glycosaminoglycans) heparan sulfate, keratan sulfate, and/or dermatan sulfate (276). All of the mucopolysaccharidoses are inherited by an autosomal recessive transmission, except for Hunter disease, which is an X-linked recessive disorder (Table 6.17). A number of characteristic clinical features are shared by these disorders, including the typical gargoyle features, numerous skeletal abnormalities (dwarfism), cardiac anomalies, CNS abnormalities, and frequent involvement of the visual and auditory systems. Morquio disease and the far less common Scheie and Diferrante diseases are the only mucopolysaccharidoses in which the patients are not severely delayed in development or are mentally retarded (276). The diagnosis of mucopolysaccharidoses is made based on the clinical presentation, family history, and enzymatic assays of cultured skin fibroblasts or peripheral leukocytes. The skeletal features of these disorders are far more characteristic than the neuroradiology findings. Hematopoietic stem cell transplantation and enzyme replacement therapy are the available treatment options (276). MRI Findings The MRI findings include poor GM–WM differentiation with multiple patchy areas of high signal intensity on the T2-weighted images within the periventricular WM (277) (Fig. 6.74). Prominent cystic or dilated perivascular spaces may also be seen, which represent vacuolated cells distended with mucopolysaccharide (Fig. 6.74). Dilated perivascular spaces may be seen normally in children but have only been described in the corpus callosum in the mucopolysaccharidoses (278). As the disease progresses, the lesions become more widespread and extensive, reflecting the development of infarcts in demyelination. Ventricular enlargement is common and is likely due to a combination of communicating hydrocephalus and WM volume loss (Fig. 6.75). MRI has been used to follow the progression of patients with Hurler syndrome treated with bone marrow transplant. Thickening of the skull and meninges can be seen. Spinal cord compression is common, especially at the foramen magnum and upper cervical level, resulting from dural thickening secondary to mucopolysaccharide deposits (277). Spinal cord compression may also be seen in association with atlantoaxial subluxation or thoracic gibbus. Nerve root compression has also been described.

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FIGURE 6.73 Gaucher disease. A: T1-weighted sequence (800/20) demonstrates subacute blood in the centrum semiovale. B: T2-weighted sequence (2,000/80) shows widespread white matter lesions.

FIGURE 6.74 Mucopolysaccharidosis VI. A: Prominent cystic or dilated perivascular spaces are seen within the white matter on sagittal T1-weighted sequence that represent vacuolated cells distended with mucopolysaccharide (800/26) (arrows). B: Axial T2-weighted sequence shows multifocal areas of high signal in the white matter reflecting predilection of the disease for perivascular involvement.

FIGURE 6.75 Hurler disease. Hydrocephalus, white matter thinning, and periventricular hyperintensity (large arrows) on T2-weighted axial image (2,000/80) are characteristic of advanced mucopolysaccharidoses. Also, note the abnormally prominent iron deposition in the thalamic and basal ganglia (open arrows), which is a nonspecific reflection of cerebral pathology.

TABLE 6.17 Classification of the Mucopolysaccharidoses

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TABLE 6.18 Peroxisomal Disorders Affecting the Nervous System

Peroxisomal Disorders Peroxisomes are membrane-bound subcellular organelles involved in lipid metabolism. They are present in all cells but are more prevalent within oligodendrocytes specialized in lipid metabolism and myelin production and maintenance. Peroxisomal disorders comprise a family of disorders characterized by abnormal peroxisomal functions (Table 6.18). The genetic defects are found in the peroxisomes or in one of the enzymes normally located in the peroxisome and lead to abnormal accumulation of biochemicals (i.e., very long-chain fatty acids, pipecolic acid, and dicarboxylic acids) (279). Neuropathologic lesions in the peroxisomal disorders can be divided into three major classes: (1) defects in the formation and maintenance of WM, X-linked adrenoleukodystrophy is the prototype; (2) migrational disorders, Zellweger syndrome is the classic example; (3) postdevelopmental neuronal degenerations, such as cerebellar atrophy seen in rhizomelic chondrodysplasia punctata. Adrenoleukodystrophy/Adrenomyeloneuropathy Clinical Features Adrenoleukodystrophy is an X-linked recessive peroxisomal disorder involving the WM of the brain and spinal cord, and also the adrenal cortex. Biochemically, there is a defect in the gene ABCD1, which codes for a peroxisomal membrane protein (280), resulting in the abnormal accumulation of very longchain fatty acids that become incorporated into myelin. This leads to instability and dysmyelination, with a possible direct cytotoxic effect on the oligodendrocytes. There is often a family history of men on the mother’s side of the family having died of Addison disease or of an unknown neurologic illness, perhaps diagnosed as Schilder disease. The clinical presentation is quite variable (279). Greater than 360

50% of patients present with progressive childhood onset, approximately 25% have a late-onset presentation with adrenomyeloneuropathy, and 10% have isolated Addison disease. Development in the first few years of life is usually normal. Neurologic symptoms appear later in childhood, between the ages of 5 and 9 years, with behavior problems, decreasing mental function, and visual and hearing disorders, progressing to motor signs and ataxia. Symptoms of Addison disease commonly appear before neurologic symptoms, but may follow mental deterioration and occasionally even never present. The disease progresses to include seizures, spastic quadriplegia, and decorticate posturing, with death ensuing within the first few years of onset. Adrenomyeloneuropathy probably represents a phenotypic adult variant of adrenoleukodystrophy. Adrenomyeloneuropathy may occur in either sex, but males with the disease have symptoms of adrenal insufficiency. Typically, the disease has a slow progression, with survival into the eighth decade. Pathologic Findings Histologically, there are confluent areas of demyelination in a symmetric fashion, usually in the bilateral occipital regions, with extension across the splenium of the corpus callosum, and relative sparing of the subcortical arcuate fibers. The occipital, parietal, and temporal lobes are more severely affected than the frontal lobe. Cerebellar involvement is common and optic nerve demyelination can be seen. Three zones of demyelination are characteristically seen. The central portion of the lesion reveals absent myelin sheaths and oligodendroglia. Glial stranding and scattered astrocytes with no evidence of active disease are present. The next zone of involvement shows evidence of active inflammation, with many macrophages filled with lipid. Intact axons are identified both with and without myelin sheaths. The outer zone is characterized by active myelin breakdown with some lipid-laden macrophages but no inflammatory changes. Characteristic lipid lamellae, best demonstrated by electron microscopy, are seen in the brain, testis, adrenal gland, skin, conjunctiva, and Schwann cells (281). MRI Findings The CT and MRI appearance of adrenoleukodystrophy is somewhat specific, with symmetric areas of WM abnormality surrounding the atria of the lateral ventricles, extending across the splenium of the corpus callosum (Fig. 6.76). The parietal and occipital WM is most commonly involved; however, frontal predominance and holohemispheric patterns have been described (282). Contrast enhancement appears at the lateral margin of the zones of demyelination corresponding to areas of active demyelination accompanied by inflammation (Schaumberg’s zones 1 and 2) (Fig. 6.77). MRI of the brain in adrenomyeloneuropathy may be normal, with neurologic involvement confined to the spinal cord and peripheral nerves. In some patients with adrenomyeloneuropathy, MRI findings may be similar to adrenoleukodystrophy and the clinical progression may be as rapid (283). 1H proton MR spectroscopy typically shows a decrease in the NAA peak, increase in the choline peak, and occasionally increased lactate (284) and has a potential for prognostic role (285). 1H MR spectroscopy has also been used to characterize the brain metabolite changes following hematopoietic stem cell transplantation in children with adrenoleukodystrophy, with preliminary evidence showing complete reversal of spectroscopic abnormalities after transplantation in two cases (286). Preliminary data suggest that high baseline tNAA levels may predict a positive clinical outcome after hematopoietic stem cell transplantation, and a baseline increase of choline with decreased NAA predicts further clinical deterioration and progression of the disease after transplantation (287). Of interest, decreased NAA levels in the corticospinal tracts have been shown in women heterozygous for X-linked adrenoleukodystrophy, suggesting axonal dysfunction (288). DT MRI studies demonstrate increased MD and decreased FA within T2 hyperintensities and in normal-appearing WM, consistent with demyelination (289–291). Zellweger Syndrome Zellweger syndrome (ZS) is a peroxisomal disorder characterized by hepatomegaly, high levels of copper/iron, and visual symptoms (292). There is evidence of decreased myelination, with hypointense subependymal germinolytic cysts (typically involving the caudothalamic grooves) on MRI. Additional MRI findings include microgyria (predominantly in the frontal and perisylvian cortex), polymicrogyria, and pachygyria (particularly in the perirolandic and occipital regions). MRI might be also useful for the in utero diagnosis of this condition (293), showing abnormal cortical gyral patterns, abnormal myelin formation, and cerebral periventricular pseudocysts. 1H MR spectra show similar peak heights of the two lipid peaks (CH2, CH3), elevated choline levels, and low NAA. 361

FIGURE 6.76 X-linked adrenoleukodystrophy. Fluid-attenuated inversion recovery images. The characteristic high signal intensity is noted in (A) the splenium of the corpus callosum, posterior periatrial white matter, and (B) further inferiorly into brainstem. Note enhancement on coronal T1-weighted image (C).

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FIGURE 6.77 X-linked adrenoleukodystrophy. A1–A6: Serial T2-weighted images (3,000/90), inferior to superior. B1– B6: Serial contrast-enhanced T1-weighted images (600/20), inferior to superior. Note the extensive high-intensity abnormality on T2-weighted images (A) in bilateral parietal and occipital white matter through the corpus callosum, extending into lateral geniculate bodies and the pulvinar of the thalami down corticopontine tracts inferiorly into the pyramids of the medulla. Postcontrast images (B) show enhancement of leading edges of these areas, including occipital optic radiations into geniculate bodies and descending corticopontine tracts bilaterally.

There is a special subset of patients with peroxisome biogenesis disorders that are biochemically similar to but clinically different from ZS, exhibiting prolonged survival (294), with evidence of leukoencephalopathy and variable cortical atrophy on conventional MRI studies. 1H MR spectroscopy in these cases shows nonspecific reduction of NAA levels in cerebral WM. Mitochondrial Disorders A variety of mitochondrial clinical syndromes (Table 6.19) have been described in the literature; however, not all patients can be categorized into one of these well-described clinical syndromes, and yet such patients can demonstrate the typical imaging findings (295) (Figs. 6.78 and 6.79). Kearns–Sayre syndrome (KSS), MERRF (myoclonic epilepsy with ragged red fibers), and MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) are examples of mitochondrial encephalomyopathies in which the clinical picture is dominated by muscle and brain dysfunction. Although these three disorders have distinguishing features (Table 6.20), they share certain clinical signs and laboratory findings (295) (Table 6.21). Leigh disease and Alper disease (defects involving the respiratory chain) are also mitochondrial encephalomyopathies, which present earlier in infancy and have a poor prognosis. Imaging findings are frequently confined to regions that have high energy requirements (e.g., GM) (Fig. 6.80). TABLE 6.19 Major Mitochondrial Disorders

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FIGURE 6.78 Mitochondrial deletion syndrome. A,B: Axial T2-weighted images show symmetric bilateral high signal intensity within the basal ganglia with small cavitary areas, likely corresponding to spongiform degeneration described on pathology. C: Axial fluid-attenuated inversion recovery image with voxel placed over the left basal ganglia shows a similar abnormality. D: 1H magnetic resonance spectroscopy (1,600/136) shows the typical findings for mitochondrial disorders: a decrease in the N-acetylaspartate/creatine ratio with elevation of the choline peak (reflecting membrane turnover) and the presence of lactate (anaerobic glycolysis).

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FIGURE 6.79 Mitochondrial disease with progression. At 8 months of age (A,B), bilateral abnormal signal in the thalami, periaqueductal region, and supratentorial white matter is present. Subsequent images at 16 months of age (C,D) demonstrate clear progression of both midbrain and white matter involvement.

TABLE 6.20 Mitochondrial Disorders: Distinguishing Clinical Features and Magnetic Resonance Findings

Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Strokelike Episodes; Myoclonic Epilepsy with Ragged Red Fibers; and Kearns–Sayre Syndromes MELAS refers to the disorder constituted by myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Affected individuals are usually normal during the first years of life, followed by stunted growth, episodic vomiting, seizures, and recurrent strokelike episodes (hemiparesis, hemianopia, or 365

cortical blindness). MELAS is distinguished from MERRF and KSS by the strokelike events and episodic vomiting. MERRF usually presents with myoclonus, ataxia, weakness, and generalized seizures. In most cases the onset of symptoms is before age 20 years and is frequently familial. KSS is sporadic and characterized by onset before age 15 years, progressive external ophthalmoplegia, and pigmentary degeneration of the retina, plus one of the following: heart block, cerebellar syndrome, or high CSF protein (greater 100 mg/dL). MRI Findings MRI findings in MELAS typically present as multiple strokelike lesions primarily in the parietal and occipital cortex. The subcortical WM, basal ganglia, brainstem, and cerebellum may also be involved, not corresponding to major vascular territories, and is believed to reflect mitochondrial angiopathy (296). 1H MR spectroscopy typically demonstrates reduced NAA, glutamate, myo-inositol, and total creatine levels, with decreased NAA/choline ratio and pronounced lactate (Fig. 6.81) and glucose peaks, particularly at long TE, likely related to increased membrane turnover (297–299). Similar but less pronounced spectroscopic abnormalities can be seen in the GM (299). Abnormally decreased FA values have been described in abnormal brain areas and cervical spinal cord (298). TABLE 6.21 Mitochondrial Disorders: Common Features

The brain MRI findings in MERRF syndrome may include hyperintense signal abnormalities in the WM and deep GM, and CT may show calcification of the dentate nucleus and globus pallidus. MRI findings in KSS reflect the pathology of spongiform degeneration and include high signal intensity on the T2-weighted images in the WM, with a predilection for involvement of the peripheral U fibers and sparing of the periventricular WM. Symmetric high signal intensity on the T2-weighted images can be seen in the medial thalami and dorsal brainstem. Calcification seen on CT in the basal ganglia and thalami has been shown to correspond to high signal intensity on both the T1- and T2weighted images (Fig. 6.82). The cerebellar WM and dorsal brainstem may also demonstrate abnormal hyperintensity. Diffuse atrophy is commonly seen, including the cerebellum. Spectroscopic findings similar to those described with MELAS have been described in patients with KSS and, in lesser degree, MERRF, including increased lactate/creatine and decreased NAA/creatine ratios (300). Subacute Necrotizing Encephalomyopathy (Leigh Disease) Leigh disease is a progressive neurodegenerative disorder that usually presents in infancy or early childhood (301). Acute respiratory failure, poor feeding, visual and auditory problems, ataxia, weakness, hypotonia, and seizures characterize the clinical presentation. The pathologic hallmarks include focal, bilateral, and symmetric spongiform lesions (302) in the thalamus, pons (tegmentum), inferior olives, and the posterior columns of the spinal cord. Ultrastructural examination of the spongy lesions has shown numerous vacuoles formed by splitting of the myelin. Lesions in the brainstem are characteristic of the disease and are uncommon in the WM and cerebral cortex. On microscopic examination, demyelination, vascular proliferation, and astrocytosis are seen.

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FIGURE 6.80 Alper disease. Axial T1-weighted image (A) and axial T2-weighted image (B) in a 10-month-old with severe atrophy (no significant white matter signal abnormality) and bilateral subdural hematomas of varying ages. Patients with rapidly progressive atrophy can develop subdural hematomas without significant head trauma. Similar findings have been described in Menkes kinky hair syndrome.

FIGURE 6.81 MELAS. A 40-year-old man with history of epilepsy and hearing loss presenting with acute onset of aphasia and right-sided weakness. Axial FLAIR and diffusion-weighted images demonstrate areas of cytotoxic edema (“strokelike”) in the left temporal and parietal lobes. Prominent lactate peaks were noted in MR spectroscopy obtained near the signal abnormalities (C) and normal appearing contralateral parenchyma (D).

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FIGURE 6.82 Kearns–Sayre syndrome. Classic findings of high signal on T1-weighted image (A) in the caudate and putamen, necrosis of globus pallidus on T1- and T2-weighted images (A, B), and relative sparing of periventricular white matter. Note the tigroid appearance of white matter involvement in the centrum semiovale (C) and dorsal brainstem involvement (D).

MRI Findings Bilateral symmetric areas of high signal intensity on the T2-weighted images in various regions of the brain are characteristic on MRI, including the basal ganglia, thalamus, brainstem, cerebellum, cerebral WM, and the GM in the spinal cord (301) (Figs. 6.83 and 6.84). Marked progressive diffuse cerebral atrophy can also be seen. A recent MRI study in patients with Leigh disease correlated brainstem lesions with loss of respiratory control and found that lower brainstem lesions (particularly situated in the periaqueductal GM and the reticular formation of the medulla oblongata) were always present when patients had near-fatal respiratory failure (301). Upper brainstem signal abnormalities were often transient, and the associated respiratory difficulties resolved. DWI shows evidence of a restricted diffusion pattern (cytotoxic edema) in the basal ganglia and thalami (303). Abnormal lactate peak with a decrease in the NAA/Cr and an increase in the choline/Cr ratios are seen, predominantly in the basal ganglia and brainstem (304).

FIGURE 6.83 Leigh disease. Axial T2-weighted images (A–C) show inferior cerebellar peduncle abnormality (dorsal medulla) (A) and more superiorly medial thalamic and marked putaminal involvement (B, C).

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FIGURE 6.84 Leigh disease. Splenium (A) and genu (B) of corpus callosum are dramatically involved along with putamen (A) and cerebellar white matter (C).

Amino and Organic Acid Disorders Disorders of amino acid or organic acid metabolism are very rare and typically involve an inherited deficiency or altered function of an enzyme or transport system that mediates the disposition of a particular amino or organic acid (Figs. 6.85 to 6.87). The oxidation of amino acids gives rise to ammonia, which is neurotoxic in high concentrations. Because the urea cycle functions in the disposal of ammonia, congenital deficiencies of the urea cycle cause hyperammonemia or elevated plasma glutamine (formed from ammonia). The urea cycle defects include carbamyl phosphate synthetase deficiency, ornithine transcarbamylase deficiency citrullinemia, and argininosuccinic aciduria. The severity of presentation is determined by the particular amino or organic acid abnormality, the duration of the accumulation, and the presence of other metabolic alterations (e.g., hypoglycemia). Hyperammonemia induces brain swelling and Alzheimer type II changes in astrocytes, and chronic elevation leads to neuronal degeneration. Most of these disorders are transmitted by an autosomal recessive inheritance. Dysmyelination, neuronal degeneration, and reactive gliosis are common in patients who die in the first few days of life (i.e., maple syrup urine disease). Table 6.22 summarizes some of the clinical features and imaging findings in several of these disorders (see also Table 6.13). Leukodystrophies with Macrocrania Canavan Disease CLINICAL FEATURES. Canavan disease (Canavan–van Bogaert–Bertrand disease), or spongy degeneration of the brain, is an autosomal recessive disorder of amino acid metabolism found predominantly in children of Ashkenazi Jewish descent. It is due to deficiency of NAA acylase with excessive accumulation of NAA. Clinical signs and symptoms become manifest within the first few months of life, marked by hypotonia, head lag, increased head circumference (greater than 98th percentile), seizures, and failure to achieve motor milestones. Death typically ensues by age 4 years. Diagnosis can be made by quantitative study of acetylaspartic acid in urine and aspartoacylase level (accumulation of abnormally high level of nonfunctional enzyme) in cultured fibroblasts. The carrier state can be detected by abnormal level of aspartoacylase in fibroblast cultures. Aspartoacylase is not present in plasma or blood cells. 369

PATHOLOGIC FINDINGS. The brain may be heavier or of normal weight. The WM is soft and gelatinous but without cavitation. Salient histologic features include vacuolization of both GM and WM and proliferation of Alzheimer type II astrocytes. The distribution of spongiotic changes is most prominent in the deeper cortex and subcortical WM, with relative sparing of the deeper WM and internal capsule. As the disease progresses, a more diffuse pattern of demyelination develops. During the first 2 years of life, the ventricles are usually narrowed and gradually increase in size as a result of loss of tissue.

FIGURE 6.85 Maple syrup urine disease. Diffuse abnormal signal intensity with swelling of the brainstem (A–C) and involvement of portions of the basal ganglia, thalami, and posterior limbs of the internal capsules (C,D). Magnetic resonance spectroscopy. (E) shows lactate and increased branched-chain amino acids. (Courtesy of Dr. Jill Hunter, Philadelphia, PA.)

FIGURE 6.86 Ornithine transcarbamylase deficiency (urea cycle defect). Axial T2-weighted images show the chronic phase with diffuse severe atrophy (and a small right subdural hematoma). In the presence of an acute metabolic derangement, swelling of the cortex and underlying white matter may be seen.

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FIGURE 6.87 Propionic acidemia (disorder of organic acid metabolism). Axial T2-weighted images show the typical findings of increased signal intensity within the bilateral caudate and putamen. A delay in myelination may also be seen.

TABLE 6.22 Disorders of Amino Acid Metabolism

MRI FINDINGS. The signal abnormality in Canavan disease has a centripetal distribution beginning in the subcortical WM of the cerebrum and cerebellum. The subcortical WM may appear swollen, with broadening of the gyri. Typically, there is diffuse, symmetric increased signal intensity on the T2weighted images throughout the WM, with relative sparing of the internal and external capsules and corpus callosum (Figs. 6.88 and 6.89). The central WM becomes involved with disease progression. High signal intensity is always seen within the globus pallidus, with frequent involvement of the thalamus and relative sparing of the putamen and caudate nucleus. Cerebral and cerebellar atrophy is a late finding. The underlying pathology of excessive accumulation of NAA in the brain is readily demonstrated by 1H MR spectroscopy with a characteristic increase in the NAA peak (Fig. 6.88). There is also evidence of decreased choline/Cr ratio, elevated myo-inositol/Cr ratio, and occasionally a lactate peak (305). There is also evidence of restricted diffusion within the abnormal WM structures (with increased signal of DWI and decreased signal on the ADC maps), likely related to myelin edema or a “gelatinous-like” state of the extracellular space. Alexander Disease 371

CLINICAL FEATURES. Alexander disease, a rare disorder, occurs sporadically with no known pattern of inheritance (306). The three forms of the disease are infantile (the most common form), juvenile, and adult. The diagnosis is usually made within the first year of life when the infant presents with developmental delay, macrocephaly, spasticity, and seizures. Progressive deterioration of intellectual functioning and spasticity are followed by death in early childhood. The duration of the illness is usually about 3 years.

FIGURE 6.88 Canavan disease. T2-weighted images in a child with macrocephaly show (A,B) near-complete high signal intensity in supratentorial white matter, which appears swollen. Note the high signal within the globus pallidus (almost always involved) and sparing of the corpus striatum. Magnetic resonance spectroscopy. (C) shows the marked elevation of N-acetylaspartate (Courtesy of Dr. Jill Hunter, Philadelphia, PA.)

FIGURE 6.89 Canavan disease. Axial T1-weighted image (A) and T2-weighted image (B) show extensive abnormality with characteristic sparing of the posterior limbs of the internal capsules with normal high signal intensity present and cavitary areas within the subcortical white matter.

PATHOLOGIC FINDINGS. The brain is abnormally enlarged. The WM is jellylike and collapsed. Histologic examination reveals extensive demyelination and rarefaction of the WM. The salient feature of Alexander disease is substantial accumulation of Rosenthal fibers found in the perivascular spaces, subpial regions, and subependymal WM (306). The basal ganglia and cortex are usually relatively preserved. Cavitation is common, and there is no sparing of the subcortical U fibers. The cerebellum is less often affected than in other leukodystrophies. MRI FINDINGS. MRI findings classically demonstrate increased signal intensity on the T2-weighted images in the frontal WM (Fig. 6.90), with extension into the temporal and parietal WM and external capsules (307). The subcortical arcuate fibers may be involved, and the WM may appear swollen, as in Canavan disease. Signal abnormality may also involve the basal ganglia and brainstem. Cystic dilation of the cavum septum pellucidum has been described. The occipital WM and cerebellum are usually spared; however, involvement should not exclude the diagnosis. With disease progression, cavitation and atrophy of the WM may be seen. When there is diffuse WM signal abnormality and swelling in a patient with macrocephaly, the differential diagnosis is mainly between Canavan and Alexander diseases. 1H MR spectroscopy may show a lactate peak, decreased NAA, and elevated myo-inositol.

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FIGURE 6.90 Alexander disease. A 2-month-old infant with macrocephaly. A: Axial computed tomography demonstrates bilateral symmetric low density within the frontal white matter, genu of the corpus callosum, and basal ganglia. B,C: Axial T2-weighted MR images demonstrate relatively higher signal intensity in the frontal white matter than the occipital and parietal white matter. There is swelling of the white matter extending into the subcortical U fibers. The basal ganglia and bilateral thalami also show abnormal high signal intensity. Note the cystic distension of the cavum septum pellucidum described in this disorder. Brain biopsy was performed to confirm the diagnosis. (Courtesy of Dr. Jill Hunter, Philadelphia, PA.)

TABLE 6.23 Vacuolating Leukoencephalopathies

Vacuolating Leukoencephalopathies This is an increasingly recognized group of leukoencephalopathies characterized by the development of cystic changes in the cerebral WM, often very extensive. Several conditions are now included in this group (Table 6.23), the most common being vanishing white matter (VWM) disease. Vanishing White Matter Disease CLINICAL FEATURES. VWM disease, also referred as childhood ataxia with diffuse CNS 373

hypomyelination, is one of the most prevalent inherited pediatric WM disorders. This autosomal recessive condition shows a wide clinical phenotype, with mild later-onset forms to fatal infantile forms (such as Cree leukoencephalopathy), characterized by cerebellar ataxia and spasticity with relative preservation of higher cognitive functions, as well as ovarian failure, growth failure, cataracts, hepatosplenomegaly, pancreatitis, and kidney hyperplasia (308). Seizures and optic atrophy have also been described, typically following a progressive relapsing–remitting course resulting in death in the second decade of life (308). Diagnostic criteria have been published for this entity (309). Almost all patients meeting the MRI criteria for VWM disease have mutations in the eIF2B gene (encoding the eukaryotic initiation factor 2B) (308). The eIF2B protein complex has an important role in protein synthesis and the cellular response to stress (308). Pathologic Features Gross inspection of the brain parenchyma shows softening of the WM, with a gelatinous consistency and cystic changes, with particular involvement of the frontoparietal WM and relative sparing of the temporal lobes and arcuate fibers (308). Histologically, myelin loss, vacuolization, and cystic changes, with foamy oligodendrocytes as well as apoptotic loss of oligodendrocytes and abnormally shaped astrocytes without surrounding inflammatory changes are seen (308). There is axonal loss grossly proportional to the degree of cavitation, and the remaining myelin sheaths may show thinning and vacuolation. Residual blood vessels associated with reactive astrocytes are present within the “radiating stripes” noted on MRI (308). MRI Findings Symmetric and diffuse abnormalities are present, with abnormal areas of hyperintensity on T2/FLAIR images, almost isointense to CSF, and decreased T1 signal, with relative sparing of the temporal lobes and cortical GM (308) (Fig. 6.91). However, involvement of the thalamus, basal ganglia, and brainstem has been described. There is no abnormal enhancement after gadolinium administration. Cystic degeneration is noted in the majority of cases, with a radiating “stripelike” pattern, likely representing remaining parenchyma (308). The cerebellum may show abnormal WM signal, but typically no cystic changes are noted (308). There might be evidence of restricted diffusion within the WM abnormalities. 1H MR spectroscopy shows decreased levels of normal metabolites (choline, creatine, NAA), with appearance of lactate and α-glucose (around 3.8 ppm) peaks (308,310) within the WM abnormalities, with variable reports of cortical GM abnormalities (310). Sudanophilic Leukodystrophies Clinical Features The sudanophilic leukodystrophies include several poorly defined diseases that are categorized based on the histopathologic findings of accumulation of sudanophilic droplets containing cholesterol and triglycerides in the WM. Pelizaeus–Merzbacher disease and Cockayne syndrome are the two welldocumented sudanophilic leukodystrophies. The clinical presentation of all the sudanophilic leukodystrophies is that of neurologic dysfunction presenting early in childhood. In Pelizaeus– Merzbacher disease, symptoms are usually observed within the neonatal period; in Cockayne syndrome, children may be normal until late in infancy. Typically, abnormal eye movements are observed, and patients have head shaking, ataxia, and slow development. Progressive dysfunction evolves rapidly to spasticity and encephalopathy. Children with Pelizaeus–Merzbacher usually die in childhood, but those with Cockayne syndrome may live long enough to develop dwarfism.

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FIGURE 6.91 A 5-year-old girl presenting with vanishing white matter disease. Axial T2-weighted (2,370/80) images show extensive symmetric involvement of the cerebral white matter with signal intensity similar to the cerebrospinal fluid signal in the lateral ventricles. (Courtesy of Dr. E. Kolodny, NYU Medical Center, New York.)

Pelizaeus–Merzbacher disease is an X-linked disease affecting males; however, female patients are occasionally found. It results from alterations (missense mutations as well as X-chromosome translocation, partial duplication, and triplication) of the proteolipid protein (PLP) gene on Xq21.33–22 (311) that leads to abnormal PLP and DM20 proteins, the two most abundant proteins in the myelin sheath. The spectrum of clinical presentation varies from mild to severe. The most consistent features include spasticity, a lack of evidence of male-to-male transmission, and diffuse WM abnormalities on MRI. Pathologic Findings In Pelizaeus–Merzbacher disease, the brain is usually atrophic, particularly in the cerebellum and brainstem. Affected infants that die during the first year of life may have a normal brain weight. The WM appears gray and ranges from gelatinous to firm in consistency. Although the cortical ribbon is of normal thickness, the GM–WM junction is not well demarcated. Cerebellar cortical degeneration is found in most cases. Histologically, there is a profound lack of myelin. The residual myelin preferentially remains around blood vessels and demonstrates a tigroid pattern. There is astrocytosis and a lack of oligodendroglia. As in other types of myelin diseases, the axis cylinders tend to be preserved. There are rare macrophages that contain sudanophilic substances. Myelination in the peripheral nerves is not affected. Cockayne syndrome is also characterized by patchy preservation of myelin without sparing of the U fibers. There is also granular mineralization of the capillaries, capillary neural parenchyma, cerebral cortex, and basal ganglia. Patients with Cockayne syndrome may also have segmental demyelination in peripheral nerves. MRI Findings In most cases, MRI demonstrates a delay, arrested or no evidence of myelination (Fig. 6.92). Diffuse WM signal abnormality (low signal on T1-weighted and high signal on T2-weighted images) and atrophy are seen in the late phase of the disease (Fig. 6.93). The tigroid appearance seen histologically is only rarely demonstrated on MRI (Fig. 6.92). The appearance of Pelizaeus–Merzbacher disease and Cockayne syndrome is similar, in that the WM is diffusely abnormal (Fig. 6.94). However, in Cockayne syndrome calcification may be seen on CT in the basal ganglia and cerebellum. 1H MR spectroscopy in patients with Pelizaeus–Merzbacher disease demonstrates increased concentrations of NAA/NAAG (tNAA) (with high NAA/Cr ratio), glutamine, myo-inositol, creatine, and phosphocreatine, with decreased levels of choline-containing compounds (with low choline/creatine ratio), in abnormal WM and GM, compatible with increased neuroaxonal density, astroglial proliferation, and decreased oligodendroglia, suggesting dys- and hypomyelination (312).

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FIGURE 6.92 Pelizaeus–Merzbacher disease. A,B: Axial T2-weighted images in a 3-year-old demonstrate diffuse high signal intensity (little evidence of myelin) within the white matter, including the internal capsules, which should be myelinated at birth. Linear low-signal-intensity regions within the corona radiata characterize the tigroid pattern. Low signal intensity in the deep gray matter and thalami is presumably due to abnormal iron deposition. C: Sagittal T1weighted image demonstrates severe atrophy of the corpus callosum.

Chromosomal Disorders Chromosomal disorders typically are associated with delayed myelination or hypomyelination. The most common of these disorders associated with WM abnormalities is 18q-syndrome. 18q-Syndrome CLINICAL FEATURES. This increasingly recognized condition constitutes one of the most common chromosomal deletion syndromes; its clinical phenotype includes short stature, microcephaly, craniofacial dysmorphism (with midfacial hypoplasia, frontal bossing, carplike mouth), limb anomalies (clubfoot, syndactyly, short thumbs), genital hypoplasia, otic dysplastic changes, hypotonia, hearing loss, nystagmus, and mental retardation (313). The deletion described in this syndrome typically involves the distal portion of the long arm of chromosome 18, typically including the MBP gene. All of the patients with abnormal WM MRI findings have absence of one of the copies of the MBP gene (314). However, other deleted genes more proximal to the MBP locus may also have a role in the abnormal myelin formation seen in this disease. The dysmyelination observed in the 18q-syndrome is characterized by delayed onset of myelin formation (particularly in the frontal and occipital lobes), a slower progression rate, and equilibrium levels of myelin of less than 50% those of age-matched normal-developing children (315,316). Minimal fibrillary gliotic changes can be seen in the corpus callosum.

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FIGURE 6.93 Pelizaeus–Merzbacher disease. Young male patient presenting with chronically progressive altered cognition, ataxia, and nystagmus. Genetic testing confirmed PLP1 mutation. Brain MRI demonstrates ill-defined areas of hyperintensity compatible with hypomyelination in the brainstem, cerebellum (A), and supratentorial white matter (B, C) on T2 weighted images.

FIGURE 6.94 Cockayne disease. Diffuse high signal intensity is seen throughout the white matter on axial T2weighted image (2,000/80).

FIGURE 6.95 18q-syndrome. Axial T2-weighted image from a patient with an 18q-deletion demonstrating areas of delayed myelination at 62 months of age. (Lancaster JL, Cody JD, Andrews T, et al. Myelination in children with partial deletions of chromosome 18q. Am J Neuroradiol 2005;26(3):447–454, © by American Society of Neuroradiology.)

MRI FINDINGS. The conventional MRI findings include subcortical WM involvement with poor GM– WM differentiation (317) or abnormal T2 hyperintensity with variable involvement of the brainstem and cerebellum, sparing the corpus callosum (Fig. 6.95). There is also evidence of abnormal T2 hyperintensity in the deep GM, probably related to abnormal iron deposition, as well as ventriculomegaly with volume loss (318). 1H MR spectroscopy findings include elevated choline and αglutamate concentrations, with normalization of the glutamate level paralleling clinical improvement, and suggested that active demyelination might play an important role in the pathogenesis of this condition (319). 377

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7 Epilepsy William B. Zucconi, Vivek Gupta, and Richard A. Bronen

Recent advances in molecular biology, genomics, and neuroimaging have led to significant improvements in the understanding, evaluation, and management of epilepsy and seizure disorders. A seizure, or epileptic seizure, is the clinical manifestation of abnormal, excessive synchronous neuronal electrical activity. The pathophysiologic basis of a seizure is the loss of normal regulation of neuronal excitation and inhibition, resulting in a state of relative hyperexcitability. The word Epilepsy stems from “epilambanem,” the Greek verb meaning “to take hold of or to seize.” Epilepsy, as recently defined by Fisher et al. (1) is “a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiologic, cognitive, psychological and social consequences of the condition”. This is often a chronic condition characterized by recurrent seizures which are unprovoked by an acute systemic or neurologic insult; the term epilepsy itself does not indicate a specific underlying pathology. Although the treatment of an isolated seizure is directed toward the immediate underlying metabolic or neurologic derangement, epilepsy usually requires long-term pharmacotherapy or, in selected cases, neurosurgical intervention to eliminate or reduce recurrent seizures and to prevent progressive neurological and social sequelae. Neurosurgery is most often considered in medically refractory epilepsy when removal or isolation of the epileptogenic region is possible without an unacceptable neurologic deficit. A variety of brain lesions causing epilepsy are amenable to surgical treatment. The clinical presentation of epileptic seizures is varied, and it is necessary to categorize them according to established classification schemes so that appropriate diagnostic workup, therapy, and prognoses can be assigned. The principal basis of current seizure classification is the distinction between focal seizures (formerly called partial seizures), and generalized seizures. A focal seizure originates in one brain area or network that is limited to its hemisphere. A generalized seizure is understood as beginning in one brain area and rapidly spreading through bilaterally distributed brain networks. Importantly, generalized seizures may still arise from a focal lesion that is amenable to surgical treatment. The most widely used classification of epileptic seizures is that put forth by the International League Against Epilepsy (ILAE) (Table 7.1, abbreviated). It was revised in 2010 and remains principally based on the clinical seizure type and interictal electroencephalography (EEG) findings (2). Notable changes from the prior scheme include replacing the term “partial” with “focal.” In addition, the terms “simple partial, complex partial, and secondarily generalized” were discarded in favor of the more straightforward descriptors: “seizure without impairment of consciousness,” “with impairment of consciousness or awareness, or dyscognitive,” and “evolving to a bilateral convulsive seizure,” respectively. Table 7.2 lists additional useful and well-established descriptors applied to focal seizures (3). There is an ongoing effort underway by the ILAE to allow greater flexibility and transparency in naming seizure types with a proposed 2016 “Operational Classification”, yet to be finalized at the time of this writing. TABLE 7.1 International League Against Epilepsy Classification of Epileptic Seizures (2010)

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The ILAE classification of epilepsy syndromes (Table 7.3) is organized by factors such as the age of onset and seizure type, by “distinctive constellations” (including mesial temporal lobe epilepsy [TLE] with hippocampal sclerosis), and those epilepsy syndromes caused by structural–metabolic pathology (including malformations of cortical development [MCDs], tumors, etc.). This classification was similarly updated in 2010 to improve precision through descriptive nomenclature, adding several electroclinical syndromes which are impractical to list here (2). This categorization is essential for grouping patients with relatively predictable prognoses and indicating specific therapy, including the choice of antiepileptic drugs (AEDs). It also forms the basis of additional workup, including neuroimaging as well as treatment trials. For epilepsies associated with structural–metabolic conditions, the current scheme suggests that less emphasis be placed on seizure location than the underlying structural or metabolic cause. TABLE 7.2 Terms Describing Focal Seizure Semiology

TABLE 7.3 International League Against Epilepsy Classification of Epilepsy Syndromes (2010, Abbreviated)

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The distinction between focal and generalized seizures has important implications, whereas the generalized seizures are usually well controlled on antiepileptic pharmacotherapy, 15% to 30% of patients with focal seizures continue to experience seizures (4,5). Surgical control of seizure activity in such patients with intractable epilepsy is an important consideration because psychosocial, medical, and financial implications are significant. Neuropathology series in patients undergoing surgical treatment of focal epilepsy show that hippocampal sclerosis (HS) is consistently one of the most common pathologic substrates (40% to 73%). MCDs (or cortical dysplasias—particularly the focal cortical dysplasias [FCDs] subtypes) are increasingly recognized in specimens in up to 45% of cases, at least in part due to improved neuropathologic analyses and more uniform adoption of MCD and FCD classification schemes. HS is commonly associated with other lesions, and is more commonly found in adult series, while MCDs, overall, are more common in pediatric populations (6–8). In one series of 243 patients with TLE, dual pathology was very common: HS was concurrently identified in 70% of MCD cases and 8% of tumors, and only in isolation in 14% of cases (6). Other common etiologies and approximate percentages include perinatal hypoxia or other insult (13% to 35%), tumors (15%), vascular malformations (3%), and traumatic gliosis (2%) (9). Table 7.4 categorizes the causes of epilepsy by the usual age of seizure onset. Even beyond the tremendous improvement in diagnosis and management of patients with epilepsy, magnetic resonance (MR) has had a great impact on the understanding of epilepsy syndromes by shifting emphasis purely from clinical and electrophysiologic diagnosis to structural abnormalities in brain responsible for the electrophysiologic and clinical features. TABLE 7.4 Cause of Epilepsy Categorized by the Age at Seizure Onset

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Neuroimaging, in the form of computed tomography (CT) and MR, has become part of the standard evaluation of unexplained seizures in children and adults. CT is an appropriate choice in emergency setting for evaluation of new-onset seizure patients with symptomatic causes (i.e., focal deficits, persistent altered mental status, fever, trauma, persistent headaches, history of cancer, anticoagulation, ventriculoperitoneal shunts, or acquired immunodeficiency syndrome), and in the elderly, in whom acute stroke and tumors are the most likely. CT, however, has little or no role in preoperative evaluation of patients with intractable epilepsy. In a recent meta-analysis, emergent use of CT has been found to alter acute management in 3% to 9% of children and infants and up to 17% of adults. It was also found that up to 50% of infants less than 6 months old had clinically relevant CT abnormalities in the emergency setting (10,11). However, for a child with a first-time simple febrile seizure, the American Academy of Pediatrics recommends that neuroimaging should not be performed (12). In children with new-onset seizures who have no detectable symptomatic cause, MR imaging (MRI) is the neuroimaging study of choice (13,14). MR is two to three times more sensitive for detecting imaging abnormalities in patients with seizures as well as patients with intractable epilepsy (13,15). TABLE 7.5 Investigative Modalities in Epilepsy Workup

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MR has emerged as the most valuable tool for preoperative localization of the epileptogenic focus because of its excellent soft-tissue contrast, allowing for detailed depiction of anatomy, freedom from beam-hardening artifact in the basal brain that occurs with CT, and capacity for multiplanar and isovolumetric or three-dimensional (3D) imaging (13,14,16). MRI also provides the capability of functional imaging, white matter tractography, and spectroscopy. Other modalities for preoperative evaluation of surgical candidates with intractable epilepsy include single-photon emission computed tomography (SPECT), positron emission tomography (PET), magnetoencephalography, neuropsychological assessment, and lateralization of language and memory functions by intracarotid amytal procedure (IAP or Wada test). Because MR is currently the best structural neuroimaging modality, it has a unique role in management of epilepsy and epilepsy surgery. Table 7.5 summarizes the role of various investigative modalities in epilepsy workup.

MRI IN EPILEPSY AND EPILEPSY SURGERY Despite continued development of AEDs, uncontrolled seizures or undesirable side effects persist for 20% to 30% or more of the population with focal epilepsy. As such, it remains crucially important to identify structural lesions in these patients as many will be considered as candidates for surgery. The choice of surgery depends on seizure type and anatomic substrate, among other factors (Table 7.6). For surgical resection or disconnection to be offered, the seizure must be focal in origin, and accurate preoperative localization of the epileptogenic focus must be available. Localization of the epileptogenic focus is, therefore, the major task in preoperative evaluation of surgical candidates. In the past, EEG was essentially the only method of localizing the seizure focus. Accuracy of the conventional scalp EEG is limited, and alone it is neither sensitive nor specific enough for preoperative evaluation. Intracranial EEG is an expensive invasive procedure with potential risks and, therefore, cannot be universally employed in epilepsy patients. Moreover, it invariably requires some preliminary localization data to guide the electrode placement. Intracranial EEG is, therefore, usually reserved to confirm the epileptogenicity of indeterminate or widespread structural lesion(s) seen on MRI, validate the results of alternative methods of functional localization such as SPECT, PET, and magnetoencephalography in MRnegative epilepsy, or pinpoint eloquent brain tissue prior to resection. With regard to refractory focal seizures, anterior temporal lobectomy and selective amgdalohippocampectomy are the most commonly performed neurosurgical procedures. The surgical resection can only be performed unilaterally because of unacceptable neurologic consequences of bilateral temporal lobectomy. Therefore, preoperative localization and assessment of laterality of seizure focus must be carried out. The algorithm for 392

localization of seizure focus and assessment of resectability varies according to institutional practice and resources (Fig. 7.1 and Table 7.7). The general goals of neuroimaging in presurgical evaluation of epilepsy patients include (i) delineation of structural and, if possible, functional abnormality in the putative epileptogenic region, (ii) categorization into a specific epilepsy substrate, (iii) detection of additional abnormalities, and (iv) mapping of sensorimotor, language, and memory functions in the epileptogenic and adjacent regions of the brain. Although strategies for surgical treatment usually begin with identification of a structural abnormality, determining the epileptogenicity of the structural abnormality by electrophysiology is crucial for successful outcome. Over the last decades, it has become clear (from EEG, PET, MR connectivity, and other data) that epilepsy is a network disorder, affecting different well-defined networks within brain tissue. Effective anti-epileptic therapies must, therefore, address disruption or resection of the epileptogenic network. By itself, MRI cannot determine the epileptogenicity of a lesion or the importance of a structural lesion in an epileptogenic network (i.e., are there several epileptogenic regions functioning as part of an epileptogenic network?). Patients with circumscribed epileptogenic lesions with convergent findings from analysis of semiology, MRI, scalp video-EEG, and neuropsychology undergo surgery without invasive recording. The standard initial strategy is to combine scalp EEG and MR, in addition to clinical semiology, and if the results are concordant, no further tests are usually necessary. In cases of discordant EEG and MR findings or when the epileptogenicity of the MR-identified lesion is indeterminate, intracranial EEG recordings using subdural or parenchymal depth electrodes are warranted. Invasive electrophysiologic studies may also be indicated in cases with more than one MR abnormality, when MR shows a large atrophic region, widespread noncircumscribed lesions or developmental abnormality, in cases of possible bitemporal epilepsy and when functional mapping of brain is warranted based on MR findings or other reasons. A minority of surgical candidates require such invasive evaluation with implantation of subdural electrodes. TABLE 7.6 Procedures in Epilepsy Surgery

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FIGURE 7.1 Surgical paradigm for intractable epilepsy. CC, corpus callosotomy; EEG, electroencephalogram; fMRI, functional MRI; IAP, intracarotid amytal procedure; MRI, magnetic resonance imaging; MST, multiple subpial transections (to treat epileptogenic functional tissue); PET, positron emission tomography; Stim, responsive neurostimulation or vagal nerve stimulation; SPECT, single-photon emission computed tomography.

TABLE 7.7 Recommended Magnetic Resonance Seizure Protocol Based on Age at Presentation

The sensitivity for detecting epileptogenic lesions varies with the clinical profile of patients evaluated. The positivity of MR is significantly lower in new-onset seizures than in intractable epilepsy. In the setting of new-onset seizures, epileptogenic abnormalities on MRI were found in 13% to 32% of patients, nearly all of whom suffered from focal seizures (15,17). In a more restricted group of subjects composed of adults with newly diagnosed focal seizures, MR abnormalities were found in 24% (10% HS and 14% other abnormalities), a higher percentage than in populations composed of all new-onset394

seizure patients (18). As such, it is generally accepted that MR aids diagnosis and should be performed in all patients with new-onset seizures with the possible exception of simple febrile seizures, idiopathic generalized epilepsy, and benign partial epilepsy of childhood. In the intractable epilepsy group, patient characteristics such as age at onset and underlying brain abnormalities also influence the sensitivity of MR. An overall sensitivity of 82% to 86% has been reported for MRI of intractable epilepsy (13,19). For TLE (focal seizures), an MR sensitivity greater than 75% for HS and greater than 90% for other focal lesions, including tumors, has been reported based on histopathologic findings as the gold standard (20–22). The sensitivity of MR for detecting epileptogenic abnormalities in children undergoing epilepsy surgery has been found to be 75% or higher (23). Coregistration of MRI with other functional imaging modalities, including PET and SPECT, has also proven valuable in localization of structural and functional alteration. Ictal SPECT, especially when quantitatively compared to interictal SPECT, has also become a valuable method for accurate localization of the epileptogenic focus. By early intraictal intravenous injection of a perfusion-dependent radiotracer, it is possible to detect local increases in cerebral blood flow caused by neuronal hyperactivity during the actual seizure. Focal blood-flow increase reflects seizure activity, either from cerebral cortex at the seizure-onset zone or from seizure spread to other areas. The accuracy of subtraction ictal SPECT coregistered to MRI (SISCOM) in the localization of the seizure focus has been assessed by several studies, comparing it with either invasive ictal EEG, site of surgery, or combined modalities (24). SISCOM can be valuable in guiding intracranial electrode placement. This application is very useful in patients with cortical dysplasia, when the onset is focally localized in the larger anatomic lesion or when the seizure-onset zone extends beyond the visible lesion on MRI, and in situations such as nonlesional epilepsy, when data from conventional methods do not provide enough localizing information to guide the electrode implantation. SISCOM findings can also result in re-evaluation of MRI in cases in which the MRI is initially considered normal (25). MRI, when reinterpreted in light of SISCOM data, may detect subtle abnormalities in nonlesional epilepsy. SISCOM localization, however, can be confounded by spreading patterns; a late injection could detect neuronal activity as a consequence of seizure spread and miss the epileptogenic region. The role of MR in epilepsy surgery (Table 7.7), in addition to its principal value in identifying the epileptogenic focus, also lies in its ability to depict topographic relationships between the epileptogenic lesion and the eloquent regions of brain. Precise anatomic localization of PET and SPECT abnormalities by coregistration with MRI is key in assessing the appropriateness and type of surgery, as well as in minimizing postoperative neurologic deficits. It is critical, however, to correlate the static anatomic abnormalities on MR with clinical and electrophysiologic data to avoid false-positive localization (Fig. 7.1) (26). As noted earlier, concordance of noninvasive tests including scalp EEG with MR findings may obviate the need for invasive monitoring. MR thus influences the need for invasive EEG and is also useful in planning the placement of subdural and parenchymal depth electrodes. Localization of intracranial electrodes by MR can be safely performed to verify the precise anatomic distribution of contacts and helps in the accurate determination of the extent of surgical resection (27). Postoperative MR may detect reasons for failure such as inadequate resection and can monitor tumor recurrence on follow-up imaging. MR is especially useful for prognosticating postoperative seizure control. Most patients undergoing MRI in surgical series are affected by focal or localization-related epilepsy. The convergence of anatomic MR abnormality and epileptogenic pathology in focal epilepsies has led to the development of the “substrate” concept of classification of focal epilepsies. Pathologic substrates for localization-related epilepsy can be categorized by characteristics such as developmental or acquired origin, histopathology, mechanism of epileptogenesis, and surgical outcome. The likelihood of postoperative seizure freedom is higher if an epilepsy substrate had been identified on MRI during the presurgical workup. A successful outcome after anterior temporal lobectomy is achieved in 70% to 95% patients with MR findings of HS, compared with 40% to 55% of patients in whom the MR is normal (14,22,28–30). Berkovic et al. (30) found the postoperative seizure-free state to depend on identification of a substrate by MR and the nature of MR abnormality—a seizure-free state in 80% with focal lesions other than HS, 62% in patients with HS, and only 36% with normal MR. In a study of 210 patients rendered seizure free after epilepsy surgery, those with normal preoperative MR had a higher rate of postoperative seizure recurrence after discontinuation of antiepileptic medication (31).

MAGNETIC RESONANCE IMAGING OF EPILEPSY SUBSTRATES The patients’ age at presentation influences the likelihood of presence of a particular epilepsy substrate 395

(Table 7.4), clinical MR acquisition protocols must be accordingly optimized to maximize the diagnostic yield (Table 7.7). Surgical and pathologic data indicate that approximately four-fifths of patients undergoing epilepsy surgery have a definable substrate on MRI (20). The accuracy of MR in determining the substrate category in intractable epilepsy has been reported to be 88% (13). Mesial Temporal Anatomy and Hippocampal Sclerosis Mesial temporal or HS is a highly epileptogenic abnormality strongly associated with focal temporal lobe seizures and has been the most common pathologic substrate encountered in patients undergoing surgery. These patients often have a history of complicated childhood febrile seizures or febrile status epilepticus, and onset of recurrent medically intractable seizures during the first decades of life. However, MR evidence of HS has also been found in medically controlled patients with complex partial epilepsy. HS is defined histologically by pyramidal and granule cell neuronal loss that occurs in the cornu ammonis and dentate sections of the hippocampus (Fig. 7.2). The ILAE has classified HS into three types based on the predominant location of severe neuronal loss and gliosis: CA1 and CA4 regions for type 1, CA1 for type 2, and CA4 for type 3; no-HS type for reaction gliosis without neuronal loss. Hippocampal reorganization and changes in energy metabolism are also associated with HS and may be the result of a brain insult occurring during brain maturation (32). Findings of reorganization include abnormal axonal sprouting and loss of interneurons, which is thought to change the balance of neuronal excitation and inhibition. The surgical treatment of HS is anterior temporal lobectomy, which, as noted earlier, has been the most rewarding and most commonly performed procedure in epilepsy surgery. Consequently, a great volume of data has been published on imaging, preoperative evaluation, and surgical outcome of HS.

FIGURE 7.2 Hippocampal histology. A: The black rectangle in this diagram of a coronal section through the temporal lobe shows the region of interest in panels B and C. Coronal histologic sections of the hippocampus using Nissl stain (original magnification, 16× to 18×) demonstrate normal histology (B) and hippocampal sclerosis (C). Note the loss of the pyramidal cells in CA1 and CA4 regions of the hippocampus (black dots) in the specimen with hippocampal sclerosis. CA, cornu ammonis; D, dentate gyrus. (Modified from Bronen RA, Cheung G, Charles JT, et al. Imaging findings in hippocampal sclerosis: correlation with pathology. AJNR Am J Neuroradiol 1991;12:933–940, with permission.)

Understanding of the anatomy of the medial temporal lobe, namely the hippocampal formation and limbic system, is an important prerequisite for recognition and accurate interpretation of MR findings in HS (33–36). The anatomic terminology used by Duvernoy has become widely accepted and is utilized here (Table 7.8) (34,37). The limbic system can be thought of as four concentric arches. From the 396

outermost inward, they are (1) the limbic lobe (i.e., parahippocampal, cingulate, and supracallosal areas), (2) a cerebrospinal fluid (CSF) space (i.e., callosal and hippocampal sulci), (3) Broca’s intralimbic gyrus (consisting mostly of the hippocampus), and (4) the fornix, which includes the fimbria (Table 7.8, Fig. 7.3) (33,34,37). Limbic structures, particularly the hippocampus and parahippocampus gyrus, are important sites for epilepsy development and propagation. This is due in part to the widespread connections between portions of the limbic arches and with extralimbic brain structures. The hippocampus itself, is a 4- to 4.5-cm–long curved structure on the medial aspect of temporal lobe forming a curved elevation in the floor of the temporal horn of lateral ventricle. It is divided into three segments based on morphology and relationship to the midbrain. The hippocampal head, or pes hippocampus, lies anterior to the brainstem, is expansile in shape and has three to four characteristic digitations on its superior surface. The cylindrically shaped body extends posteriorly around the midbrain, and the terminal portion—the tail of hippocampus—rapidly narrows behind the brainstem. Internally, the hippocampus consists of two interlocking U-shaped layers: the dentate gyrus and cornu ammonis (Figs. 7.2 and 7.4). The cornu ammonis can be further segmented into four portions, CA1 through CA4. CA4 is normally completely enveloped by the dentate gyrus and is also known as the endfolium. On the other, inferolateral end, cornu ammonis blends into the subiculum inferiorly which forms the transition to the neocortex of parahippocampal gyrus below. Along the superior surface of the hippocampus, its primary efferent fibers called alveus pass medially, just beneath the ependymal lining of the ventricular floor. They converge to form the fimbria and continue as the fornix. The amygdala is a gray matter structure located superomedial to the tip of the temporal horn of lateral ventricle (also known as the uncal recess), which separates it from hippocampal head (Fig. 7.5). When there is paucity of CSF in the uncal recess, the alveus may help delineate these structures. TABLE 7.8 Limbic System

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FIGURE 7.3 Hippocampal and limbic anatomy. A,B: Gross anatomy. The limbic system is composed of a series of arches: the limbic lobe (purple), the callosal and hippocampal sulci (black), the intralimbic gyrus (pink), and the fornix (green). The limbic lobe is composed of the uncus (U), parahippocampal gyrus (PHG), isthmus of the cingulate gyrus (I), cingulate gyrus, and subcallosal area (SCA). Broca intralimbic gyrus is composed primarily of the hippocampus (hippocampal formation or HF) and the vestigial supracallosal and paraterminal gyri. The hippocampus is located on the medial aspect of the temporal lobe situated above the PHG and posterior to the amygdala (Am). The hippocampus is composed of the bulbous digitated hippocampal head (H), body (B), and tail (T). The hippocampus connects with the mammillary body (mb) and in turn the thalamus via the fornix (F) and fimbria (F). The widespread

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connections to the brain by the hippocampus and limbic lobe explain the prominent role of the medial temporal lobe with seizure propagation. A, anterior commissure; LOTG, lateral occipital temporal gyrus; TH, temporal horn; TP, temporal pole. (From Bronen RA, Cheung G. Relationship of hippocampal and amygdala to coronal MRI landmarks. Magn Reson Imaging 1991;9:449–457, with permission.)

FIGURE 7.4 Coronal diagram of the medial left temporal lobe. The hippocampus is composed of two U-shaped lamina of gray matter, the cornu ammonis (C) and the dentate gyrus (D). The stratum radiatum, lacunosum, and moleculare make up the white matter (asterisks) between the cornu ammonis and dentate gyrus. White matter tracks extend from the cornu ammonis to form the alveus (arrowheads), which converge medially to form the fimbria (F). Laterally, the hippocampus is surrounded by the temporal horn (TH), which also extends superiorly. More superior medially is the choroidal fissure (ChF). Medially, the ambient cistern (AC) and the brainstem (BS) are located. Inferiorly, the subiculum (S), parahippocampal gyrus (PHG) and subcortical white matter are found, as well as the collateral sulcus (CS). The fusiform gyrus (FG), which is also known as the lateral occipital temporal gyrus, and the inferior temporal gyrus (ITG) are found along the basal portion of the temporal lobe. (From Bronen RA. Epilepsy: the role of MR imaging. AJR Am J Roentgenol 1992;159:1165–1174, with permission.)

The MRI of amygdala and hippocampus is best performed in a slightly oblique coronal plane, perpendicular to the long axis of hippocampus (Figs. 7.5 and 7.6). For volumetric assessment of the hippocampus and amygdala, the criteria used most often for defining anatomic boundaries are those described by Watson et al. (35), with the posterior hippocampal boundary extending to the crus of the fornix. For the particular volumetric technique used at a center, nomograms of hippocampal volume may need to be established using data derived from normal subjects, normalizing for variables including head size, age, sex, and hemispheric side. Both amygdala and hippocampus are isointense to gray matter on all MR pulse sequences. The hippocampus, however, may be slightly hyperintense to gray matter on fluid-attenuated inversion recovery (FLAIR) images due to incomplete suppression of CSF (7-6B), but may provide better T2-weighted signal detection. Conventional or fast spin-echo T2-weighted acquisitions are also sensitive for assessing hippocampal signal changes and for detecting focal abnormalities in rest of the brain. Coronal, T1-weighted, 3D volume gradient echo is optimal for quantitative volumetry (7-6A), whereas high-resolution fast spin-echo and inversion recovery sequences are important for depiction of hippocampal architecture (Figs. 7.5 and 7.6), which includes an internal, curved T2-hypointense band representing the stratum lacunosum (38). Enhancement with intravenous gadolinium has been shown to be of no value in imaging HS. The principal MR abnormalities in HS are hyperintense signal on T2-weighted images and hippocampal atrophy (Figs. 7.7 and 7.8) (20,22,39–41). These findings occur in an overwhelming majority of patients with surgically proven HS. Loss of the hippocampal internal architecture is another frequent feature, and is especially well seen on inversion recovery sequences. Evidence suggests that very high-field MR is highly sensitive and specific for such findings (42) (Fig. 7.9). Other MR findings associated with HS include ipsilateral loss of hippocampal head digitations, dilation of temporal horn of lateral ventricle (Figs. 7.7, 7.8, and 7.10), and atrophy of the white matter in parahippocampal gyrus between the hippocampus and collateral sulcus. Increased T2 signal in the anterior temporal lobe white matter and atrophy of fornix and mammillary bodies (Fig. 7.8) from degeneration of hippocampal tracts can also be seen (43–45). The MR spectroscopy (MRS) findings of hippocampal sclerosis are described later in the chapter.

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FIGURE 7.5 Normal magnetic resonance anatomy. Routine 3 T Coronal T2 FSE, anterior to posterior sections. The anatomy is labeled on the right to allow clear visualization of the left hippocampus for comparison. A: The amygdala (A) is a gray matter structure situated anterior and superior to the hippocampal head (H) and separated from the hippocampus by the uncal recess (U, arrow) of the temporal horn and the alveus. Note the undulations of the hippocampal head digitations (asterisks). B: Coronal section through the level of hippocampal body. The rectangle indicates the area of detail in C. C: Magnified image of right hippocampal body. The alveus (white arrow, Alv) and fimbria (Fim) are positioned along the superior margin of the hippocampus, inferior to choroidal fissure (Ch F). The temporal horn of the lateral ventricle (TH) is lateral. The internal structure of the hippocampus is represented by a consistently seen hypointense band, at least partially reflecting the stratum lacunosum (SL). D: The hippocampal tail (H) is the narrowest portion of the hippocampus as it extends behind the brainstem. The fimbria becomes the crus of the fornix (FC) at this point.

FIGURE 7.6 Normal T1 and FLAIR appearances of the hippocampal body at 3 T. A: Coronal reformat of routine 3D T1 gradient pulse sequence shows the hippocampus as isointense to gray matter. B: Coronal FLAIR shows the hippocampus is slightly hyperintense to gray matter on FLAIR sequences. One must be careful not to overinterpret hippocampal signal changes on FLAIR images. As in this case, normal internal structure can be seen on FLAIR imaging.

FIGURE 7.7 Diagram of hippocampal sclerosis. This representation of a T1-weighted coronal image shows the typical hippocampal atrophy on the right side (open arrow) along with mild hypointensity and loss of the internal architecture as defined by stratum radiatum. Other findings include temporal horn dilation (black arrowheads), collateral white matter (CWM) atrophy, parahippocampal atrophy, temporal lobe atrophy, and atrophy of the fornix and mammillary body (mb) on the ipsilateral side. CS, collateral sulcus. (From Bronen RA. MR imaging of mesial temporal

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sclerosis: how much is enough? AJNR Am J Neuroradiol 1998;19:15–17, with permission.)

FIGURE 7.8 Right hippocampal sclerosis (pathologically proven). Coronal T2-weighted FSE images, anterior to posterior. A,B: The right hippocampal head is hyperintense and atrophic (arrowhead), having lost the digitations along its superior surface in A (compare to left hippocampal head). There is ipsilateral mammillary body atrophy (MB, B). C,D: The posterior body and tail of the hippocampus remain small and hyperintense, with loss of internal architecture (arrowheads). Also, in D, the body of the right fornix is atrophic.

FIGURE 7.9 Unilateral hippocampal sclerosis, 7-T imaging (courtesy of M. Zeineh, Stanford, CA). Sagittal thinsection T2 images demonstrate normal morphology and internal architecture of right hippocampus. Note the loss of internal architecture and focal atrophy in left hippocampus (arrows).

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FIGURE 7.10 Dual pathology. Coronal T1-weighted (A) and T2-weighted (B) images demonstrate a small hyperintense hippocampus (arrow) on the right side consistent with hippocampal sclerosis. On a more anterior T1weighted image (C), bilateral subependymal heterotopic gray matter (arrows) is also seen.

Quantitative evaluation of hippocampal volume has been found to increase the sensitivity over visual analysis in the detection of HS (46,47). Quantitative methods may be of value both in large epilepsy surgery centers and centers with limited observer experience. Hippocampal volumetry can be useful in diagnosis of bilateral hippocampal atrophy without visually appreciable signal changes (Figs. 7.11 and 7.12). Bilateral hippocampal atrophy occurs in about 10% to 20% of cases and is frequently associated with developmental anomalies of temporal lobe (48). T2 relaxometry and FLAIR techniques are also useful in detecting associated abnormalities of amygdala not seen on routine MR. Detection of associated involvement of amygdala is important because seizure-free surgical outcome is better in isolated hippocampal atrophy (49).

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FIGURE 7.11 Bilateral hippocampal sclerosis after prolonged seizures. A: Coronal T2-weighted image shows bilateral hyperintensity within normal-sized hippocampi. This study was done shortly after prolonged seizures. B: Coronal T1-weighted image taken several years after the image in panel A demonstrates subtle bilateral hippocampal atrophy that is difficult to detect visually but was measured quantitatively. Subtle bilateral hippocampal atrophy is easily missed visually.

Quantitative methods have great value in research, allowing the investigator to test hypotheses correlating anatomic data with clinical and pathologic indices. Hippocampal volume from quantitative MR has been correlated with cell loss, frequency of childhood febrile seizures, memory functions, and successful surgical outcome (28). Several studies have correlated hippocampal volume loss with duration of epileptic disorder. One study correlated recurrent temporal lobe seizures with hippocampal volume loss, whereas generalized seizures were linked to progressive neuronal damage, as deduced from the association of frequent generalized seizures with metabolic derangement in temporal lobes on MRS (50). Early intervention for seizure control may, therefore, be indicated to prevent progressive brain damage from recurrent seizure activity. The clinical utility of quantitative MR volumetry will likely grow with the availability of increasingly automated software analyses which overcome traditional barriers such as operator time, the need for dedicated personnel, workstations, and software, and the requirement of a truly representative data sample of normal control subjects (47). The combination of hippocampal sclerosis with another potentially epileptogenic extrahippocampal abnormality, referred to as dual pathology (Fig. 7.10), has been observed in 15% of surgical epilepsy cases with MRI (51). Surgical pathology series have identified dual pathology in up to 71% of temporal lobe specimens (6). Dual pathology is associated with less favorable surgical outcome. For successful control of seizures, both abnormalities must be resected (52). Therefore, a search for additional abnormalities must be continued after detection of a possible epileptogenic lesion on MR. The most often encountered abnormality associated with hippocampal sclerosis is cortical dysgenesis (Fig. 7.10).

FIGURE 7.12 Bilateral hippocampal sclerosis. Coronal T1-weighted image shows bilateral hippocampal atrophy, detectable without quantitative measures. The patient underwent right temporal lobectomy and had histologically proven hippocampal sclerosis.

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MRI findings together with EEG data strongly guide the workup of TLE patients. Anterior temporal lobectomy is performed at our center if there is concordance of MR with EEG and no discordance of other lateralization tests, such as PET, SPECT, neuropsychological testing, functional MR, magnetoencephalography, or IAP. Otherwise, invasive EEG is necessary except for the rare cases of concordance of EEG with PET and a normal MR exam. Although fluorodeoxyglucose F18 PET imaging demonstrates decreased regional uptake of glucose in the epileptogenic temporal lobe, the area of hypometabolism may be more extensive than that requiring surgical excision for seizure control. Neoplasms and Vascular Malformations MR has nearly 100% sensitivity for detecting epileptogenic neoplastic and vascular lesions (21). As an overview pertinent to this chapter, most epileptogenic neoplasms occur in the temporal lobe, in or adjacent to the cerebral cortex. Indolent tumors such as ganglioglioma, dysembryoplastic neuroepithelial tumor, and low-grade gliomas are often associated with chronic intractable seizures lasting years or decades if they are not resected. In the elderly population, cerebral metastasis is the most frequent neoplastic lesion associated with late-onset seizures. It is usually difficult to predict the histologic type of neoplasms by MR features alone. Mass effect may not be present in more than onethird of neoplasms associated with epilepsy. Most tumors responsible for chronic recurrent seizures tend to be small and well localized, with little or no perilesional edema. Remodeling of the calvarial inner Table may occur due to a longstanding nature. Hemorrhage and seizure are the principal clinical manifestations of intracranial vascular malformations, with seizures being common in both arteriovenous malformations and cavernous hemangiomas (also referred to as cavernous angiomas or cavernous malformations). Most capillary telangiectasias and venous angiomas are clinically silent. Although cavernous hemangiomas demonstrate a stereotypical appearance of central hyperintensity due to hemoglobin products surrounded by a hypointense rim of hemosiderin, thrombosed arteriovenous malformations may have a similar appearance. The vessels of high-flow vascular lesions typically appear as curvilinear signal voids. Developmental Abnormalities (Malformations of Cortical Development) Developmental disorders are an important cause of epilepsy and are increasingly identified in MRI exams performed in such patients—4% to 25% in adult and 10% to 50% in pediatric MR studies (53). Although many of these abnormalities are highly epileptogenic, the actual epileptogenic zone may be separate from or more extensive than anatomic lesion (54). The pathology may be diffuse and bilateral, and therefore surgical decision-making may not be straightforward even when a distinct abnormality is identified on MR. Because of these factors, presurgical evaluation in developmental cortical malformations often includes an invasive electrophysiologic study. Classification of developmental malformations is very difficult because clinical and imaging phenotypes may not accurately reflect the underlying genetic defect and etiology. The classification was revised in 2012 and reflects the complexity and numerous recent discoveries in this field of study (55,56). Familiarity with normal embryologic development of the cortex is essential to understand the pathogenesis of these anomalies. On a very basic level, formation of the six-layered cerebral cortex in part involves neuronal and glial proliferation in the germinal matrix located in the subependymal embryologic layers, migration of developing neurons along the radial glial units to the brain periphery, with organization of migrating neuronal bundles into the six-layered cortex. Arrest or disturbance at any of these stages results in malformed cortex, associated with abnormalities of subsequent stage(s) of cortical development. The newest classification system referenced above by Barkovich et al. (55) is now divided into three major groups (Table 7.9) and is partly organized by the mode of inheritance (autosomal recessive, autosomal dominant, x-linked recessive, etc.). In addition, many new syndromes, genes, and mutations have been incorporated. The names of Groups I and II are “Malformations of Abnormal Neuronal and Glial Proliferation or Apoptosis,” and “Malformations Secondary to Abnomal Neuronal Migration,” respectively. Group III is now called “Malformations Secondary to Abnormal Postmigrational Development” to reflect the fact that neuronal organization begins before the process of migration is complete. The fourth group from the prior classification has been eliminated (previously “Malformations of Cortical Development Not Otherwise Specified”) and those entities have been integrated into the remaining framework. TABLE 7.9 Classification of Malformations of Cortical Development (Abbreviated to Major Categories, Subcategories, and Selected Specific Entities) 404

Abnormal cell proliferation can affect neuronal or glial cell lines. Cell proliferation affecting both glial and neuronal cells lines manifest as developmental neoplasms, consisting of dysembryoplastic neuroepithelial tumor (DNET), ganglioglioma, and gangliocytoma (56). These are the most common tumors in chronic epilepsy, usually low grade, typically cortical in location and appear as focal lesions on MR, often with a cystic component. Less common tumors associated with epilepsy, but not considered within the current classification as MCDs are the pleomorphic xanthroastrocytoma, pilocytic astrocytoma, and oligodendroglioma. Abnormal neuronal proliferation is typified by disorders with “balloon cell” proliferation (Fig. 7.13), such as tuberous sclerosis, FCD type IIb (FCD IIb, also known as balloon cell FCD of Taylor), and hemimegalencephaly. Balloon cells are large progenitor cells with both neural and glial characteristics. The imaging findings in FCD IIb (Figs. 7.13 and 7.14), and tuberous sclerosis (TS) are similar (57), as are their histologic characteristics and protein phenotypes. Important developments have been made in understanding the underlying molecular mechanisms that lead to abnormal cell proliferation in these patients. On a basic level, TS complex gene mutations ultimately lead to activation of the mammalian target of rapamycin (mTOR) pathway which is linked to cell proliferation and altered development of the cerebral cortex. The detection of hyperactivated mTOR signaling is well reported in TSC brain lesions including tubers and subependymal giant cell 405

astrocytomas (SEGAs) (56,58). An interesting novel pathogenic mechanism in FCD IIb was recently suggested by Chen et al. (59), pointing to a potential role of HPV 16 E6, which is an activator of mTOR. Both TS and FCD IIb have hyperintense cortical lesions on T2-weighted images, often with cortical thickening and radial bands extending toward the ventricle. However, unlike tuberous sclerosis, the balloon cell FCD is not associated with multiplicity of cortical lesions, subependymal nodules, or systemic manifestations (such as the cardiac, renal, and dermatologic abnormalities found in tuberous sclerosis). Because of focal hyperintensity on T2-weighted images, balloon cell cortical dysplasia may mimic a tumor. Other features of balloon cell dysplasia (i.e., cortical thickening, homogeneous bright signal in subcortical white matter, and radial bands) facilitate the distinction (Figs. 7.13 and 7.14), which may be crucial for surgical management (57). FCD IIb may also present with cortical thickening without hyperintense signal changes on T2-weighted images. Features of hemimegalencephaly include hemispheric enlargement (or a portion of it), white matter hyperintensity, ipsilateral ventricular enlargement, heterotopia, and thickened cortex. One variant of FCD IIb with a characteristic imaging appearance is known as “bottom-of-sulcus” dysplasia. Three major imaging features have been described: cortical thickening at the bottom of a sulcus, a funnel-shaped extension or radial band extending toward the ventricle, and an abnormal gyration pattern occasionally associated with local widening of the subarachnoid space (Fig. 7.15) (60).

FIGURE 7.13 Glioma versus FCD IIb. A: In this patient with low-grade glioma, hyperintense signal is seen within the subcortical white matter (arrow). However, there is no evidence of cortical thickening or radial bands extending to the

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ventricle. B–D: In this patient with FCD type IIb, (balloon cell cortical dysplasia of Taylor), axial and coronal long repetition time images demonstrate similar findings to the glioma, with the hyperintense subcortical white matter as demonstrated in panels B and C. However, note the cortical thickening (arrowheads) and the radial band extending from lesion to ventricle (small arrows). E: Photomicrograph (hematoxylin–eosin, original magnification ×370) from the dysplasia patient demonstrating balloon cells (arrows)—the abnormally enlarged cells with abundant cytoplasm, eccentric nuclei, and prominent nucleolus (similar to neuronal nuclei, but there is absence of Nissl substance). (From Bronen RA, Vives K, Kim JH, et al. MR of focal cortical dysplasia of Taylor, balloon cell subtype: differentiation from low grade tumors. AJNR Am J Neuroradiol 1997;18:1141–1151, with permission.)

FIGURE 7.14 FCD type IIb. A: Axial high-resolution T2-STIR image demonstrates cortical thickening and subcortical signal hyperintensity along the medial surface of the right frontal lobe (arrowhead). B: Coronal FLAIR image shows the radial band—an extension of the signal abnormality from cortex to lateral ventricle indicative of a malformation of cortical development.

FIGURE 7.15 Bottom-of-sulcus dysplasia. Axial volumetric T1-weighted image demonstrates subtle cortical thickening and blurring of the gray–white junction (arrowheads) isolated along the depth of an asymmetrically prominent frontal sulcus. This is a subtype of focal cortical dysplasia, type IIb (with balloon cells).

FIGURE 7.16 Bilateral perisylvian polymicrogyria, HIMAL (hippocampal malrotation) and subependymal heterotopia. Axial and Coronal T1-weighted images. This patient has extensive bilateral frontal and perisylvian polymicrogyria with

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abnormal cortical thickening (arrowheads, A) and indistict gray-white matter margins (arrowheads, B). In addition, this patient has bilateral hippocampal malformations with rounded morphology and increased craniocaudal dimensions of the hippocampus compatible with HIMAL. Note the small foci of subependymal heterotopia along the lateral ventricles.

Abnormal neuronal migration is often due to anomalies in tubulin and microtubule associated proteins and includes classic lissencephaly (the agyria–pachygyria spectrum), cobblestone lissencephaly, and gray matter heterotopia. These disorders often have a genetic origin and may be sex linked. Detection of these often subtle MR abnormalities is important because resective strategies and outcome are often poor. Heterotopic gray matter refers to ectopically situated gray matter, which may be periventricular (subependymal, Figs. 7.16 and 7.17) or subcortical. One form of bilateral periventricular nodular heterotopia is X-linked and is due to a mutation involving the filamin 1 gene, which encodes a protein important for cell locomotion. Classic lissencephaly is either X-linked or associated with LIS1 gene on chromosome 17 and appears as cortical thickening with either almost no sulci/gyri (agyria) or a decreased number of gyri (pachygyria) or a variable combination of both (Fig. 7.18). X-linked lissencephaly (defect in DCX/XLIS gene) has several phenotypes. Although it appears similar to LIS1 lissencephaly in males, it manifests as subcortical laminar heterotopia (also known as double cortex or band heterotopia) in females (56). Some of these genetic defects are related to dysfunction of microtubules essential for neuronal migration from germinal matrix to cortex along the radial glial unit. Lissencephaly, pachygyria, subcortical laminar heterotopia, and subependymal heterotopia have a common origin in failure of normal radial neuronal migration.

FIGURE 7.17 Subependymal heterotopia. Coronal T1- and T2-weighted images demonstrate small nodules (arrowheads) along the lateral margin of the lateral ventricle which are isointense to gray matter.

The category of abnormal postmigrational development includes polymicrogyria, schizencephaly, and non–balloon cell cortical dysplasias (FCD I and III). In this group of disorders, the neurons will fail to organize into a normal six-layered cortex during and after completing migration from germinal matrix. Therefore, the imaging features of these entities include cortical thickening, indistinctness of the gray– white matter junction, CSF cleft, and/or altered sulcal morphology. Polymicrogyria most commonly involves the perisylvian region, as described in congenital bilateral perisylvian syndrome (61). Patients with this disorder present with seizures, pseudobulbar palsy, and developmental delay. The MR reveals abnormally thickened opercular region with polymicrogyric cortex lining the sylvian fissures (Figs. 7.18 and 7.19) (61). With high-resolution imaging, multiple small gyri can be visualized. Schizencephaly is a CSF-containing transcerebral cleft connecting pial and ependymal surfaces, usually lined by polymicrogyric cortex (Fig. 7.20). FCD without balloon cells often has subtle findings on imaging, such as focal cortical thickening, abnormal sulcal morphology, and blurring of the gray–white matter interface (Fig. 7.21) (62). Because these findings are often extremely subtle, utilization of highresolution techniques with thin sections is indicated. Regarding differentiation between balloon cell and non–balloon cell FCD, the balloon cell type usually presents as hyperintense signal on long repetition time (TR) acquisitions with radial bands, whereas the non–balloon cell type usually does not. However, both entities can be variable in appearance and mimic each other.

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FIGURE 7.18 Pachygyria. Coronal T1-weighted image demonstrates a paucity of sulci, thickening of the cortex, and indistinctness of the gray–white matter junction in the frontal lobes (arrows). Compare this with the normal cortex and gray–white matter junction in the temporal lobes. This patient also has agenesis of the corpus callosum (asterisk) and an unfolded vertically oriented hippocampus (H). As commonly occurs with disorders of abnormal migration, there is also subependymal heterotopia seen bilaterally along the bodies of the lateral ventricles.

Hypothalamic hamartomas merit consideration and may be categorized into two types: intrahypothalamic and parahypothalamic (63). The intrahypothalamic type is located within the hypothalamus, typically distorts the third ventricle, and has intrinsic epileptogenesis (Fig. 7.22). These patients may present with both intractable seizures and precocious puberty (63). The parahypothalamic hamartoma is found either in the floor of the third ventricle or in the tuber cinereum (63). These patients present with precocious puberty but not seizures.

FIGURE 7.19 Perisylvian polymicrogyria in two patients. Axial (A) and sagittal (B) 3D T1-weighted images show abnormal morphology along the sylvian fissures with cortical thickening (arrowheads).

FIGURE 7.20 Schizencephaly. Axial T2-weighted image (A) and sagittal T1 3D IR (B) demonstrate a wide left frontal cerebrospinal fluid cleft extending from the cortical surface to the ventricle, lined by abnormally thickened gray matter.

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FIGURE 7.21 FCD II. A: Note the abnormal morphology of the sulci on the left side with the deep cerebrospinal fluid cleft (arrow) on the T2-weighted (A) and T1-weighted (B) images. Scrutiny of the underlying cortex shows an indistinctness of the gray–white junction and possible cortical thickening. These are subtle but typical features of focal cortical dysplasia. (From Bronen RA, Spencer DD, Fulbright RK. Cerebrospinal fluid cleft with cortical dimple: an MR imaging marker for focal cortical dysgenesis. Radiology 2000;214:657–663, with permission.)

The MRI features of developmental malformations may vary widely. Findings associated with cortical dysgenesis (Table 7.10) include cortical thickening (Figs. 7.13, 7.15, 7.17–7.21, and 7.23), morphologic surface alterations (Figs. 7.17, 7.19, 7.21, 7.23, and 7.24), blurring of the normal gray–white matter interface (Figs. 7.15, 7.18, 7.21, 7.23, and 7.24), hyperintensity of gray matter (Fig 7.13 and 7.14), heterotopic gray matter (Figs. 7.16 and 7.17), radial bands (Figs. 7.13 and 7.14), and CSF clefts (Figs. 7.20, 7.21 and 7.23). Because of the variety and subtlety of these developmental findings, a systematic approach during interpretation of MR scans from epilepsy patients is warranted (Fig. 7.25).

FIGURE 7.22 Hypothalamic hamartoma. Coronal T1-weighted (A) and T2-weighted (B) images demonstrate a subtle mass involving the right hypothalamus. The inset in panel B shows this mass to be isointense to gray matter (arrowheads), protruding into the third ventricle (3 V) and depressing the ipsilateral mammillary body (m).

It is increasingly clear that a significant proportion of patients with “nonlesional” epilepsy on MR actually have focal abnormalities on either high-resolution high–field strength MR or other imaging studies. Dedicated pulse sequences are needed to detect subtle cortical malformations—sequences that emphasize high contrast between gray and white matter and/or high spatial resolution. Inversion recovery sequences are well suited for this purpose, allowing detection of subtle gray matter thickening and indistinctness of gray and white matter junction. High spatial resolution can be achieved through the use of thin-section 3D volume gradient-echo imaging, or smaller in-plane resolution imaging, such as with phased-array surface coils or high–field strength magnets (Fig. 7.24) (64). Dedicated sequences 410

with ≥3-T imaging, expert readers, multimodality approach, and quantitative and advanced methods allow detection of subtle dysplastic lesions not previously identified. TABLE 7.10 Magnetic Resonance Features of Malformations of Cortical Development

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FIGURE 7.23 Cerebrospinal fluid (CSF) cleft. A: Coronal T1-weighted image shows a prominent CSF cleft on the right. B: Coronal T2-weighted image could pass for normal. C: Magnification of the region adjacent to the CSF cleft shows that the underlying cortex is actually thickened with an indistinct gray–white junction. D: Three-dimensional reformation of brain viewed from above shows the right-sided CSF cleft (arrow), which is adjacent to the primary sensory cortex (S). The patient had several prior magnetic resonance studies that were interpreted as normal. Seizures began with abnormal sensation to the left leg, indicative of early involvement of right primary sensory cortex. Because of the location, multiple subpial transection surgery was performed with good relief of seizures. Biopsy at the periphery of this eloquent region revealed FCD type IIb (balloon cell focal cortical dysplasia). E: Diagram of the CSF cleft adjacent to area of cortical dysgenesis. White arrows show the cortical dimple associated with the CSF cleft. In this patient, the CSF cleft alerted the radiologist to scrutinize the underlying cortex in greater detail and led to the detection of this dysplastic cortex. (From Bronen RA, Spencer DD, Fulbright RK. Cerebrospinal fluid cleft with cortical dimple: an MR imaging marker for focal cortical dysgenesis. Radiology 2000;214:657–663, with permission.)

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FIGURE 7.24 Cortical dysgenesis. A: Axial spoiled gradient T1-weighted image using conventional quadrature coil shows abnormal morphology of the left perirolandic area. However, it is difficult to discern the gray–white matter junction clearly. B: A phased-array surface coil was used in conjunction with inversion recovery sequence (which is photographic inverted). Here not only is the abnormal morphology obvious, but in addition one can visualize the irregularity of the gray–white matter junction on the dysplastic side (D) compared with the normal contralateral side. C, central sulcus; PC, precentral sulcus; SF, superior frontal sulcus.

Unique issues arise in the consideration of epileptogenic developmental anomalies for surgical treatment. FCD (also, focal subcortical gray matter heterotopia)–related epilepsy is usually refractory to drugs. FCD is also an important etiology of potentially life-threatening partial continuous epilepsy. Surgical treatment is therefore important, and preoperative assessment is along the general guidelines previously detailed. FCD in the resected specimens may be undetectable or less extensive on the preoperative MRI. As noted previously, the epileptogenic zone may be larger or extend beyond the lesion, potentially into adjacent eloquent cortex. Intracranial EEG monitoring and corticography, therefore, are often required due to the obvious need of tailoring and individualizing the surgical resection (54). However, if the dysplasia is focal and well circumscribed, postoperative outcome can be good if the abnormality is completely resectable (65). Surgical treatment of periventricular heterotopia has been limited and is usually precluded by their location and difficulty in confirming their epileptogenicity (52,54,66). Resective surgery for widespread lissencephaly and pachy- and microgyria is usually ineffective, and occasionally callosotomy is offered (66).

FIGURE 7.25 HIPPO SAGE mnemonic. A systematic approach for the interpretation of magnetic resonance scans of seizure patients is necessary because many epileptogenic abnormalities are subtle and easy to miss, especially developmental anomalies. We assess hippocampal size and symmetry after taking into account head rotation by assessing the internal auditory canals. We scrutinize the scans for the following findings that may be associated with developmental anomalies: periventricular heterotopia, sulcal morphologic changes, region of atrophy or cerebrospinal fluid cleft, gray matter thickening, and temporal lobe encephalocele. Last, we evaluate the obvious finding. The letter H can also remind one to inspect the hypothalamus for hamartomas. abn, abnormality. (From Bronen RA, Fulbright RK, Kim JH, et al. A systematic approach for interpreting MR images of the seizure patient. AJR Am J Roentgenol 1997;169:241–247, with permission.)

Gliosis and Miscellaneous Abnormalities This heterogeneous and somewhat arbitrary group is usually associated with cortical gliosis, the final common outcome of a multitude of different brain insults. The principal categories in this group are inflammatory, posttraumatic, and cerebrovascular. A rare encephalocele that occurs in the temporal 413

lobe and causes seizures can also be categorized with this group (Fig. 7.26). Irrespective of the etiology, gliosis usually appears as a region of increased signal change on T2-weighted images, often associated with volume loss (i.e., an associated CSF cavity or cleft). Resective surgery is usually not as successful for neocortical gliosis as it is for hippocampal sclerosis. Late-onset or delayed posttraumatic seizures are defined as seizures occurring at least 1 week after initial trauma. Although early posttraumatic seizures have a favorable prognosis, as many as 25% of patients with late-onset seizures develop intractable drug-resistant epilepsy. The pathologic mechanisms for posttraumatic epilepsy include deposition of tissue hemosiderin, which is a potent epileptogenic agent, and cortical gliosis. Risk factors for posttraumatic seizures include posttraumatic amnesia lasting more than 24 hours, intracranial hemorrhage, penetrating brain trauma, depressed skull fractures, and residual intracerebral foreign bodies (67,68). Beyond age 50 years, stroke is the most frequent cause of seizures. Similar to posttraumatic epilepsy, delayed-onset seizures after an acute stroke carry much greater risk of developing into chronic epilepsy (69). The pathologic mechanism is likely similar to that of posttraumatic epileptogenesis. CNS infections, including viral, bacterial, mycobacterial, fungal, and helminthic lesions are associated with seizures, most of which present in the acute phase of illness. Chronic epilepsy, however, may result from postinflammatory glial scarring. In certain developing regions of the world, neurocysticercosis has been reported to be one of the most common causes of new-onset partial seizures. Inflammation surrounding the cerebral lesions of cysticercosis manifests as acute seizure disorder. In the inflammatory vesicular colloidal stage provoked by the dying parasite, the cerebral lesions of cysticercus appear as small enhancing rings on CT and MR with variable degree of edema in surrounding brain (69). The lesions usually spontaneously resolve and may calcify on healing, representing the nodular calcified phase of the disease.

FIGURE 7.26 Encephalocele. A: Coronal T2-weighted image of a patient who presented with new-onset left temporal lobe seizures. There is herniation of the temporal lobe (arrowhead) into the left sphenoid sinus compartment through a defect in the lateral sinus wall (arrows). The hyperintense temporal parenchyma is surrounded by fluid. B: Colored fractional anisotropy (FA) map was co-registered to the anatomic images and demonstrates an arc of presumed temporal white matter curving into the sinus.

There is a growing body of literature describing seizures and epilepsy secondary to autoimmunemediated encephalopathy (AME). The role of inflammation is supported by a positive response to the anti-inflammatory effects of corticosteroids and a ketogenic diet in certain cases. Limbic encephalitis is one of the more common clinical and radiologic manifestations, characterized by memory impairment, mood disturbances, and recurrent temporal lobe seizures. It is associated with serum or intrathecal antibodies directed against intracellular (Hu, Ma, amphiphysin, or CV2) or neuronal membrane molecules (VGKC via LGI1), and can be associated with tumors as a paraneoplastic syndrome. MRI sensitivity is limited in these disorders and most commonly reflects limbic and mesial temporal involvement as increased T2 and FLAIR signals (Fig. 7.27). The changes may be unilateral, bilateral, symmetric, or asymmetric. Striatal, brainstem, and cerebellar involvement may be seen in some forms (70). Anti-NMDA encephalopathy deserves to be mentioned here, as it was first described in 2007 and is now the most common AME. The antibody is often associated with ovarian teratomas and may present with recurrent seizures as part of the symptom complex (71). MRI abnormalities occur in about onethird, with a minority affecting limbic structures. Epilepsy may also be a feature in a small minority (1.2% to 0.5%) of patients with gluten sensitivity autoimmunity as part of the rare CEC syndrome (celiac disease, epilepsy, and cerebral calcifications) or gluten sensitivity encephalopathy. In CEC, the 414

cerebral calcifications are typically subcortical, helping to distinguish the syndrome from Sturge–Weber and is typically the only imaging manifestation, which on MRI is best demonstrated on susceptibilityweighted imaging (72). Gluten sensitivity encephalopathy may present with white matter signal hyperintensities on MR, which arrest once a gluten free diet is adopted (73). Widespread cerebral gliosis and atrophy, exemplified by entities such as infantile hemiplegia, Sturge– Weber syndrome, and end-stage Rasmussen encephalitis, is typically easily appreciated both on MR and CT. Rasmussen encephalitis syndrome is clinically characterized by intractable partial seizures, progressive neuropsychiatric deterioration, and developmental delay (74,75). This rare syndrome results from chronic, unilateral T cell immune-mediated cortical inflammation with progressive hemispherical atrophy and gliosis. It usually presents in children younger than 15 years old with epilepsia partialis continua, although an adult form has also been recognized. MR findings in early stages include high-intensity cortical foci extending into subcortical white matter on long-TR sequences, which are sometimes transient (i.e., related to the localization of the tissue that is seizing at the time). Insular hyperintensity, caudate head atrophy, and putamen atrophy are also involved early. Nonspecific lobar or holohemispheric atrophy is typically seen in end-stage disease. Recurrent seizures are the most common and clinically important manifestation of Sturge–Weber syndrome, also known as encephalotrigeminal angiomatosis. This syndrome consists of a facial port-wine nevus in the trigeminal nerve distribution, leptomeningeal angiomatosis, epilepsy, developmental delay, and other neurologic deficits. The brain involvement is usually unilateral, requiring hemispherectomy or corpus callosotomy in intractable cases. Characteristic tram-track gyriform calcification is seen on plain films and CT appearing as linear low signal on MR. The involved hemisphere is atrophic, often with overlying calvarial thickening.

FIGURE 7.27 Autoimmune-mediated encephalitis (AME). Coronal FLAIR image illustrating symmetric, bilateral hyperintense signal in the hippocampi and mesial temporal lobes, one of the many imaging manifestations of AME. This patient suffered from limbic encephalitis preceded by characteristic faciobrachial dystonic seizures secondary to anti LGI1/VGKC (voltage-gated potassium channel) antibody encephalitis.

FIGURE 7.28 Status epilepticus with bilateral hippocampal abnormality over time. A: Initial axial fluid attenuated

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inversion recovery (FLAIR) images show extensive white matter abnormality with bilateral hippocampal high signal. Abnormal subarachnoid space is also identified. B: On follow-up 2 weeks later, axial FLAIR images now show more obvious hippocampal high signal, but temporal horns of ventricles are more prominent, indicating less swelling of hippocampi. Also note the marked diminution of other white matter abnormality. The hippocampal abnormality is likely secondary to the seizures, and it returned to normal on long-term follow-up (not shown).

In a subset of patients undergoing surgery for TLE known as non-HS gliosis or paradoxical medial TLE, MR is usually normal. In this group, hippocampal gliosis occurs without neuronal loss, and postoperative outcome is somewhat poorer than in hippocampal sclerosis (31). Transient MR signal changes have been observed immediately after a prolonged seizure or multiple repetitive seizures. The characteristic findings include hyperintensity on FLAIR and T2-weighted images (Figs. 7.28 and 7.29) and at times abnormal focal contrast enhancement involving the hippocampus or cortex (76,77). Status epilepticus (seizure lasting greater than 30 minutes) has been shown to cause decreased diffusion on diffusion-weighted MR in animal experiments and human patients (78). Prolonged focal or febrile seizures can result in hippocampal enlargement and increased signal on T2weighted images in acute phase, followed by atrophy (Fig. 7.11) (79).

STRATEGIES FOR SUCCESSFUL INTERPRETATION MRI of epilepsy is usually more challenging than routine brain imaging because the abnormalities are often subtle and not apparent on routine sequences. This warrants tailored imaging sequences, a high index of suspicion, and an algorithmic review of the images. Several lesions manifest as slight asymmetry of brain structure, and therefore one must be able to differentiate normal variations from pathology. The following subsections address the practical issues in MRI of epilepsy. Normal Variations and Incidental Findings A number of MR findings may be found in patients with seizure disorders that bear no relationship to seizures and are incidental. Venous angioma, arachnoid cysts, and choroidal fissure cysts are included in this category. However, venous anomalies are not infrequently associated with other potentially epileptogenic abnormalities, such as cavernous angiomas and MCDs, including perisylvian and other polymicrogyral syndromes. Arachnoid and choroidal fissure cysts remain isointense to CSF on all MR sequences and demonstrate no contrast enhancement. Perivascular (Virchow–Robin) spaces are quite frequently observed in epilepsy imaging because the dedicated, higher-resolution imaging sequences provide better anatomic detail. Dilated Virchow–Robin spaces in the anterior perforated substance and subcapsular region are common. Subinsular Virchow–Robin spaces between the extreme and external capsules often mimic a lesion on T2-weighted fast spin-echo sequences. However, their characteristic location, CSF-like signal intensity, and featherlike configuration help to differentiate these benign variations from pathologic lesions. Unfortunately, partial voluming with the brain may cause intermediate hypointensity of these on T1-weighted images rather than the usual CSF signal found in the ventricles, but FLAIR may clarify. These incidental findings may also be present in the anterior temporal subcortical region and again need to be distinguished from pathology. Another normal variant known as hippocampal sulcus remnant should also be distinguished from tumor and hippocampal sclerosis. This developmental variant occurs in more than half of normal hippocampi, appearing as small 1- to 2-mm round CSF intensity cyst(s) between the dentate gyrus and cornu ammonis (Fig. 7.30) (36). It results from failure of complete involution of the embryonic hippocampal sulcus. The uncal recess, the anterior end of the temporal horn, is asymmetric in 60% of routine MR scans and easily misinterpreted (Fig. 7.31) (80). When searching for MCDs, the interpreter needs to be familiar with normal variations of gyral and sulcal configuration. Asymmetry of calcar avis can be misinterpreted as cortical dysplasia. The normal convolution of the cortex may make it appear thickened on crosssectional images if the gyrus is parallel to the MR section. Therefore, the diagnosis of dysplasia should only be made when cortical thickening persists in another orthogonal plane (Fig. 7.32). Another wellknown possibility for mistaking the normal findings for cortical dysplasia is in the perirolandic region. On coronal images, the gray matter thickness, and the gray and white matter junction in this region often appears indistinct. This appearance results from parallel, coronal orientation of the rolandic fissure and normally thinner cortex lining the fissure. Therefore, reference to axial (or axial reformatted) images should be routinely made when evaluating this region for dysplasia.

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FIGURE 7.29 Transient postictal cortical signal changes on fluid attenuated inversion recovery following status epilepticus.

FIGURE 7.30 Hippocampal sulcal remnant. Coronal T1-weighted image (A), coronal FLAIR image (B), axial T2weighted image (C). The hippocampal sulcus (arrow, A) usually involutes (from lateral to medial) by birth. When this does not occur, a residual cyst (i.e., the hippocampal sulcal remnant, arrowheads) may form laterally. They may be numerous and bilateral, as in this case, and are labeled only on the left in C.

The technique of evaluation of the hippocampus also involves potential pitfalls. As previously described, the principal features of hippocampal sclerosis are hippocampal asymmetry and hyperintensity on FLAIR. Artifactual size asymmetry is easily created by head rotation because the hippocampus is largest anteriorly, tapering progressively on posterior sections. Correct interpretation entails accurate head positioning and accounting for head rotation when present. The signal intensity of the hippocampus on FLAIR is normally slightly brighter than that of cortex, potentially misleading the less experienced observer to a diagnosis of bilateral hippocampal sclerosis. The variable configuration of the hippocampus may also cause difficulties in interpretation. The hippocampus body usually has an oval or round shape in the coronal plane. Infrequently, it may have a more vertical configuration and erroneously suggest hippocampal dysplasia. An entity known as HIMAL (hippocampal malrotation) was introduced as a unique variant in 2000 by Barsi et al. reflecting failure of normal developmental inversion, or rotation of the hippocampus (Fig. 7.18) (81). There were many original features detailed in this report, including abnormally rounded hippocampus with normal T2 signal intensity, “blurring” of the inner hippocampal structure, low-lying ipsilateral fornix, vertical orientation of the collateral sulcus and enlarged temporal horn. Some support the term incomplete hippocampal inversion (IHI) for this finding. HIMAL was recently described as an association in 9 of 14 patients with chromosome 22q11.2 microdeletion—a deletion associated with a significantly elevated risk of seizures. HIMAL’s significance is not completely understood, but rather than a direct cause of epilepsy, it is felt to likely reflect a sign of cerebral maldevelopment which may lead to the condition (82).

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FIGURE 7.31 Asymmetrically large left uncal recess. This is a normal variant and should not be mistaken for ipsilateral volume loss.

FIGURE 7.32 A: False appearance of dysplasia resulting from coronal sectioning through the vertically oriented posterior extension of superior temporal sulcus. B: The sagittal image shows normal cortex lining the sulcus.

Differential Diagnosis: Pitfalls to Consider In addition to the normal variations listed previously, potential for misinterpretation of imaging findings in seizure patients may arise from a number of other situations. The most important of these are transient abnormalities. Alterations resulting from seizures can present as focal or regional hyperintensity of the cortex (Fig. 7.29) and hippocampus (Fig. 7.28) on T2- and diffusion-weighted images. In Rasmussen encephalitis, signal changes may not only be transient, but also may shift from one location to another. Therefore, due caution must be exercised in interpreting the MRI and recommending further management for immediate postictal and actively seizing patients. Differentiating neoplasms from FCD and hippocampal sclerosis may occasionally be difficult. Imaging findings suggestive of cortical dysplasia (particularly FCD IIb) include cortical thickening, the presence of a radial band extending to the ventricle, and homogeneous appearance of the subcortical hyperintensity (57) (Fig. 7.27). The presence of subependymal nodules or multiple subcortical lesions should raise the possibility of tuberous sclerosis. In occasional cases, when the abnormal hippocampal signal is not accompanied by atrophy, findings favoring neoplasm over sclerosis include heterogeneity and extension of signal changes beyond the hippocampus into the parahippocampal white matter. An important pitfall pertains to dual pathology. As described previously, dual pathology refers to the coexistence of an extrahippocampal lesion with hippocampal sclerosis (Fig. 7.10). It is important to carefully assess the hippocampus in all cases regardless of the presence of another more obvious lesion, particularly if there are correlative clinical and electrographic features of medial temporal epilepsy. Surgical success is often predicated on the removal of both hippocampus and the extrahippocampal lesions.

MAGNETIC RESONANCE IN EPILEPSY BEYOND ANATOMIC IMAGING Whereas anatomic imaging has been the major impact of MR in the diagnosis and management of epilepsy, significant contributions have also been made by its capabilities in detecting alterations in the chemical and physical environment caused by epilepsy. These “functional” capabilities of MR should always be combined with anatomic imaging to enhance its sensitivity and accuracy. The most significant of these applications are currently MRS and diffusion mapping. Proton MRS has been predominantly targeted at the hippocampal/medial temporal lobe region while 418

comparing the metabolite concentrations with those in contralateral hippocampus region. Reduced Nacetylaspartate (NAA) has been the most important finding in TLE. NAA is a marker of metabolically active neurons, and decreased NAA:creatine or decreased NAA:(creatine + choline) ratio signifies neuronal loss and/or metabolic dysfunction. A decrease in these ratios has been shown to lateralize TLE in 65% to 96% of patients with bilateral temporal lobe structural abnormalities on MR (83). In cases of TLE with normal structural MR studies, NAA ratios can provide lateralizing evidence in at least 20% of patients (84,85). Bilaterally decreased NAA ratios have been associated with surgical failure. NAA has been suggested to be a dynamic marker of epileptic activity and neuronal function and not simply a reflector of decreased neuronal number. Postoperative recovery of NAA concentrations has been documented in the unoperated temporal lobe. In extratemporal epilepsies, the epileptogenic zone is frequently larger and more difficult to delineate in comparison with TLE. Diffusely low NAA values have been documented in patients with generalized epilepsy. The proton MRS findings in developmental cortical malformations have been somewhat inconsistent (86). In FCD, low NAA has been observed, whereas variably normal or abnormal NAA concentration has been found in heterotopias (86). However, abnormal findings and metabolic dysfunction are sometimes widespread. Minor abnormalities have also been found contralateral to the epileptogenic focus in some patients, a finding supported by Leite et al., alerting practitioners to the potential pitfall of using contralateral normal-appearing contralateral tissue as a control (87). This is similar to other studies with abnormal structural MRI (52) where a predominance of widespread alterations in metabolite concentration have been detected. Proton MRS has also been used to estimate the cerebral concentrations of several neurotransmitters, including γ-aminobutyric acid, glutamate, and glutamine, using special spectral editing techniques. This approach may become useful for characterizing neurochemical derangements in various epilepsy syndromes and pharmacokinetic monitoring of the AED treatment. Diffusion imaging has been used in the diagnosis of TLE, with several investigators reporting abnormally elevated hippocampal apparent diffusion coefficients (ADCs) and decreased fractional anisotropy in hippocampal sclerosis, even in cases of negative conventional MRI (88). In MCDs, changes in anisotropy and diffusivity have also been noted, often extending beyond the region of malformation defined by conventional MRI (89). This finding may explain, at least in part, the poorer surgical outcome in this group of disorders. A significant correlation has been found between diffusion tensor imaging (DTI) abnormalities and associated white matter changes in FCD. DTI has been useful in assessing the integrity of the white matter adjacent to the FCD. The aberrant course of the underlying white matter tracts in FCD can be detected with DTI fiber tractography. These results suggest that only minor ultrastructural disorganization may be associated with epileptogenesis in MRI-negative patients. DTI fiber tracking is also used in mapping of the major motor and sensory tracts in surgical planning of both lesional and nonlesional epilepsies (90,91). Rapid advances in other realms of imaging technology may have direct applications for seizure imaging. High-resolution imaging techniques include the use of high–field strength MR systems (3 T and greater) and phased-array surface coils (Fig. 7.24) (64). Advances in MR image processing include computerized segmentation techniques, texture analysis, curvilinear reformatting, and automation of quantitative methods. Computerized gray and white matter segmentation has been used in several epilepsy patient populations, with aberrations from normal groups indicative of developmental anomalies. Functional brain mapping using functional MR has become widespread at many epilepsy centers and is often part of epilepsy imaging protocol at these institutions. The applications of functional MR include mapping of language function, memory indices, sensorimotor function, activated cortex during a seizure ictus, and interictal EEG-registered-changes (see Chapter 33). Noninvasive mapping of anatomic connections and comprehensive evaluation of connectivity throughout the entire brain have been made possible by resting-state BOLD MRI and DTI. By combining the functional MRI data with DTI, connectivity of functionally eloquent noncontiguous cortical regions of brain has been demonstrated. This may lead to a better understanding of seizure origin and spread, and also to a new realm of non-resective, minimally invasive surgical treatment strategies. These advanced imaging techniques are likely to have an impact not only on the clinical management of epilepsy and seizure disorders but also on the direction of epilepsy research (10).

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8 Adult Brain Tumors Bruno Telles, Francesco D’Amore, Mahesh V. Jayaraman, Jerrold L. Boxerman,Meng Law, Mark S. Shiroishi, and Alexander Lerner

Primary brain tumors are uncommon. They account for less than 2% of all malignant neoplasms (1) in adults, with a similar prevalence reported in the United States (2) compared to other parts of the world (3). In absolute numbers, there is an incidence of 6.4/100,000 (men and women) per year. About 0.6% of the population will be diagnosed with brain or other nervous system neoplasm at some point in their lifetime, based on 2009–2011 data (4). In 2014, the estimated number of deaths caused by these tumors (brain and other nervous system neoplasms) in the United States number 143,204. Despite the relative rarity of these lesions, the challenge they present is uniquely problematic. In distinction from most forms of cancer, the overall death rate from malignant brain tumors has not significantly declined over the past 25 years, despite the advances in diagnostic tools, microneurosurgery, drug treatment, and decades of huge expenditures on research. An increased incidence in brain tumors has been reported recently, primarily in benign neoplasms. This may result, at least in part, from recent improvements in diagnostic techniques and changes in neoplasm reporting practices (5). Treatment for elderly patients, the most affected age group, is often a subject of debate due to both perceived risks and costs. However, we believe that such treatment must be individualized, and age alone clearly should not preclude the use of more aggressive therapies, as reported by Nayak and colleagues (1,6). The interpreting radiologist should have a solid background of knowledge in other clinical neuroscience fields, such as neuroanatomy, pathophysiology, and neuropathology, which in combination with the imaging findings and demographic information, is necessary to generate an appropriate differential diagnosis and provide meaningful guidance for the multidisciplinary team treating the patient. Aside from the initial recognition and characterization of these lesions, the mechanical effects and structural deformities resulting from intracranial neoplasms are also of great importance because the cranium has extremely limited compliance to accommodate increases in intracranial pressure. Therefore, the neuroradiologist must be able to appreciate the consequences resulting from the combined effects of tumors and their edema, many of which are potentially life-threatening, such as transtentorial or uncal herniation. With the advent and refinement of magnetic resonance imaging (MRI), intracranial neoplasms and their effects can be more readily recognized, so that appropriate therapy can be instituted without delay and at an earlier time point in their natural history. This capability has further improved with the introduction of high-field equipment during the last decade (clinical 3-Tesla (T) and research 7-T MRI scanners). Among all the primary intracranial neoplasms, the neuroepithelial tumors are the most common cancers, representing almost two-third of all these lesions. Meningothelial origin tumors also have a high prevalence, and occur more frequently with increasing age. Tumors arising from cranial and spinal nerves, central nervous system (CNS) lymphomas, and germ cell tumors are less common and are discussed later in this chapter (1). The widely used classification of brain neoplasms has been developed by the World Health Organization (WHO), which includes over 100 different tumor types and subtypes in the CNS, with the latest version published in 2007. There are eight new tumor entities and four new variants included in this new version of WHO classification, with the most important neuroradiologic features of these newly described neoplasms presented in this chapter (1,7,8). Recent major discoveries regarding biologic and molecular features of CNS tumors have raised the question of how all of this nonhistologic data will be assimilated into the WHO classification (9). 423

At the time of this writing, it is widely acknowledged that MR has become the only imaging study used in the evaluation of intracerebral tumors with two main exceptions—the scenario in which it is simply not available, and for the patient in whom MRI is contraindicated. The most important reason for the reliance on MR in the search for brain tumors lies in its inherently high sensitivity for these lesions. As MR technology continues on its path of continued innovation in hardware, software, image processing, and contrast agents, and as data emerge to suggest that MR can even serve as a surrogate for genomic and proteomic markers of significance (10,11), it is virtually unimaginable that MR will yield its position of dominance anytime soon.

FUNDAMENTALS OF LESION LOCALIZATION AND CHARACTERIZATION When imaging a patient with a known or suspected brain tumor, the radiologist’s goals are to identify and localize the lesion, provide a reasonable and accurate differential diagnosis, and guide further diagnostic and therapeutic interventions. Although advances in MRI have made great strides, the basic principles in identifying a primary brain tumor have remained unchanged (Fig. 8.1). However, the potential for MR in brain tumor imaging is far greater than in the past. Recognition of specific anatomic clues and signal intensity patterns on MR that correlate to known pathology further increases the possibility of identifying specific histopathologic tumor types, and in the great majority of cases results in a more succinct differential diagnosis. In reality, most lesions are fairly obvious and simple tasks like measurements can be performed by anyone involved in the care of the patient with a brain tumor. However, it is the role of the neuroradiologist to go further and provide a detailed analysis of the findings. This facilitates a more concise differential diagnosis and a more thoughtful treatment plan, ultimately adding significant value to the patient’s management.

FIGURE 8.1 Tumor, not acute infarction, proven by magnetic resonance. T2-weighted images (A) demonstrate a left posterior temporal–parietal lesion involving the cortex and white matter with sulcal effacement and mild ventricular compression. Partial enhancement after contrast (B) is seen. Diffusion-weighted images (C) fail to demonstrate restriction of diffusion. Notwithstanding the fact that the lesion falls into the territory of the left middle cerebral artery,

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the diagnosis of acute infarction should be eliminated from consideration because an infarction with mass effect does not enhance significantly, and an infarction with mass effect should have restricted diffusion.

When evaluating a mass lesion, the first task of the radiologist is to determine if the lesion is intraaxial or extra-axial. This compartmental localization of an intracranial mass lesion is of paramount importance and is fundamental to diagnosis because it completely determines the appropriate pathway for correct differential diagnosis and discussion and it obviously impacts treatment planning. At its most basic level of use, multiplanar MRI has clearly improved our ability to make that distinction. The correct assessment of the relationship of a mass to the ventricular system is also made easier by using coronal and/or sagittal planes in addition to the traditional axial plane of scanning (Fig. 8.2), which aids in differential diagnosis. That said, it is the attention to detail that underscores the value of MR in this fundamental consideration. One can divide the key MR signs of extra-axial mass lesions into two categories: those that merely suggest the extra-axial location of a brain mass, and other findings that are in fact specific for extra-axial localization (Table 8.1). It is absolutely essential for the radiologist to be cognizant of these findings and their significance. Findings suggestive of but not specific for extra-axial localization include the following: peripheral location along the inner table of the skull (Figs. 8.3 and 8.4), associated bone change in overlying calvarium (Fig. 8.5), and enhancement of adjacent meninges (Fig. 8.6). All of these “suggestive” findings can also be found in the presence of superficial intra-axial lesions (Fig. 8.7), and so they mainly serve to prompt a closer inspection of the images for the more specific signs. On the other hand, the absence of these findings may be confirmatory in some cases in the decision that a given lesion is intra-axial. TABLE 8.1 Magnetic Resonance Findings in Extra-axial Mass Lesions

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FIGURE 8.2 Central neurocytoma, value of sagittal for lesion localization. Axial diffusion-weighted (A), T2*-weighted GRE (B), FLAIR (D), T2-weighted (E), and T1-weighted postcontrast MR (F) demonstrate a hypercellular, heterogeneous mass centered in the region of the lateral ventricles. Sagittal FIESTA (C) confirms that the neurocytoma is entirely intraventricular and separate from the adjacent corpus callosum.

The more important and, in fact, cardinal feature of an extra-axial lesion is clear separation of the mass from the brain surface. This distinction between the mass and the brain surface is made on the basis of identifying the interface between the lesion and the brain by an interposed cleft or “boundary layer.” These boundary layers can consist of cerebrospinal fluid (CSF) within the subarachnoid space, pial blood vessels, cortical draining veins traversing the subarachnoid space (Fig. 8.8) or (if the lesion is epidural) a sheet of dura, all of which may or may not be visible on MR between the tumor mass and the brain. CSF clefts are recognized as crescentic bands whose intensity follows that of the spinal fluid, being most visible as high intensity on T2-weighted images (Fig. 8.4). It should be noted that CSF clefts are frequently identified only over a portion of the brain–tumor interface, particularly near edges of the mass in question. Vascular clefts are recognized as rounded or curvilinear signal voids at one or more locations on the margin of the lesion on spin-echo sequences. Vascular clefts may represent either the normal arteries and veins located on that surface of the brain or may be due to increased blood flow from the tumor draining into abnormally prominent veins on the brain surface. An additional, highly important “boundary layer” that should also be sought out when assessing an intracranial mass is the cortical gray matter itself (Fig. 8.9). Because edema in underlying cerebral white matter often accompanies adjacent extra-axial neoplasms, and the edema preferentially accumulates in the white matter with its more prominent extracellular space, the edematous white matter should be separated from the mass by intervening cortex if the lesion is extra-axial (Figs. 8.4, 8.10–8.12). If the tumor touches the edema (i.e., the edematous white matter), then the tumor must be in the gray matter (i.e., intra-axial). This is an extremely useful but often underappreciated finding in lesion localization.

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FIGURE 8.3 Epidural lymphoma with extracranial and intracranial components. T1-weighted (A) and T2-weighted (B) images show a homogeneous, low-intensity, extra-axial, intracranial mass with significant subcutaneous extracranial component. Mass enhances homogeneously (C), as well as within skull marrow, consistent with transcalvarial tumor extension.

FIGURE 8.4 Meningiomas demonstrating characteristic features of an extra-axial mass. Axial T2-weighted (A,C) images demonstrate a cerebrospinal fluid cleft between the brain and the lesions, which confirms the extra-axial location. Also note the flow voids on a sagittal T2-weighted image (D, arrow) between the mass and adjacent brain, as well as adjacent vasogenic edema, best seen on T2-weighted images (C,D). After the contrast injection, these lesions display marked homogeneous enhancement (B,E,F). Hyperostosis is also noted of the overlying calvarium (B).

FIGURE 8.5 Meningioma with adjacent bone invasion. Postcontrast T1-weighted images (A,B) show an intensely enhancing extra-axial parietal mass with a nodule of enhancing tissue within the marrow of the calvarium. Computed tomography (C) demonstrates a sequestrumlike bone change due to direct tumor invasion.

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FIGURE 8.6 Superficial intra-axial, extra-axial and cranial vault metastasis, with associated meningeal enhancement. Sagittal FLAIR (A) images show extensive white matter edema in the parietal lobe. Coronal and sagittal T1-weighted postcontrast images (B) and axial T1-weighted postcontrast images (C) show edema and areas of intraparenchymal enhancement. These findings are consistent with intra-axial and extra-axial metastases with dural and leptomeningeal enhancement and cranial vault involvement.

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FIGURE 8.7 Superficial intra-axial metastasis with meningeal enhancement. Sagittal (A) and axial (B) T1-weighted images show extensive white matter edema in the posterior frontal lobe. T2-weighted images (C) show edema and a focus of low intensity that indicates solid metastasis. After contrast (D), an enhancing mass is seen. The mass abuts edematous white matter with no intervening cortex and does not displace subjacent brain. This intra-axial mass is associated with meningeal enhancement (D).

FIGURE 8.8 Dural metastases, prostate carcinoma. Coronal T1-weighted images after intravenous contrast show a superficial enhancing tumor with a nodular component clearly depressing high vertex brain tissue. Note that the enhancing tissue is even superior to overlying veins and superior sagittal sinus, indicating extra-axial origin. Also note the absence of tumor in the overlying calvarium, confirming that the site of metastasis is dura rather than bone.

FIGURE 8.9 Cystic meningioma. Axial T1-weighted (A) and T2-weighted (B) images show a largely cystic mass. Superficial enhancing nodule (C) led to the erroneous diagnosis of pleomorphic xanthoastrocytoma, an intra-axial neoplasm. The extra-axial localization, made by identification of a rim of displaced cortex on axial images (A,B), is the key to the correct diagnosis.

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FIGURE 8.10 Superficial intra-axial tumors. Note the absence of normal cortical gray matter between the lesions (A,B) and the subjacent white matter. There is also massive perilesional edema in the second lesion (B). These findings are seen more frequently in intra-axial lesions.

FIGURE 8.11 Superficial exophytic dysembryoplastic neuroectodermal tumor, intra-axial localization. High-resolution coronal T1-weighted (A) and T2-weighted images (B) show a rounded mass eroding the inner table of the calvarium. Despite the exophytic nature of the lesion, the absence of gray matter between the mass and subjacent white matter localizes the tumor to an intra-axial location.

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FIGURE 8.12 Peripheral but intra-axial mass (breast carcinoma metastasis). Proton density–weighted (A) and T2weighted (B) images demonstrate a heterogeneous mass extending all the way to the periphery of the frontal pole with subjacent edema and mass effect. Note that the lesion extends right to the edematous white matter rather than being separated from the white matter by intervening cortex, indicating the intra-axial localization of the lesion. Diffuse enhancement of the mass (C,D) and clear meningeal enhancement (C, arrowheads) are features that can be seen in both intra-axial and extra-axial neoplasms.

FIGURE 8.13 Dural-based metastases with brain invasion. The rind of the extra-axial tumor is of low intensity on T2weighted (A) and fluid-attenuated inversion recovery (B) images and is associated with extensive brain edema and cystic intra-axial changes. After contrast (C), the meningeal tumor with invasive component is clearly demonstrated.

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The enhancement of extra-axial lesions often makes their anatomic compartmentalization obvious. We recommend the routine use of intravenous contrast in the search for all intracranial mass lesions. Tissue characterization of masses already noted to be situated in the extra-axial compartment is also a valuable secondary benefit of contrast enhancement (see later sections of this chapter). Having noted all of these factors, we must acknowledge that occasionally even the compartmental localization of some masses represents a diagnostic dilemma, despite a detailed analysis by the neuroradiologist. Sometimes, the question arises as to whether lesions are multicompartmental (i.e., extra-axial lesions invading the intra-axial compartment (Figs. 8.13–8.15)). These difficult cases should serve as reminders that careful scrutiny of MR images is essential to ascertain the correct diagnosis and to minimize patient morbidity from surgical treatment.

FIGURE 8.14 Extra-axial cerebellopontine angle meningioma with associated intra-axial radiation necrosis. The extraaxial left cerebellopontine angle mass has typical features of meningioma on T2-weighted (A) and postcontrast T1weighted (B,C) images. However, extensive and unusually heterogeneous edema on T2-weighted images is concerning and shown to be due to intra-axial enhancing tissue, consistent with radiation necrosis in underlying pons.

The multiplicity of lesions within the brain is another important determinant in lesion characterization that would make primary brain tumor less likely. In adult patients, the most common solitary brain lesion is still a metastatic lesion. Therefore, the radiologist should scrutinize the entire imaging study, including the marrow signal and both intra- and extra-axial compartments, for additional lesions. The presence of multiple lesions in an adult patient makes metastatic disease more likely, and the radiologist should suggest a search for primary lesion, which may include imaging the chest, abdomen, and pelvis to search for a primary carcinoma. Multifocal lesions may also be seen in infectious etiologies, or in other tumor-mimicking entities such as demyelinating disease. Occasionally, primary brain tumors such as glioblastoma multiforme (GBM) may be multicentric or multifocal or may result in ependymal or leptomeningeal seeding; however, even in these cases, metastases often remain high in the differential diagnosis.

LESION CHARACTERIZATION Unfortunately, the progress of MRI in the area of specificity in brain tumor evaluation has not paralleled its gains in sensitivity and anatomic depiction, although several new techniques are promising in potentially improving diagnostic specificity. With that in mind, MRI provides significant information 432

about intrinsic tissue characterization, a capability that should be fully exploited by the neuroradiologist in determination of tumor type. This ability to discriminate differences in tissue corresponding to variations in signal intensities parallels findings on gross pathology in many cases (Tables 8.2 and 8.3) and applies to several aspects of tumor imaging. For instance, one of the major pathologic changes in astrocytomas and one of the few prognostically significant factors in histopathology, aside from general tumor cell type and overall grade, is the presence of necrosis. The identification of intratumoral necrosis is considered a poor prognostic sign and found in the more aggressive astrocytomas, and should be sought by the neuroradiologist interpreting MR of brain tumors. Necrosis may be either hemorrhagic or nonhemorrhagic. The effects of necrosis on MRI are complex and varied (Table 8.4); however, it is often identified with near certainty when T1-weighted, T2-weighted, and FLAIR sequences are used. In general, necrosis may be either high intensity or low intensity on T1-weighted images, as well as on T2weighted images, due to the presence of naturally occurring paramagnetic cations and free radicals. These substances usually shorten relaxation times, whereas regions of cystic necrosis prolong relaxation times (12). Cystic necrosis demonstrates signal intensities consistent with high water content although virtually always different from CSF on fluid-attenuated inversion recovery (FLAIR) (Fig. 8.16), and hemorrhagic necrosis parallels in most ways the complex intensities relevant to paramagnetic bloodbreakdown products (Fig. 8.17) with some important differences (Fig. 8.18). Among the newer MRI techniques, diffusion-, perfusion-, and permeability-weighted imaging, as well as MR spectroscopy (MRS), may all play a role in assisting further characterization of a lesion (see later discussion).

FIGURE 8.15 Invasive meningioma (extra-axial and intra-axial components). Axial T1-weighted (A) and T2-weigthed (B) images show a heterogeneous right occipital mass with significant edema and mass effect. No clear cerebrospinal fluid, venous, or gray matter cleft is identifiable. After intravenous contrast (C,D), the mass enhances homogeneously underlying the occipital lobe and within the interhemispheric fissure. Frondlike interdigitations of enhancing tumor represent invading tumor into the intra-axial compartment.

TABLE 8.2 Causes of Low Intensity in Tumors on T2-Weighted Magnetic Resonance Images

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TABLE 8.3 Causes of High Intensity in Tumors on T1-Weighted Magnetic Resonance Images

TABLE 8.4 Effects of Tumor Necrosis on Signal Intensity

The association of cysts with certain neoplasms has long been used as an aid to differential diagnosis by neuroradiologists (Table 8.5). Preoperative cyst delineation is also helpful to the neurosurgeon when planning the surgical approach. It is problematic that most neoplasms have prolonged T1 and prolonged T2, just like CSF, so that most tumors are low intensity on T1-weighted images and high intensity on T2-weighted images. This does not necessarily indicate cystic structure, however. Morphology is just one of several criteria for the diagnosis of a cyst by MRI (Table 8.6). Cysts are generally very sharply demarcated, round, or ovoid masses, but there are many exceptions to these features (13). The identification of cystic areas on MRI also requires careful scrutiny of lesion intensity relative to CSF on all images. FLAIR imaging, a T2-weighted sequence with suppression of the signal intensity of CSF (or any fluid with the T1 of CSF), can be particularly useful in proving the cystic content of a lesion. If a lesion is exactly isointense to CSF on T1-weighted, T2-weighted, and FLAIR images (Fig. 8.19), then one can state very confidently that the lesion is cystic, a pattern followed by arachnoid cysts and many cysts 434

associated with extra-axial masses. Unfortunately for the radiologist, tumor cysts and cystic necrosis within neoplasms are often proteinaceous or contain dilute concentrations of paramagnetic substances that can shorten T1 enough to alter intensity on these images (14). Therefore, these regions are hyperintense to normal CSF on FLAIR (Figs. 8.20–8.22). Fluid–debris intensity levels are a pathognomonic sign of cystic tissue and are often quite striking and frequent in cases of cystic tumors (Figs. 8.22 and 8.23). Another definite sign that reveals the cystic nature of a lesion is the presence of artifacts due to fluid motion within the lesion. This may occasionally be seen as “ghost” images propagated along the phase-encoding direction on conventional images or more commonly as areas of signal loss due to dephasing. Flow-sensitive techniques can illustrate this dramatically (15) and can occasionally be useful adjuncts in evaluating tumors with MRI. Diffusion-weighted imaging (DWI) can also aid in differentiating cystic necrotic regions from bacterial brain abscesses (Fig. 8.24), which have reduced diffusion (16).

FIGURE 8.16 Extensive necrosis in high-grade glioma. Axial diffusion (A), ADC map (B), sagittal fluid-attenuated inversion recovery (FLAIR) (C), axial FLAIR (D), and T1-weighted postcontrast (E) images demonstrate cystic necrosis in a glioblastoma multiforme. Note also the irregular, thick enhancement of the posterior rim.

FIGURE 8.17 Hemorrhagic non-germinomatous testicular tumor metastases. A: T1-weighted magnetic resonance (MR). B: T1-weighted postcontrast MR. C: T2-weighted MR. D: T2*-weighted GRE MR image. The intratumoral hemorrhagic necrosis (A,C) displays the high intensity of methemoglobin, dependent levels of intracellular deoxyhemoglobin, and irregular strands of hypointensity within and along the periphery of the lesion. Mild heterogeneous contrast enhancement (B) and marked GRE blooming is noted (D). The high intensity in perilesional white matter represents edema (C).

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FIGURE 8.18 Hemorrhagic necrosis in a supratentorial primitive neuroectodermal tumor. A: T1-weighted magnetic resonance (MR) (600/20). B: T2-weighted MR (3,000/90). The intratumoral hemorrhagic necrosis displays the high intensity of methemoglobin (1), dependent levels of intracellular deoxyhemoglobin (2), and minimal irregular strands of hypointensity (open arrows) within and at parts of the periphery of the lesion. The high intensity in perilesional white matter (B, closed arrows) represents both edema and infiltrating tumor.

TABLE 8.5 Frequently Cystic Tumors

Hemorrhage is uniquely depicted by MRI because of the paramagnetic properties of many of the blood-breakdown products. On MRI, old hemorrhage is easily distinguished from other fluid (like CSF) because of the paramagnetic properties of methemoglobin, one of the major constituents of chronic intracranial hemorrhage (17). The characteristic tendency of certain primary intracranial neoplasms (e.g., glioblastoma, ependymoma, and oligodendroglioma) and metastases (e.g., melanoma, lung carcinoma, renal cell carcinoma, choriocarcinoma) to hemorrhage can be an important clue to the diagnosis (18,19), and so sensitivity and specificity are desirable for seeing the appearance of hemorrhage (Table 8.7). TABLE 8.6 Magnetic Resonance Criteria for Cystic Lesions

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FIGURE 8.19 Fluid-attenuated inversion recovery (FLAIR) for cystic content, arachnoid cyst. The mass in the left cerebellopontine angle is exactly isointense to normal cerebrospinal fluid on T1-weighted (A), proton density– weighted (B), and T2-weighted (C) images. Corresponding FLAIR images (D) confirm that the lesion is precisely isointense to cerebrospinal fluid, thereby proving the diagnosis of arachnoid cyst.

Although it is important to discover hemorrhage, it is also critical to define its etiology, and CT is of limited value for this. The signal intensity pattern of intratumoral hemorrhage differs from that of benign intracranial hematomas (20) in several ways (Table 8.8). Signal intensity is extremely heterogeneous in tumor bleeds (Fig. 8.25) due to the combination of simultaneously appearing stages of evolving blood (from continual or repeated intermittent bleeding), frequent intracellular blood–fluid or intracellular blood–extracellular blood levels from bleeding into cystic or necrotic portions of tumor (Figs. 8.26, 8.27), and mixed areas of tumor with edema and hemorrhage (20). Blood may not evolve as rapidly if it is within tumor tissue (20) in comparison with the evolution of benign hematomas (Fig. 8.28). This delay in evolution (seen usually as persistent deoxyhemoglobin, which is normally found only within the first 3 to 5 days after hemorrhage) may be related to the well-documented intratumoral hypoxia found in human neoplasms (21) or due to repeated episodes of bleeding (22). Long after hemorrhage into tumor tissue, there is often a marked reduction or irregularity of the expected hemosiderin on T2-weighted images around the bleed (20) compared with the prominent hypointensity at the periphery of chronic benign intracranial hematomas. A clear sign of neoplasm as the underlying cause of the bleed is the identification of nonhemorrhagic tumor tissue itself (18). Persistence of prominent high intensity on T2-weighted images in the parenchyma surrounding tumor hemorrhage, even when the blood is chronic, is a common and ominous sign (Fig. 8.29) that necessitates follow-up MRI or biopsy (20). In addition, tumor-associated hemorrhage tends to have a larger collar of vasogenic edema, often greater than twice the size of the hemorrhage as compared with bland hemorrhage (23). In the presence of any of these signs accompanying intracranial hemorrhage, one cannot ascribe the hemorrhagic event as being due to a benign cause, and a workup to exclude neoplasm must be 437

performed. TABLE 8.7 Hemorrhagic Tumors

FIGURE 8.20 Fluid-attenuated inversion recovery (FLAIR) evaluation of cystic content (right ependymal cyst) that follows CSF signal on all sequences—axial and coronal T2-weighted images (A,C), axial FLAIR (B) image, and axial DWI (D). There is a cystic-appearing mass along and extending into the right lateral ventricle without diffusion restriction. Occasionally, the cyst may be hyperintense to CSF on FLAIR if there is a high protein content. Fast imaging employing steady-state acquisition (FIESTA) is another important sequence to demonstrate the cystic nature of the lesion and to better characterize its wall (E).

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FIGURE 8.21 Cystic necrosis in high-grade glioma. T1-weighted (A) and T2-weighted (B) images demonstrate a right insular lesion without calcifications or hemorrhage evident on gradient-echo image (E). Contrast-enhanced image (F) further suggests central necrosis. Fluid-attenuated inversion recovery image (C) demonstrates that fluid within the lesion is not isointense to cerebrospinal fluid (i.e., hyperintensity) due to the proteinaceous content of the neoplastic cystic necrosis. No significant diffusion restriction is noted (D).

FIGURE 8.22 Cystic necrosis and hemorrhage in a thyroid metastasis. A: Axial T2-weighted MR. B: Axial T2*weighted GRE MR image. Note the fluid–debris level inside this lesion, that also exhibits prominent perilesional edema, features that are frequently seen in hemorrhagic and necrotic tumors.

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FIGURE 8.23 Cystic necrosis in metastases. T1-weighted (A) and T2-weighted (B) images demonstrate left frontal and parietal metastases. Note intralesional fluid–debris levels, proving the cystic nature of the lesions, with ventral fluid being apparently isointense to cerebrospinal fluid. Contrast-enhanced images (C) further suggest central necrosis. Fluid-attenuated inversion recovery (D) demonstrates that ventral fluid within the lesions is not isointense to cerebrospinal fluid (i.e., hyperintensity) due to the proteinaceous content of the neoplastic cystic necrosis.

FIGURE 8.24 Diffusion-weighted imaging assisting in the differentiation of inflammatory/infectious disorders from neoplastic lesions. Axial FLAIR (A), DWI (B), and T1-weighted postcontrast (C) images of the upper row demonstrate a ring-enhancing lesion displaying a characteristic homogeneous restricted diffusion, typical features of pyogenic abscess. In the bottom row, coronal T2-weighted (D), axial DWI (E), and a different patient with axial T1-weighted postcontrast (F) images also show findings which may inflammatory or infectious etiology. However, this lesion demonstrates heterogeneous peripheral restricted diffusion (fungal abscess). Similar findings may be seen in necrotic neoplasms.

TABLE 8.8 Intratumoral Hemorrhage Versus Benign Intracranial Hematomas

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FIGURE 8.25 Hemorrhagic metastasis. A: FLAIR MR image. B: T2*-GRE MR. A heterogeneous and irregular mass exhibiting surrounding edema is present in the right posterior frontoparietal region demonstrating a fluid level. The anterior portion of the mass demonstrated nonhemorrhagic components of the tumor. Persistent edema, in the setting of an old hemorrhage, and enhancing nonhemorrhagic tumor tissue, allow for differentiation between benign and tumor-associated hemorrhage. (Courtesy of Victor Hugo Rocha Marussi, MD; Sao Paulo/Brazil.)

FIGURE 8.26 Cystic hemorrhagic metastasis. A: Axial T2-weighted MR. B: Axial T2*-weighted GRE MR image. Note the fluid–debris level within this hemorrhagic lesion in the right frontoparietal region with extensive perilesional edema, features that are frequently seen in cystic hemorrhagic tumors.

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FIGURE 8.27 Intratumoral hemorrhage with complex signal intensities (retinoblastoma metastasis). A: Sagittal T1weighted magnetic resonance (MR) imaging (600/25). B: Axial T2-weighted MR (2,500/80). C: Necropsy specimen. The right inferior frontal hemorrhagic mass shows marked heterogeneity on MR (B,C), with several different stages of hemorrhage: (1) methemoglobin, (2) deoxyhemoglobin, and (3) ferritin/hemosiderin. High-intensity edema (C,4) and fluid level (C, arrow) contribute to the complex appearance. The tumor is grossly hemorrhagic on pathology. (C: Courtesy of Dr. Lucy Rorke, Philadelphia, Pennsylvania.)

FIGURE 8.28 Intratumoral hemorrhage with delayed evolution of blood (lung carcinoma metastasis). A: T1-weighted

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magnetic resonance (MR) (600/20). B: T2-weighted MR (2,500/80). C: T1-weighted MR (600/20) after 7 days. D: T2-weighted MR (2,500/80) after 7 days. E: T1-weighted MR (600/20) after 17 days. F: T2-weighted MR (2,500/80) after 17 days. The dependent layer of deoxyhemoglobin (open arrow) with ventral fluid (closed arrow) represents hemorrhage into a cystic or necrotic tumor. Note the persistence of deoxyhemoglobin after 17 days (normally, deoxyhemoglobin disappears by 3 to 5 days), indicating slowed evolution of blood-breakdown products. This is probably due to marked and persistent intratumoral hypoxia.

FIGURE 8.29 Intratumoral hemorrhage with minimal ferritin/hemosiderin and persistent perihematoma high intensity (anaplastic astrocytoma). A: Sagittal T1-weighted magnetic resonance (MR) (600/20). B: Sagittal T2-weighted MR (3,000/80). Even though hematoma is chronic (A, B, arrows), note the very minimal and irregular ferritin/hemosiderin on the T2-weighted image (B). Persistent hyperintensity in the temporal lobe around the chronic hematoma on the T2-weighted image (B) indicates tumor plus edema. C: A brain autopsy section from anaplastic astrocytoma with hemorrhage and necrosis shows persistent expansion of the involved parenchyma and mass effect despite the chronic nature of the hemorrhage. (C: Courtesy of Dr. N. K. Gonatas, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.)

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FIGURE 8.30 Tumoral fat on the basis of the signal intensity pattern and chemical shift artifact. A: Coronal T1weighted magnetic resonance (MR) (600/20). B: Coronal T2-weighted MR (2,800/80). C: Proton density–weighted MR (2,800/30). D: T2-weighted MR (2,800/80). Intraventricular rupture of a high-intensity temporal dermoid (A,B, arrows) is indicated by fat floating within the lateral ventricles (C,D). Note that the signal intensity of the material parallels that of subcutaneous fat and shows a chemical shift artifact (C,D, arrows) (high intensity at the water–fat interface and signal void at the fat–water interface along the frequency-encoding gradient, which is oriented anterior– posterior).

Some components of tumors may have specific and (occasionally) pathognomonic signal intensities other than hemorrhage. Fat-containing neoplasms (e.g., teratoma, dermoid, lipoma) are easily identified on MRI because fat is high intensity on T1-weighted images and intermediate intensity on conventional T2-weighted images and parallels the intensity of subcutaneous fat. The high signal of fat on fast spinecho techniques makes this distinction somewhat more difficult. A more specific clue to the diagnosis of fat in tumors is the “chemical shift artifact,” which is related to the difference in resonant frequencies between fat and water protons. This artifact is displayed as a region of signal void at fat–water interfaces and hyperintensity at water–fat interfaces along the frequency-encoding axis (Fig. 8.30). Fatselective suppression methods also can play a role in the distinction of etiologies of hyperintense tumors on T1-weighted images (Fig. 8.31). Melanin in tumors (see Metastatic Disease) is also seen as high intensity on T1-weighted images, but it is intermediate intensity on T2-weighted images (Fig. 8.32) (24), distinct from amelanotic tumors and from hemorrhage based on this unique combination of signal intensities (Table 8.9). Unfortunately, melanoma metastases are commonly both hemorrhagic and melanotic (Fig. 8.33), which makes the imaging less specific. Profound hypervascularity associated with tumors markedly narrows the differential diagnosis to hemangioblastoma, glioblastoma, anaplastic oligodendroglioma, or rarely hypervascular metastases like renal cell carcinoma (Figs. 8.34 and 8.35). These large vessels are shown on spin-echo images as linear or serpentine regions of signal void within and about neoplastic masses and are an important sign for the diagnostician and the surgeon. Another useful sign for differential diagnosis is seen in markedly hypercellular neoplasms, especially those with only minimal cytoplasm. These tumors are, characteristically, relatively low intensity on T2-weighted images and approximate the intensity of normal gray matter (Fig. 8.36). This is a characteristic MR feature of lymphoma and undifferentiated small round cell tumors, such as medulloblastoma, pineoblastomas (PBs), and neuroblastomas. Other tumor types also typically have low intensity on T2weighted images, including mucinous adenocarcinomas (Figs. 8.37 and 8.38) (particularly from the gastrointestinal or genitourinary tracts or occasionally lung). Metastases from small-cell lung cancer can 444

also have somewhat lower signal intensity on T2-weighted images owing to their hypercellular nature. Similarly, highly cellular astrocytic (generally higher grade) neoplasms have lower water content.

FIGURE 8.31 Ruptured dermoid, use of fat suppression. Sagittal T1-weighted magnetic resonance images without (A) and after (B) fat suppression show a midline superior cerebellar cistern hyperintense mass with foci of hyperintensity in the vermian subarachnoid space (A) that all become low intensity after fat suppression (B).

FIGURE 8.32 Tumoral melanin in melanoma metastasis. A: Coronal T1-weighted magnetic resonance (MR) (600/20). B: Axial T2-weighted MR (2500/80). C: Histopathologic specimen (hematoxylin and eosin, ×100). The densely melanotic, nonhemorrhagic melanoma metastasis (A,B, arrows) is hyperintense on the T1-weighted image (A) and isointense or only minimally hypointense to cortex on the T2-weighted image (B). This mass was densely melanotic (C, dark reddish-brown staining) with no evidence of iron on microscopic examination.

TABLE 8.9 Intratumoral Melanin Versus Hemorrhage

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FIGURE 8.33 Melanoma metastases with both hemorrhage and melanin content. Brain autopsy sections (A) show hemorrhagic melanoma metastasis in the mid-parietal gyrus. A microscopic section from another case (B) exhibits nests of neoplastic cells containing melanin (fine brown pigment), in addition to hemosiderin-containing macrophages (coarse brown pigment) and fresh blood. (A: Courtesy of Dr. N. K. Gonatas, Hospital of the University of Pennsylvania, Philadelphia, PA.)

FIGURE 8.34 Renal cell carcinoma metastasis as a hypervascular hemorrhagic mass. Sagittal T1-weighted images (A1,A2) show an intra-axial mass with a hemorrhagic component. T2-weighted images (B1,B2) confirm intra-axial localization, demonstrate hemorrhagic and nonhemorrhagic components with extensive edema, and note important regions of signal void in the nonhemorrhagic portion of the lesion (B1). Marked enhancement of the nonhemorrhagic component (C1,C2) is seen on magnetization transfer–suppressed T1-weighted images. The differential diagnosis of hypervascular intra-axial masses is very limited; the presence of hemorrhage makes renal cell metastasis (or glioblastoma) far more likely than hemangioblastoma.

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FIGURE 8.35 Anaplastic oligodendroglioma. The lesion shows several specific features that allow characterization of the lesion. First, there is irregular heterogeneous signal intensity with central fluidlike signal on T1-weighted (A–C), T2-weighted (D), and postcontrast (E) images, suggesting necrosis. Second, there are several linear and focal regions of signal void (B–D), indicating hypervascularity. Third, there is relatively low intensity on the T2-weighted images in the solid nonnecrotic portion of the mass (isointense to cortex), suggesting hypercellularity (D). Fourth, there is a large amount of “edema” and mass effect. Fifth, thick irregular enhancement is present (E). Anaplastic oligodendrogliomas are virtually identical to glioblastomas on magnetic resonance. Necrosis, neovascularity and hypercellularity are shown on the histopathologic specimen in this case (F).

TUMOR ENHANCEMENT AND THE BLOOD–BRAIN BARRIER The brain is highly dependent on a constant internal milieu. This critical function is accomplished mainly by the unique endothelial cells (ECs) of brain capillaries, which form a continuous wall that restricts the movement of many substances from the bloodstream to the interstitial space of the brain, exhibiting some important and vital functions, such as maintenance of brain homeostasis, regulation of influx and efflux of various molecules, and protection from harm, all of them determined by its specialized multicellular structure (25). These capillary cells are part of a very complex physiologic phenomenon known as the blood–brain barrier (BBB), a concept postulated first by Goldmann in 1913 (26) but not conclusively demonstrated until the 1960s by electron microscopy (27). The cerebral blood 447

vessels are formed by the ECs which represent the primary elements of the BBB. ECs of the BBB differ from those in other tissues due to their unique continuous intercellular tight junctions (TJs), lack of fenestrations, and extremely low rates of transcytosis, limiting both the paracellular and transcellular movement of molecules through the EC layer (25). In addition to TJs in cerebral capillary endothelium, these cells are also surrounded by a sheath of astrocytic foot processes (Fig. 8.39). The passage of molecules through the BBB is regulated by a series of specific transporters, which allow for delivery of nutrients to the brain and extrusion of potential toxins (25). An insult to this finely regulated equilibrium results in increased permeability or breakdown of the barrier, resulting in extravasation of plasma proteins and vasogenic edema. In this context, metalloproteinases (MMP), an enzyme family found among components of the neurovascular unit (NVU), play an important role: it has been shown that inhibition of these enzymes yields a decreased infarct size and prevents BBB breakdown after a focal ischemic stroke (28–30). Permeability can be also mediated by the expression of vascular endothelial growth factor (VEGF), with isoform A reported to increase permeability in gliomas and isoform B reported to prevent BBB breakdown (31,32). Astrocytes have numerous crucial roles in addition to BBB maintenance, and act as modulators in synaptic transmission via gliotransmitters and synaptogenesis (33), serve as progenitors of neural cells (34,35), and act as professional phagocytes.

FIGURE 8.36 Tumor with dense hypercellularity and scant cytoplasm as low intensity (lymphoma). A: T1-weighted magnetic resonance (MR) (600/20). B: T2-weighted MR (2,800/80). C: Histopathologic specimen (hematoxylin and eosin, low-power field). D: Histopathologic specimen (hematoxylin and eosin, high-power field). The right cerebellar lymphomatous mass (A,B, arrows) is of relatively low intensity on the T2-weighted image (B), consistent with its dense hypercellularity and minimal cytoplasm (high nucleus:cytoplasm ratio) revealed by microscopy (C,D).

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FIGURE 8.37 Mucinous carcinoma metastases from colon carcinoma. Sagittal T1-weighted (A), sagittal FLAIR (B), coronal T1-weighted postcontrast (C), and axial T2-weighted images demonstrate a right cerebellar mass with peripheral enhancement and central necrosis. The central nonenhancing region demonstrates low signal intensity on T2-weighted images (D). No diffusion restriction seen on DWI (E).

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FIGURE 8.38 Mucinous carcinoma metastases from colon carcinoma. Axial T2 (A,B), fluid-attenuated inversion recovery (C,D), gradient echo (E,F), T1 precontrast (G,H), and T1 postcontrast (I,J) images demonstrate a right cerebellar mass with peripheral enhancement and central necrosis. The central nonenhancing process demonstrates low signal intensity on the T2-weighted images. In addition, the lack of susceptibility artifact on the gradient-echo images excludes hemorrhage, further allowing refinement of the differential diagnosis. Mucinous metastases from adenocarcinomas of the lung or gastrointestinal or genitourinary tract can appear this way.

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FIGURE 8.39 The normal blood–brain barrier. A: Artist’s conception, cerebral capillary structure. B: Normal cerebral capillary, electron microscopy. Cerebral capillaries are enveloped by astrocytic foot processes and have endothelial cells with partially fused membranes (“tight junctions,” A), seen at the lower right of the electron micrograph (B) of a normal rat brain capillary cross section. C,D: Microscopic imaging of normal and angiogenic blood vessels. C: Scanning electron microscopic (SEM) imaging of a polymer cast of normal microvasculature, showing the simple, organized arrangement of arterioles, capillaries, and venules. D: SEM image of cast of tumor microvasculature, showing disorganization and lack of the conventional hierarchy of blood vessels. Arterioles, capillaries, and venules are not identifiable as such. (A: Courtesy of Dr. P. Cancilla, Los Angeles, CA. B: Modified from Goldstein and Betz, with permission. C,D: McDonald DM, Choyke PL. Imaging of angiogenesis: from microscope to clinic. Nat Med 2003;9:713–725, with permission.)

Aside from EC structure and other unique morphologic features of cerebral capillaries, several carrier systems and specialized enzyme-mediated systems are found in these cells, which also represent part of the barrier. BBB interfaces are not found in some regions of the brain, notably the choroid plexus, pituitary gland, and circumventricular organs such as median eminence, area postrema, and pineal gland (36). Capillaries in these regions lack TJs, as they do in dura and pia mater. The outermost layer of arachnoid has TJs and acts as a barrier between CSF and brain (37). Blood–CSF barriers are also present in the choroid plexus; that is, intravascular substances enter the choroid extracellular space at a much faster rate than they enter the CSF surrounding the choroid. In normal brain and areas of intact BBB, the capillaries are impermeable to intravascularly injected contrast agents. On MR images, only those regions of tissue that lack an intact BBB enhance in the conventional sense. Note that tumor enhancement on MRI is due to accumulation of the paramagnetic contrast in the water-containing interstitial space. The contrast agent enhances the relaxation of the water protons nearby, that is, the water in the enhancing tissue is visualized as high intensity on T1weighted images (in the case of gadolinium-containing agents). The rationale for tumor enhancement is multifactorial but relatively simple. Generally speaking, tumors have a tendency to evoke the formation of capillaries within and sometimes adjacent to their tissue. Glioma cells interact with vessels by invading and migrating along the pre-existing vasculature. Subsequently, co-option of the host vessels occurs and the tumor starts to grow (38). As the tumor continues to expand, growth factors such as the VEGF, tend to promote angiogenesis and increase vascular permeability, causing a structural and functional BBB disruption (39–46). This angiogenesis supports further growth (47). Notably, the new blood vessels are leaky and dilated (48), as well as disorganized, tortuous, and demonstrate anomalies in the endothelial wall (40–42,49–52). Inflammatory cascade in pericytes may contribute to BBB breakdown in neoplastic diseases (53). The enhancement pattern thus reflects this extremely variable 451

and complicated series of events. Generally, tumors containing vessels lacking an intact BBB demonstrate enhancement on post contrast imaging. Metastatic lesions possess non-CNS capillaries that are similar to their tissue of origin, so brain metastases virtually always enhance. Extra-axial tumors (e.g., meningiomas) arise from tissues whose capillaries lack TJs, and consequently these tumors enhance. Enhancing tumor vascularity and vascular permeability may also be assessed with dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) MR perfusion techniques (Figs. 8.40 and 8.41). It is believed that the presence or absence of capillary endothelia with TJs is the most important factor in predicting enhancement (36); however, the volume of available extracellular space is also an important contributor (54). Ultimately, several factors are necessary for contrast enhancement to occur: absence of the BBB, adequate delivery of the contrast agent (i.e., perfusion), sufficient extracapillary interstitial space for the accumulation of contrast agent, appropriate contrast agent dosage, spatial resolution and imaging parameters to allow its detection, and sufficient time for the contrast agent to accumulate in the region in question. Note that formation of tumor capillaries deficient in BBB constituents, rather than active destruction of the BBB, is presumed to account for tumor enhancement. Moreover, the enhancement of a particular tumor may not merely be an “all-ornone” phenomenon; instead, the function of the BBB should be thought of as a continuum, and capillary structure (and other factors) may be aberrant to different degrees in tumors. Therefore, enhancement may be immediate or delayed, transient or persistent, dense and homogeneous, or minimal and irregular. Contrast enhancement in the traditional sense can be thought of as a snapshot in time, reflecting the degree of contrast agent accumulation in the extravascular, extracellular space at one instant in what is a continuous process. Permeability imaging (see later discussion) quantifies the rate of contrast agent extravasation (e.g., ktrans), providing a measure of BBB permeability and a possible metric for tumor angiogenesis. Perhaps one of the most important points for the radiologist to remember is that the lack of enhancement does not necessarily signify the absence of tumor. In other words, one cannot use enhancement to “separate tumor from edema” in infiltrative gliomas as the tumor is often present in areas that do not enhance. It has long been recognized that the intravenous injection of contrast agents aids in the CT delineation of many intracranial disease processes, especially neoplasia. Similarly, intravenous contrast is definitely indicated for complete evaluation by MRI. Distinction of nonspecific high-intensity foci attributed to ischemia and aging in the deep white matter from metastases or lymphoma can be virtually impossible unless one uses intravenous contrast. Small lesions, especially metastases to cortex, can be missed without contrast enhancement, and metastases may be indistinguishable from other chronic insults in elderly patients in the absence of contrast (Fig. 8.42). Patterns of contrast enhancement and relationship to mass effect often alter differential diagnosis. Leptomeningeal and subependymal metastases are certainly much better detected with intravenous contrast if one is relying on conventional images, but more recent data show FLAIR to be highly sensitive and perhaps even more sensitive than contrastenhanced T1-weighted images (55).

FIGURE 8.40 Anaplastic astrocytoma with high cerebral blood volume (CBV) discordant with enhancement. The right thalamic grade III astrocytoma (A: axial T2-weighted image) shows just areas of faint enhancement (B: Axial T1weighted postcontrast with fat saturation) at the lateral aspect of the lesion. However, the optimal site for biopsy was revealed on rCBV map (C) with the highest values seen in the posteromedial aspect of the lesion where only mild enhancement was noted. (Courtesy of Renato Mendonca, Sao Paulo.)

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FIGURE 8.41 Glioblastoma with high cerebral blood volume (CBV) discordant with regional enhancement. The right temporal and occipital glioblastoma shows classic irregular ring enhancement in the occipital pole (A) but relatively normal CBV in that region (B). The optimal site for biopsy in the right temporal lobe was revealed by CBV abnormality in a different area where only mild enhancement was noted (C,D).

FIGURE 8.42 Separating chronic nonmalignant microvascular changes from metastatic lung carcinoma using

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intravenous gadolinium. Axial fluid-attenuated inversion recovery (FLAIR) (A,B) and postcontrast T1 weighted image (C,D) show multiple small punctate areas of enhancement with minimal adjacent edema (arrows). These lesions are difficult to separate from underlying chronic microvascular changes on the FLAIR images, illustrating the importance of intravenous gadolinium in the evaluation of suspected metastases.

Newer higher relaxivity gadolinium-based contrast agents (GBCA) such as Gadavist and MultiHance have demonstrated improvement in percentage lesion enhancement, yielding better lesion characterization (56–65). Heightened sensitivity to contrast enhancement has been shown by using the magnetization transfer saturation technique to suppress background parenchyma (66), although this method has not been universally accepted because of secondary, unwanted nonpathologic enhancement and an overall reduced signal-to-noise ratio.

ADVANCED LESION CHARACTERIZATION TOOLS: DIFFUSION, PERFUSION, PERMEABILITY, SPECTROSCOPY, FUNCTIONAL MRI, AND MOLECULAR IMAGING There are several advanced MRI techniques that have become widely available including DWI and diffusion tensor imaging (DTI), perfusion and permeability imaging, MRS, and functional MR imaging (fMRI). These techniques, often referred to as the advanced imaging methods, can play an important role in several areas of neuroradiology, such as imaging of tumors, cerebrovascular disease, infectious disease, epilepsy, Alzheimer’s disease, and psychiatric disorders (67). In this section, the most important clinical applications of these sequences and technical considerations are highlighted. Brain tumor imaging is one of the most important applications of advanced imaging with at least six common goals in preoperative and posttreatment setting: (1) differentiation of neoplasm versus non neoplastic process; (2) differentiation of primary brain tumor versus metastatic disease or lymphoma; (3) grading of glial neoplasms; (4) optimal guidance for biopsy; (5) differentiation of recurrent tumor versus treatmentrelated changes; and (6) posttreatment evaluation of tumor (67). Posttreatment imaging of high-grade gliomas and metastases represent a rapidly evolving field, and although the advanced techniques cited above have emerged as promising in the differentiation of recurrent tumor from treatment-related changes, at present, these techniques have not been validated in clinical trials. Perfusion Imaging Perfusion-weighted imaging (PWI) encompasses both DSC MRI and DCE MRI, as well as arterial spinlabeling (ASL), which will be discussed later on this chapter. In brain tumors, DSC perfusion is most conventionally used to measure cerebral blood volume (CBV) and DCE is used to measure vascular permeability. Dynamic Susceptibility Contrast MRI and Cerebral Blood Volume DCE MRI is a first-pass bolus technique monitored by a series of T2-weighted or T2*-weighted MR images (68), sometimes referred to as perfusion-weighted or bolus tracking (68), which is based on indicator-dilution methods that can estimate some parameters using magnetic susceptibility properties of paramagnetic contrast agents (e.g., gadolinium chelates). DSC MRI perfusion reflects tumor vascular morphometry and the relative cerebral blood volume (rCBV) and appears to be the most useful, robust, and commonly used perfusion metric derived from DSC MRI in patients with brain tumors that has been correlated with tumor grade and vascular density (68,69). rCBV has also been shown to correlate positively with choline (a marker of proliferative tumor activity) (70), correspondingly increasing with evolution of a low-grade to a high-grade glioma (71). In addition, rCBV may help to differentiate primary CNS lymphoma (PCNSL) and GBM (72) and certain metastases from high-grade astrocytomas (73,74), aid in the differentiation of posttreatment changes from tumor recurrence (74,75), and predict early local recurrence or malignant transformation (76). rCBV has also been proposed as a guide for the stereotactic biopsy of the portions of gliomas most likely to yield the highest grade (77). rCBV thresholds have been proposed for distinguishing low-grade from high-grade gliomas and predicting which low-grade lesions may have a propensity for malignant transformation (78), and rCBV measurements may also help to distinguish low-grade oligodendrogliomas from astrocytomas (79). Furthermore, rCBV has been incorporated into integrated MRI-based strategies that are accurate in the differentiation of several intra-axial brain masses (80). At the time of this writing, rCBV images have become standard in most brain tumor imaging protocols, both at the initial time of diagnosis for characterization, as well as in follow-up scans to search for recurrent tumor. 454

Dynamic Contrast-Enhanced MRI and Vascular Permeability DCE MRI is a technique that provides radiologists with several metrics which are useful in quantitative or semi-quantitative assessment of the BBB integrity and leakiness of tumor microvasculature (68). It should be noted that the primary DCE MRI variable of interest in most brain tumor studies is ktrans, generally used as a surrogate of vascular permeability in oncologic studies. The ktrans value may be increased in neoplasms that produce various vascular permeability factors. It has been demonstrated that ktrans correlates with glioma grade (81,82) and that there exists a direct relationship between ktrans and length of survival in high-grade gliomas. Moreover, substantial changes in ktrans have been documented in high-grade gliomas very soon after initiation of antiangiogenic chemotherapy, well before any notable change in tumor volume, and before correlated changes in CBV, suggesting that this tool may serve as an imaging biomarker for therapeutic response to angiogenesis inhibitors (83). Ongoing clinical trials are exploring the role of permeability imaging, as well as perfusion MRI and MRS, in the monitoring of high-grade glioma therapy. Arterial Spin-Labeling (ASL) ASL has emerged recently as a useful MRI technique for evaluation of cerebral perfusion. Arterial blood water is labeled using radiofrequency pulses in ASL and therefore does not require contrast agent administration. Additionally this technique has reduced scan duration, higher SNR, and potential for CBF (cerebral blood flow) quantification (84,85). Jiang et al have conducted a prospective study of brain tumors without any prior treatment to evaluate the potential application of ASL as an alternative for DSC perfusion in brain neoplasms (including primary brain tumors, meningiomas, and metastases). All patients underwent both 3D ASL and DSC examinations on the same 3 T scanner, and showed evidence of close correlation between these two techniques. Although further studies using a larger sample size would be necessary to confirm their findings, this method appears to represent a viable and noninvasive method for evaluation of brain tumors (85). MR Spectroscopy H-MRS is an in vivo noninvasive technique that aims to detect tumor recurrence on a biochemical level, and has been used during the last decades in the evaluation of the posttreatment brain tumors, especially gliomas (69,86). Relatively normal spectra in adults tend to have a relative predominance of N-acetylaspartate (NAA) as the dominant peak. When choline peaks predominate, especially when the choline-to-NAA ratio exceeds 2:1, the spectral signature suggests cellular proliferation, as can be seen in tumors (87); suppression of all key metabolite spectral peaks, with or without presence of lactate, suggests tissue necrosis (88). Myo-inositol (mI) levels may also correlate with glioma grade, with a trend toward lower mI levels in the presence of anaplastic astrocytomas and GBMs compared with those of low-grade astrocytomas (89). High-grade neoplasms such as GBM tend to exhibit the following typical features on MRS: elevated peaks of choline due to high cellular turnover, presence of lipids/lactate peaks due to anaerobiosis in necrotic regions, and reduced NAA levels reflecting the neuronal damage (69). Although there was great initial enthusiasm for MRS, many would concede that it has failed to meet those lofty expectations. First, there can be overlap between normal spectra and tumor-type spectra, especially among low-grade astrocytic tumors. In addition, areas of radiation necrosis can have relative choline peak elevation, and histologically both radiation necrosis and recurrent or residual tumor can be seen to coexist. Active demyelination as seen in multiple sclerosis or acute disseminated encephalomyelitis can also present with marked choline peak elevation (90). Nevertheless, although enthusiasm for MRS has waned, it can be a useful adjunct to conventional MR sequences in patients with brain tumors (80), and imaging strategies combining PWI and MRS have been shown to be useful in select cases for distinguishing surgical from nonsurgical lesions and solitary metastases from high-grade gliomas (91,92). Diffusion-Weighted Imaging DWI is a technique that is sensitive to microscopic proton diffusion in tissue. Whereas DWI is most often used to identify acute arterial ischemia, other processes that interfere with or “restrict” the movement of water can cause notable changes on DWI, including encephalitis, pyogenic abscesses, and occasionally demyelinating disease. In addition to diffusion rate, DWI signal intensity includes a T2-weighted component as well, and hence true restricted diffusion is typically ascertained by corroborating DWI 455

signal hyperintensity with reduced values on apparent diffusion coefficient (ADC) maps. Slightly reduced diffusion can be seen in highly cellular tumors such as lymphoma (Fig. 8.43), meningioma, and GBM due to the relative paucity of interstitial space and water. Practically speaking, however, it must be noted that the degree to which diffusion is reduced is far subtler and often more heterogeneous than the dramatic reduced diffusion in acute arterial infarction. Moreover, the hypercellular nature of these neoplasms is easily ascertained from the signal intensity patterns on conventional images. Several reports have suggested an inverse correlation between ADC value and glioma grade for grade II through IV astrocytomas, which likely reflects increased cellularity and relatively decreased extracellular water (93–97). Histograms of tumor ADC values have been shown to facilitate analysis of tumor ADC values and may aid in the distinction of low-grade astrocytomas from oligodendrogliomas (98), although group-to-group differences of statistical significance are often not applicable to individual cases. ADC has also been proposed as a surrogate marker for treatment response of gliomas and metastases to radiation and chemotherapy that can be observed earlier than relatively slow changes in the volume of tumor enhancement on sequential MRI scans. Successful intervention tends to increase tissue ADC, whereas decreasing ADC tends to be a harbinger of tumor recurrence. Very rapid increases in ADC have been shown to precede the development of radiation necrosis (99–103). DTI techniques sample water motion in at least six noncollinear directions, providing information about both the rate and the direction of water proton motion (104). White matter tracts in normal brain are highly structured, with the myelinated fiber tracts imparting a strong orientational bias toward microscopic water diffusion, which is therefore termed anisotropic. DTI has been explored in a number of disease states that disrupt fiber tract structure. Less-compact white matter pathways exhibit lesser degrees of anisotropy, and all types of white matter typically show greater degrees of anisotropy than are seen in gray matter structures. DTI provides a means to detect alterations in the integrity of white matter structures, although its importance in individual clinical cases has yet to be fully determined. Because infiltrating gliomas would theoretically disrupt the ordered white matter pathways to a greater degree than vasogenic edema, DTI has been proposed as a method for delineation of glioma margins and regions of tumor infiltration (105,106), and changes in fractional anisotropy (FA) in gliomas have been correlated with the degree of tumor cell infiltration determined histologically (107). In some reports, peritumoral DTI metrics enabled the differentiation of solitary intra-axial metastatic brain tumors from infiltrating gliomas, and FA-based infiltration indices enabled distinction of presumed tumor-infiltrated edema from purely vasogenic edema (108,109) but most reports have found little statistical difference between FA in infiltrating tumor and vasogenic edema (108,110) and in pure edema and tumor-infiltrated edema when data from gliomas, meningiomas, and metastases were compared (111). The use of DTI for tumor margin delineation may therefore be speculative (112). DTI also provides a means of visually depicting actual white matter pathways (diffusion tensor tractography [DTT]) (Figs. 8.44 and 8.45) (113,114), which may be useful for providing guidance in neurosurgical procedures by preoperatively depicting important white matter tracts, helping to determine the infiltration of white matter tracts by tumor, and providing evidence of degeneration of white matter tracts distal to tumor sites (wallerian degeneration). DTT has been used for visualization of tumor location relative to eloquent white matter tracts and has been found to be beneficial in the neurosurgical planning and postoperative assessment of gliomas (115,116). That said, DTI has not necessarily been uniformly accepted at the time of this writing by the neurosurgical community as an important clinical tool in mass lesion resection.

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FIGURE 8.43 Diffusion weighted-imaging. Axial T2-weighted image (A) shows a right thalamic mass isointense to gray matter on T2WI with avid enhancement (B). Despite hypercellularity causing low T2-weighted signal intensity, note only a mild diffusion restriction on DWI (C), when compared to dramatic diffusion restriction in acute stroke (D–F) (in this case, secondary to varicella zoster virus).

FIGURE 8.44 Diffusion tensor imaging. Left frontal gliomas on fluid-attenuated inversion recovery (FLAIR) (A,D) displacing corticospinal and middle longitudinal fasciculus fibers, as demonstrated by color-encoded fractional anisotropy map (C,F) and diffusion tensor imaging tractography (B,E), which may be helpful for guiding resection of these neoplasms.

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FIGURE 8.45 Intrathalamic glioma on fluid-attenuated inversion recovery (A) and T2 (B) displaces internal and external capsule fibers, as demonstrated by color-coded fractional anisotropy map (C) and diffusion tensor imaging tractography (D), helpful for guiding resection of this deep-seated neoplasm. (Courtesy of L. Tannenbaum, Edison, NJ.)

Functional MRI fMRI follows from the neurovascular coupling between neuronal electrical activity and cerebrovascular physiology as localized brain activity causes increases in cerebral blood flow and CBV that tend to overcompensate for the metabolic demand for oxygen, thereby increasing the blood oxygenation level and decreasing the amount of paramagnetic deoxyhemoglobin. This results in increased echo-planar T2weighted fMRI signal, and this effect gives the technique the name blood oxygenation level–dependent fMRI (see Chapter 33). Changes in blood oxygenation are typically detected by using high-speed gradient-echo echo-planar imaging sequences that are sensitive to the paramagnetic state of deoxygenated hemoglobin, and fMRI techniques can be used to obtain completely noninvasive tomographic maps of human brain activity responding to various stimulus paradigms, including visual, motor, and sensory (117,118). The ability to identify eloquent cortex in close proximity to brain tumors is a critical component of surgical planning prior to resection (Fig. 8.46). It is also important to determine the hemisphere dominant for speech and language function before surgical resection of many tumors. The use of electrocortical stimulation during awake neurosurgical procedures remains the gold standard for mapping functional areas, but the preoperative use of fMRI is gaining popularity as a supplemental surgical planning tool (119–122). Although randomized trials or outcome studies that definitively show benefits to the final outcome of the patient when applying fMRI presurgically have not been performed, results have suggested that the combined use of fMRI and DTI can provide a better estimation of the proximity of tumor borders to eloquent brain systems subserving language, speech, vision, and motor and premotor functions and that preoperative planning with these combined techniques may improve surgical outcomes compared to those previously reported in the literature (123,124). Several caveats must be included in dictating such cases for clinical use, most notably that the sensitivity of fMRI to brain activation is highly dependent on field strength, and that the depiction of functioning brain is 458

highly operator-dependent.

FIGURE 8.46 Task activation fMRI for preoperative planning, right frontal anaplastic astrocytoma. Series of images from fMRI study maps primary sensorimotor cortex and supplemental motor area in relationship to astrocytoma. Multiplanar reformatting shows primary motor function is posterior and superior to tumor margin.

Emerging MR Imaging Techniques Digital subtraction of postcontrast from precontrast MR images is a technique that has the potential to improve visualization and provide a more accurate delineation of the enhancing tumor extent compared to unsubtracted postcontrast images, also allowing for better differentiation from the hemorrhagic tumoral component. T1 subtraction maps could be implemented relatively rapidly in clinical trials and might play a role in facilitation of automated, computer-aided lesion segmentation and detection of tumor recurrence. Additionally, there are a variety of promising physiologic imaging techniques on the horizon, such as 23Na MRI which is able to detect changes in tissue sodium concentration and chemical exchange saturation transfer (CEST) imaging which is sensitive to endogenous mobile proteins and peptides, that may become a part of treatment response assessment in the future (125).

PRIMARY BRAIN TUMORS According to the Central Brain Tumor Registry of the United States (CBTRUS) report, 66,240 cases of primary brain and CNS tumors are expected to be diagnosed in 2014, of which 22,810 expected to be malignant and 44,430 nonmalignant (126). Tumor classification is an inexact science because of incomplete understanding of tumor histology, molecular genetics, and sometimes even clinical features. Histopathology still remains crucial for the accurate diagnosis of brain tumors and the assessment of their prognosis and treatment; however, its impact remains controversial for both tumor classification and grading. The WHO periodically edits and updates their classification in order to address these controversies, adding multiple new entities and variants in 2007 (7). Gliomas account for 28% of all tumors and 80% of all brain malignant neoplasms (126–128). Most adult gliomas are supratentorial, whereas most of these tumors in childhood are infratentorial. More men than women are affected, and brain tumors are found more commonly in whites than in blacks (4). Classically, astrocytomas could be separated in two different groups based on their imaging appearance: (1) localized (Table 8.10)—pilocytic astrocytoma (PA), subependymal giant cell astrocytomas, and pleomorphic xanthoastrocytoma (PXA); (2) infiltrative (Table 8.11)—representing the vast majority of cases and that include the low-grade (grade II) and high-grade (grades III and IV) gliomas. Symptoms and signs are linked to direct tissue destruction, infiltration, or secondary increase in intracranial pressure. As will be discussed later on this chapter, MRI plays an important role in the preoperative evaluation, in terms of tumor detection, grading, and lesion delineation, as well as in the 459

posttreatment evaluation. At present, DWI and DSC MR PWI have been used as a part of a preoperative neuroradiologic evaluation in combination with histopathology, demonstrating a strong correlation between glioma grade and rCBV (129), and attempting to establish the correct tumor lineage (oligodendroglial or nonoligodendroglial components) and predict clinical outcomes (68,130,131). TABLE 8.10 Classification of Astrocytic Brain Tumors

TABLE 8.11 Diffuse Astrocytic Brain Neoplasms

Histopathologic Grading of Astrocytic Neoplasms WHO grade is one of the most important of the aforementioned criteria and the primary factors for this classification are cell density, nuclear and cytoplasmic pleomorphism, mitoses, necrosis, and vascular endothelial and pericytic proliferation. Using structural sequences and PWI, MR is able to estimate the tumoral cellular density, presence of necrosis, and vascular proliferation; however, pleomorphism and mitoses are characterized only by pathologic examination. Grade I tumors have none of these features, except for slight increased cellularity and minimal cellular pleomorphism, featuring a low proliferative potential and there is a high probability of successful surgical treatment. Grade IV is assigned to those tumors showing a high mitotic rate, cytologic malignant features, and frequent necrosis and is associated with rapid disease evolution to a fatal outcome. Grade IV tumors not only demonstrate cytologic atypia (common in diffuse astrocytoma grade II), anaplasia, and mitotic activity (such as in anaplastic astrocytoma grade III) but also microvascular proliferation (7). In conclusion, although histologic classification and grading play a key role in tumor diagnosis, they have significant limitations. It is well known that these tumors may have coexisting areas with different degrees of anaplasia. Moreover, malignant transformation of lower-grade tumors is not infrequent and often malignant features may appear in specific portions of the mass at a given time, presenting a challenge for accurate pathologic diagnosis. It is also important to realize that pathology interpretations vary greatly among experienced tumor pathologists, even for the most important findings like necrosis, endothelial proliferation, and mitotic figures (132). Additionally, involvement of eloquent areas may limit the surgical approach, thus altering prognosis. Inclusion of the tumors’ genetic profile in initial evaluation may not only improve diagnostic accuracy but may also identify those patients who can benefit the most from a targeted therapy (133). Infiltrative Astrocytic Tumors Fibrillary astrocytomas are the most common and well-known grade II neoplasms, characterized by the presence of fibrillary astrocytes within a loose microcystic matrix. Gemistocytic and protoplasmic astrocytomas are other variants in this group. They differ from each other not only in regard to the 460

imaging findings, but also in aspects of management, clinical behavior, and overall survival (OS) rates (134). In adults, these tumors are found most often in the cerebral hemispheres (i.e., in a supratentorial location), whereas in children, infiltrative astrocytomas are typically found in the brainstem. As opposed to the fibrillary astrocytes, the protoplasmic astrocytes are found in the gray matter. Mixed gliomas (e.g., oligoastrocytoma) may also occur infrequently. Prognosis also varies by the age of the patient. In general, when these tumors are found in older patients, they are more frequently anaplastic, more aggressive, and more symptomatic. On the other hand, in younger patients, infiltrative astrocytomas are usually asymptomatic for a longer period of time, show slower rates of growth, and tend to be more well differentiated histologically (135). Similarly, tumor dedifferentiation occurs more frequently and over a shorter period of time in older patients. Discovery of several different molecular pathways of glioma progression with identification of specific gene loci involved in this process has provided new insights, which may provide targets for future chemotherapeutic regimens (136,137). Fibrillary (Diffuse) Astrocytoma Astrocytoma (WHO grade II) represents the well-differentiated subtype of infiltrative astrocytomas and accounts for 25% to 30% of hemispheric gliomas in adults and perhaps up to 30% of cerebellar gliomas found in childhood (18). Although astrocytoma represents the benign end of the spectrum of infiltrative astrocytomas and shows a more indolent course than glioblastoma and anaplastic astrocytoma, the overall prognosis of such lesions is still grim, with median survival rates reported as approximately 7 to 8 years (138,139). Furthermore, it is recognized that about 10% of these low-grade lesions “dedifferentiate” into more malignant forms over time (139). When astrocytomas recur, progression to anaplastic astrocytoma is seen in 50% to 75% of cases (139). Mutations in IDH1 are present in approximately 70% to 80% of grade II or III gliomas (140). Degenerative microcyst formation may be encountered in these well-differentiated neoplasms, but macroscopically they are solid tumors. Microscopically, there is usually a clear region of hypercellularity situated within white matter, often with considerable cellular heterogeneity, even in the absence of frank anaplasia. However, the lesions can be so subtle that reactive astrocytic change is also considered. The tumor can show marked infiltration of structures without significant distortion of gross morphology. MRI demonstrates adult astrocytomas as relatively homogeneous mass lesions of the cerebral hemisphere, although heterogeneity can be seen in a proportion of cases. Because these tumors are typically hypocellular (Fig. 8.47), they are high in water content and therefore hyperintense on T2weighted images (Fig. 8.48). These lesions usually lack significant peritumoral “edema,” which distinguishes them from more malignant astrocytic tumors on MR. Furthermore, the borders of welldifferentiated astrocytomas often appear isodense to normal brain on CT. MRI, because of its higher contrast resolution, misleadingly displays these lesions as clearly defined regions of abnormal signal. However, it has been documented that tumor tissue may extend beyond the confines of the imaging abnormality (141–143). Intratumoral regions suggestive of flow within vessels on MRI are not typical for astrocytoma. Although focal cystic areas may occasionally be seen on imaging studies, it may not be possible to distinguish microcystic change (which is not surgically drainable) from macroscopically cystic regions of tumor on either CT or MRI. In fact, the most common glial neoplasm with calcification is the astrocytoma, despite the fact that oligodendrogliomas have the highest frequency of calcification.

FIGURE 8.47 Histologic features of astrocytoma. Note moderately cellular proliferation of astrocytes in a vacuolated matrix and occasional microcyst formation (A,B). In this low-grade astrocytoma, nuclear pleomorphism is mild, mitotic figures are rare, and no necrosis or vascular proliferation is seen. However, cell borders are ill defined, and tumor cells may infiltrate beyond the grossly appearing tumor boundaries.

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FIGURE 8.48 Diffuse astrocytoma. A–C: Proton density–weighted magnetic resonance (3000/30), right frontal temporal–insular astrocytoma (inferior to superior). D: Coronal necropsy specimen, myelin stain. The high-intensity right-sided, low-cellularity mass (A–C, arrows) is homogeneously hyperintense, with no evidence of hemorrhage or necrosis. Note the absence of high signal in adjacent white matter. The poorly delineated nature of an infiltrating astrocytoma from a different patient (D) with a similar lesion is seen as an ill-defined extensive region of decreased staining in the right insula and deep temporal region. (D: From Okazaki H, Scheithauer B. Atlas of Neuropathology. New York: Gower Medical; 1988, with permission.)

Usually, these tumors do not show significant enhancement after administration of a gadoliniumbased MR contrast agent; however, this atypical feature has been reported in approximately 20% of low-grade gliomas (144). In general, contrast enhancement is not recognized as a reliable indicator of the grade of infiltrative astrocytomas. MR perfusion imaging, however, has shown promise for differentiation between low-grade (WHO II) and infiltrative (WHO III, IV) astrocytomas (129,145,146) and for identification of “low-grade” lesions likely to behave more aggressively (78); therefore, this technique may be used to identify tumors that either high-grade gliomas that have been undergraded because of sampling error at pathologic examination or low-grade gliomas with new angiogenesis which are undergoing progression ultimately resulting malignant transformation (147). The degree of CBV elevation has been shown to be a stronger predictor of both tumor grade and survival than degree of contrast enhancement (148). MRS in low-grade gliomas is characterized by a relatively high concentration of NAA, low level of choline, and absence of lactate and lipids, and may demonstrate a significant elevation of the mI peak, generally with choline/creatine (Cho/Cr) and choline/NAA ratios lower than 2.0. Nonetheless, mI/Cr ratio is typically higher than in high-grade gliomas. ADC values may also be helpful in grade differentiation, with higher values usually found on low-grade tumors (Figs. 8.49 and 8.50) (69). The optimal treatment of these astrocytomas is unclear, but removal of all tumor tissues detected by MRI or visualized intraoperatively by the surgeon may result in longer survival than partial resection or biopsy alone (149,150). Because many of these patients can present in young adulthood and survive beyond 5 or even 10 years, deferring radiotherapy after surgery in patients younger than 50 years until progression is reasonable. Substantial postsurgical tumor warrants radiotherapy, as do patients older than 50 years. Chemotherapy is generally reserved for tumor progression. Protoplasmic Astrocytoma

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This variant of astrocytoma represents a rare subtype of grade II astrocytomas, consisting of processpoor astrocytes on a microcystic background (151). Most are found in the periphery of the frontotemporal region. This tumor affects patients generally at a younger age than the more common fibrillary subtype. As a low-grade glioma, it displays a relatively indolent behavior, although there is insufficient literature on this subject. On MRI, DWI plays an important role in its characterization showing a rim of reduced ADC around a T2-hyperintense mass, in which the central portion shows suppression on FLAIR sequence (usually greater than 50%) (151). Calcifications and enhancement are uncommon. It is also important to note that despite the low-grade designation, this subtype may share some imaging features with high-grade gliomas on MR perfusion and spectroscopy, such as elevated rCBV and high choline peaks (151) (Fig. 8.51). Differential diagnosis typically includes other astrocytic, glioneuronal, and mixed tumors, as well as oligodendroglioma.

FIGURE 8.49 Diffuse astrocytoma—two different patients. Note that both lesions are homogeneously hyperintense on T2-weighted/FLAIR images (arrows), with no evidence of hemorrhage or necrosis. There is no significant contrast enhancement.

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FIGURE 8.50 Diffuse astrocytoma—structural images and advanced imaging. An intra-axial mass in the right frontal lobe involving gray and white matter seen on T1-weighted images (C) and is fairly homogeneous and hyperintense on fluid-attenuated inversion recovery (A) and T2-weighted images (B). Note the absence of significant edema within the adjacent white matter (A, blue arrow), a common feature of astrocytoma on MRI. DSC perfusion imaging (E) reveals just a slight increase in rCBV, as well as mild elevation of choline on MR spectroscopy (F). However, elevated peak of myo-inositol is seen, which may also be demonstrated on the color map (G), findings which support the diagnosis of low-grade glioma.

Anaplastic Astrocytoma The intermediate form of the infiltrative fibrillary astrocytoma is the anaplastic astrocytoma (WHO grade III). This lesion is somewhere between the astrocytoma and the glioblastoma in its histologic features and in its biologic behavior. It may arise as a dedifferentiated astrocytoma, as noted earlier, where it is found on histopathology in greater than half of the cases of recurrent astrocytoma (18). It may also arise de novo (152). Clinically, the anaplastic astrocytoma is highly malignant, with median survival times of only 2 to 3 years after surgery and radiation therapy (153–155). As in grade II astrocytomas, IDH1 and P53 mutations may also be present (140). These lesions generally occur in patients who are older than those with low-grade astrocytomas but younger than those with glioblastomas. The peak incidence of anaplastic astrocytoma of the cerebral hemisphere is in the fifth decade. On macroscopic pathology, anaplastic astrocytomas are usually more obvious and more heterogeneous mass lesions than their lower-grade counterpart. On microscopic examination (Fig. 8.52), the lesion shows more cellularity, nuclear pleomorphism, and mitotic figures than astrocytoma. As compared with glioblastoma, the necrosis and high degree of vascular proliferation are less common and hypercellularity is more moderate (135). In fact, in some cases, the presence of necrosis is considered diagnostic of glioblastoma rather than anaplastic astrocytoma. The treatment for anaplastic astrocytoma combines gross total resection with adjuvant radiation therapy and chemotherapy. MRI of anaplastic astrocytoma is variable, which is to be expected in a lesion that on histopathology represents a relatively wide spectrum of intermediate grade tumors from low-grade astrocytoma to glioblastoma. Having said this, these lesions are typically more heterogeneous than a low-grade astrocytoma but usually do not show signs of frank cystic necrosis that are typical in glioblastoma. The high-intensity abnormality on T2-weighted images is commonly accompanied by an adjacent pattern consistent with vasogenic edema, as is also commonly found in glioblastoma but is uncommon in lowergrade astrocytoma. This “edema” pattern is a reflection of a combination of tumor and edema on histology, so the radiologist should not be misled into thinking that the tumor can be separated from the 464

edema. These lesions can show areas of hypercellularity, as opposed to the lower-grade astrocytoma, and intratumoral hemorrhage or neovascularity may be seen on MR (Figs. 8.53 and 8.54).

FIGURE 8.51 Protoplasmic astrocytoma. MR imaging reveals a peripheral left frontal mass that demonstrates a rim of restricted diffusion on DWI (D), with corresponding low ADC values (E, blue arrow). Note also the absence of enhancement (C) and that its central portion, which is hyperintense on T2WI (A), is hypointense on FLAIR (B). Despite the low-grade nature of this lesion, it may present with features of high-grade tumors on MR spectroscopy (F), such as elevated choline peak. DSC perfusion shows elevation of rCBV (G).

Contrast enhancement is extremely variable in anaplastic astrocytomas in both extent and pattern (Figs. 8.53 and 8.55). The type of enhancement is variable and can be focal and nodular, homogeneous, or ringlike. Intraventricular, subarachnoid, or subependymal spread can be seen in these lesions and in other gliomas. As in high-grade gliomas, areas of heterogeneously abnormal diffusion may be found, reflecting hypercellularity which is associated with increased rCBV on PWI, as well as elevated Cho/Cr and Cho/NAA ratios (>2,0) and lipides/lactate on MRS (Figs. 8.56 and 8.57) (69). The differential diagnosis on imaging studies can be lengthy for these lesions and most commonly includes other malignant lesions (i.e., solitary metastasis, mixed glioma, oligodendroglioma, and, occasionally, lymphoma). Nonneoplastic considerations might include abscess or cerebritis, which is often clarified by DWI (156).

FIGURE 8.52 Anaplastic astrocytoma, microscopic examination. A high cellular density of pleomorphic cells in a fibrillary eosinophilic background is noted (A). Higher magnification (B) shows nuclear and cytoplasmic pleomorphism with occasional mitotic figures. Necrosis, neovascularization, and giant cell formation are not prominent features here, as they are in glioblastoma.

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FIGURE 8.53 Anaplastic astrocytoma with hemorrhage, not cavernous angioma. A focal subacute–chronic hemorrhage in the right basal ganglia on T1-weighted (A), fluid-attenuated inversion recovery (B), and T2-weighted (C) images shows several features indicative of hemorrhagic neoplasm rather than cavernous angioma: (1) an irregular, incomplete rim of hemosiderin/ferritin, (2) marked hyperintensity in tissue peripheral to the hemorrhage despite the chronic nature of the hemorrhage, (3) persistence of mass effect in the chronic hematoma, and (4) irregular peripheral enhancement (D).

Mixed Oligoastrocytomas and Oligodendrogliomas Oligodendrogliomas (ODs) and mixed oligoastrocytomas are often perceived as relatively uncommon brain tumors; however, they represent 5% to 20% of all glial tumors, with a peak incidence in the fourth to sixth decades, and as with pure astrocytic tumors, low-grade subtypes tend to occur in slightly younger patients (157). According to the WHO 2007, they are classified as grade II or III neoplasms, with the latter displaying distinctly higher cell density and pleomorphism. Most of these tumors are located superficially in the frontal and frontotemporal cortex, although a smaller number may be seen in other locations, such as the ventricular walls, cerebellum, and within the spinal cord (18). Survival appears to depend on tumor grade and prognosis is considerably better than that of infiltrative astrocytomas of similar histologic grade, due to their relative sensitivity to chemotherapy which is associated with 1p/19q codeletion (157). Anaplastic transformation of ODs occurs as it does in diffuse astrocytomas, but dedifferentiation evolves over longer periods of time (135).

FIGURE 8.54 Anaplastic astrocytoma with intratumoral hypervascularity. Proton density–weighted (A) and T2weighted (B) magnetic resonance show a large septum pellucidum mass that is hyperintense. Note intratumoral regions of flow due to prominent neovascularity, a more common feature of glioblastoma.

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FIGURE 8.55 Anaplastic astrocytoma with enhancement. A large heterogeneous mass with extensive “edema” (A) enhances prominently in an irregular fashion (B).

FIGURE 8.56 Anaplastic astrocytoma. A hyperintense mass in the left frontoparietal region is seen on fluid-attenuated inversion recovery (A,B) showing extensive “edema” in white matter, which represents an infiltrative tumor mixed with edema. A focal area within the lesion enhances after administration of contrast (B). The pattern of vasogenic edema and the focal enhancement would not favor a low-grade astrocytoma. Additionally, high values of rCBV on DSC perfusion (D) also favor this diagnosis.

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FIGURE 8.57 Anaplastic astrocytoma—structural images + advanced methods. MR imaging reveals a focal mass located in the right parietal lobe displaying low T1-weighted signal intensity (A) and a characteristic hyperintensity on FLAIR (B) and T2-weighted imaging (C) images, as well as restricted diffusion (E) and faint enhancement (D) on its periphery. Note also the elevated peaks of choline and lipid/lactate and decreased NAA on MR spectroscopy (F), associated with high values of rCBV on DSC perfusion (G).

Pathologically, ODs are solid infiltrative lesions with poorly defined borders, like infiltrative astrocytomas. They often contain cellular elements of other glial types, and are considered “mixed” in up to one-half of cases (18). These lesions are densely cellular, with only minimal acellular stroma. The lesions classically exhibit extensive infiltration of cortex, a key distinction from astrocytomas. The presence of perinuclear halos, or the “fried egg” artifact (Fig. 8.58), is a distinct feature of OD, created by autolytic imbibition of water accompanying delayed fixation. Focal cystic necrosis and intratumoral hemorrhage are frequent findings, and calcification is extremely common, being associated with the walls of intrinsic blood vessels (18). Grading of ODs is an unsettled area of histopathology, so obviously grading is not realistic with MR. Data show that microcysts and low cellularity are favorable features, whereas mitoses, vascular hypertrophy, pleomorphism, and cellular atypia are unfavorable (135). ODs are usually heterogeneous and are of relatively lower intensity than low-grade astrocytomas (i.e., isointense to gray matter) on T2-weighted images because they are typically hypercellular. This appearance can mimic that of glioblastoma. Perhaps the most useful finding on MR in the specific diagnosis of OD is the cortical infiltration and marked cortical thickening (Fig. 8.59), a finding that distinguishes these neoplasms from the astrocytic brain tumors, which arise within white matter. Pronounced thickening of cortex in a heterogeneous intra-axial mass, especially when tumoral calcification is present, should prompt the consideration of OD in adult patients, and evidence of the longstanding nature of the mass can clinch the diagnosis in a patient of the appropriate age group. Small cystic-appearing regions and hemorrhage are commonly found within these masses, which are particularly identifiable on MRI. Linear or nodular tumoral calcification is a common feature in ODs, which are the intracranial neoplasms with the highest frequency of calcification. Edema is not usually a significant feature of lower-grade ODs (158). Contrast enhancement has been reported in about one-half of the cases (159). The differential diagnosis of these lesions usually includes OD and astrocytoma, although astrocytomas are usually more homogeneous, not as frequently calcified, and are often deeper within the hemisphere, arising within the white matter (Figs. 8.60–8.63). PWI and MRS may be helpful in these patients in the differentiation of ODs with 1p/19q codeletion from those with intact alleles, usually depicting increased rCBV and high Cho/Cr ratios in the former (160).

FIGURE 8.58 Oligodendroglioma. The microscopic section demonstrates cells with regular round nuclei and perinuclear halos (“fried egg appearance”) arranged within a delicate capillary network.

Traditionally, the treatment has centered on surgical excision; however, these lesions are infiltrative and, therefore, generally not cured by surgery alone. Coexistence of deletions of chromosomes 1p/19q 468

is associated with the oligodendroglial phenotype, chemosensitivity to procarbazine, lomustine, and vincristine, and 5-year survival in excess of 90%. Thus, well-differentiated ODs with these genetic markers may be best suited for initial treatment with chemotherapy, with radiotherapy deferred until relapse or used for anaplastic lesions. Differentiation of stable lesions into more aggressive ODs or mixed OD/astrocytoma has also been seen, even after several years of stability. Gliomatosis Cerebri Gliomatosis cerebri (GC) is a rare neoplastic process that exhibits extensive involvement of brain affecting at least three cerebral lobes, generally with bilateral involvement of the cerebral hemispheres and relative preservation of the underlying neural structures. Extension to the brain stem, cerebellum, and even the spinal cord is not uncommon (161). GC is considered a grade III neoplasm by the WHO classification (2007) and this term includes “de novo” or primary gliomatosis, as well as the “secondary gliomatosis,” referring to a diffuse pattern of growth of a pre-existent focal glioma (156). GC does not apply to all gliomas that are extremely large and the term should not be used by neuroradiologists in that context, because the term means diffuse cerebral involvement. However, pathology studies have shown that infiltrative gliomas may be present in tissue that appears normal on MRI, so this distinction is sometimes difficult to ascertain with certainty. The clinical presentation is nonacute and progressive with symptoms lasting for weeks to years. The peak incidence is in the second to fourth decades (162), but all ages are affected. It is still a matter of some debate whether GC is a specific pathologic entity or is a term that includes a widely diverse group of astrocytic tumors that share the feature of extraordinary infiltration.

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FIGURE 8.59 Oligodendroglioma, value of gradient-echo imaging for characterization. Axial T2 (A,B), fluid-attenuated inversion recovery (FLAIR) (C,D), coronal FLAIR (E,F), and axial gradient-echo (G) images demonstrate a left frontal mass in a 39-year-old man. The presence of cortical thickening, well seen on the coronal FLAIR images, should suggest the diagnosis of oligodendroglioma. The area of susceptibility artifact on the gradient-echo images (G, arrow) corresponds with calcification on the computed tomography scan (not shown).

On pathologic studies, involved portions of the brain typically include nearly the extent of the cerebral hemispheres, with both gray and white matter affected and the distinction between these regions lost. On gross examination, GC can be categorized as two types: type 1 (classical form)— without tumor mass or type 2—discrete mass in addition to extensive CNS involvement (161). On microscopic examination, neoplastic (usually fibrillary) astrocytes in several stages of differentiation are evident infiltrating both gray and white matter, mainly arranged in a perineuronal and perivascular distribution. There is concomitant thickening of the white matter and extensive demyelination in areas of neoplastic involvement, without any definite focal mass production (162). MRI shows extensive parenchymal involvement, especially of the white matter, as manifested by ill-defined regions of high intensity on T2-weighted images. Contrast enhancement is not believed to be a typical feature unless dedifferentiation has occurred, developing in 30% of cases (156), although irregular enhancement in parts of the lesion is not rare at initial presentation (Figs. 8.64 and 8.65). At present, there is no standard treatment or this entity, and the therapeutic decisions should be made on case-by-case basis. 470

Surgery is rarely offered, except to relieve mass effect or to establish histopathologic diagnosis. Radiotherapy and chemotherapy may be also used.

FIGURE 8.60 Oligodendroglioma. MR imaging—(A) axial FLAIR, (B) gradient-echo, (C) T1-weighted image, and (D) T1 postcontrast—reveals a mildly T2 hyperintense (A) peripherally located ill-defined lesion displaying a faint enhancement after the contrast injection (D) and some foci of calcification on T2*weighted-GRE (B, blue arrow).

Glioblastoma Multiforme (GBM) GBM (WHO grade IV) represents the most malignant end of the spectrum of astrocytic tumors and accounts for the majority of gliomas, representing 28% of all primary brain tumors and 80% of the malignant ones (163). Half of all adult hemispheric gliomas are GBM. Data from this same source also estimated the incidence of 20,000 newly diagnosed GBM cases for the next two years (2014–2015), just in the United States (163). It is believed that most glioblastomas arise from an existing astrocytoma or anaplastic astrocytoma, but some arise de novo. Most cases are diagnosed in patients older than 50 years of age, with its peak incidence in the sixth decade. Typically, clinical signs and symptoms of elevated intracranial pressure progress rapidly over a period often as short as 1 month from their initial onset. Despite the emergence of therapeutic options during the last decades, the median OS has only shown a modest increase after the standardization of care in 2005, consisting of maximal surgical resection, followed by radiotherapy plus concomitant and adjuvant chemotherapy (Temozolamide) (164). Most GBM patients die within one year from diagnosis, and only about 5% survive more than five years, despite all aggressive therapies. Factors that appear to correlate with a somewhat better prognosis (165) include younger patients, development of glioblastoma as a secondary dedifferentiation rather than as the initial presentation, and surgical debulking. MGMT status, as well as IDH1, 1p/19q, and P53 mutations may also play a role in predicting outcomes and rates of therapy response. IDH1 and P53 are usually found in secondary GBMs, whereas the 1p/19q mutation is strongly associated with the oligodendroglial lineage and with a better prognosis (166). Additionally, other information, such as analysis of TERTp-mut in combination with EGFR amplification refines the prognostic classification of GBMs (167).

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FIGURE 8.61 Oligodendroglioma B: value of susceptibility weighted-imaging for characterization. Axial T2-weighted (A), sagittal fluid-attenuated inversion recovery (FLAIR) (B), coronal T1 postcontrast (C), and axial susceptibilityweighted (D) images demonstrate a left frontal mass in a 39-year-old man. The presence of cortical thickening, well seen on axial T2-weighted image, should suggest the diagnosis of oligodendroglioma. Mild contrast enhancement is noted (C). The area of susceptibility artifact on susceptibility-weighted images (D, blue arrow) corresponded with calcification on the computed tomography scan (not shown).

FIGURE 8.62 Oligodendroglioma C, magnetic resonance (MR) versus computed tomography (CT). A 39-year-old man presented with seizures and was found to have a densely calcified lesion in the left frontal lobe on CT (A). Sagittal T1-weighted image (B) shows signal void in the location of dense temporal calcification. Axial DWI (D), T2*weighted GRE (E), FLAIR (F), T2-weighted (G), and T1-weighted postcontrast (H) images show faint enhancing areas in the periphery of the mass, with associated white matter signal abnormality. Biopsy revealed oligodendroglioma (WHO grade II).

Favored sites of localization include the frontal lobe most commonly, followed by the temporal lobe, although frequently glioblastomas involve more than one lobe and can be situated in any lobe. One characteristic distribution is the butterfly pattern of bihemispheric involvement with intervening corpus callosum infiltration, but this is also a pattern in lower-grade astrocytomas. There is a distinct tendency for malignant gliomas, especially those that are located superficially, to invade leptomeninges and dura with subsequent dissemination via the subarachnoid space (Fig. 8.66). It is quite rare for these lesions to metastasize outside the CNS.

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FIGURE 8.63 Oligoastrocytoma. Grade II oligoastrocytoma in the left frontal lobe seen a atypically hyperintense on FLAIR (A–C) images and showing faint enhancement (D) after the contrast administration. Note also the high rCBV on DSC perfusion MRI (E) and absence of foci of hypointense calcifications on gradient-echo image (F).

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FIGURE 8.64 Gliomatosis cerebri. Extensive, heterogeneous gliomatosis involves the brainstem, right hemisphere, and most of the left hemisphere on T1 (A) and T2 (B) images and shows significant mass effect. Despite significant heterogeneity and necrosis, note only minimal enhancement (A).

FIGURE 8.65 Gliomatosis cerebri—perfusion color map. Extensive, heterogeneous gliomatosis cerebri involves the brainstem, right cerebellar hemisphere, and most of the frontoparietal regions of the bilateral cerebral hemispheres on FLAIR (A–C) and T1-weighted (E) images and shows significant mass effect. Only minimal enhancement (F–G) is noted after the contrast injection. On DSC rCBV color map (D) areas of increased perfusion are detected, suggesting a possible dedifferentiation and higher grade components.

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FIGURE 8.66 Glioblastoma—dissemination via subarachnoid space. Axial FLAIR (A), DWI (B), SWI (C), and T1weighted postcontrast images (D–F) reveal a large infiltrative, heterogeneous tumor with a characteristic distribution of bihemispheric involvement and corpus callosum infiltration. There is a distinct tendency for malignant gliomas to invade the leptomeninges and ependyma, and to disseminate via the subarachnoid space (F, blue arrows).

Large, irregular, but seemingly well-circumscribed mass lesions are seen on gross pathology, which typically demonstrate central necrosis, hemorrhages of varying ages, and hypervascularity, often with regions of thrombosed vessels (Fig. 8.67). Extensive mass effect and edematous white matter are often seen that may accompany even relatively small tumor masses. The precise mechanism of peritumoral edema formation is poorly understood, but it is presumed to be related to the production of a vascular permeability factor known to be associated with gliomas. In support of this, glioblastomas are typically noted to have substantially elevated vascular permeability (ktrans) to gadolinium as compared with lower-grade gliomas (81,82). The histopathologic appearance of this lesion is reflected in its name of GBM. The diverse nature of cell forms, coupled with regions of markedly cellular tumor and focal necrosis (Fig. 8.68), often makes the diagnosis obvious, yet the lesions are extremely variable in their appearance. Vascular endothelial proliferation within and adjacent to the tumor and intratumoral necrosis is highly characteristic of glioblastoma and is of great prognostic significance among the many and varied features of these lesions on histopathology (13). This endothelial proliferation not only is found strictly within the tumor, but it is also seen in the brain parenchyma adjacent to, but not involved with, the infiltrating margin. Some pathologists separate glioblastoma from anaplastic astrocytoma on the basis of the presence of necrosis, although necrosis alone is obviously not pathognomonic of the lesion.

FIGURE 8.67 Glioblastoma multiforme, gross specimen. A brain section from an autopsy specimen shows a nonhomogeneous cut surface with hemorrhage and necrosis. (Courtesy of Dr. N. K. Gonatas, Hospital of the University of Pennsylvania, Philadelphia, PA.)

The MRI features of these malignancies clearly reflect the pathologic findings. MRI demonstrates marked intratumoral heterogeneity, reflecting sites of hemorrhage, necrosis, and varying degrees of hypercellularity (Figs. 8.69 and 8.70). These changes are best seen on T2-weighted images, often showing foci of cystic necrosis and hemorrhage with debris–fluid levels and lower-intensity regions in areas of hypercellularity (Figs. 8.71 and 8.72). Linear or serpentine regions of flow voids within the 476

tumor mass indicate the often prominent angiogenesis that characterizes glioblastomas. Calcification is uncommon and even if seen not particularly helpful in this diagnosis. Because glioblastomas, along with OD and ependymoma, have a tendency to bleed (18,19), it is helpful to identify any of the several features of intratumoral hemorrhage that differ from those seen in benign intracranial hematomas and suggest malignancy. These neoplasms typically show significant mass effect, mainly due to fairly extensive edema mixed with tumor that is usually apparent in the adjacent white matter. Enhancement patterns are usually very heterogeneous but virtually all GBMs at least partially enhance with intravenous contrast, classically with ringlike pattern depicted as being thick, irregular, and nodular and surrounding necrotic areas (Fig. 8.70). Note that the pattern of ring enhancement can change over several minutes (Fig. 8.73), so a difference in the pattern of enhancement compared to a previous study may or may not indicate a change in the lesion. The enhancement features of GBM alone are virtually indistinguishable from those seen in other neoplasms, including metastases, and may also be seen in radiation necrosis. Of course, most glioblastomas are solitary lesions (as opposed to most metastases); truly multicentric glioblastomas are distinctly unusual (168) (it should be noted that some neuro-oncologists think that multifocal malignant gliomas really represent GC). These lesions may still be difficult to differentiate from metastases; however, perfusion imaging may assist in making this differentiation (69,131). As demonstrated by Cha and colleagues (168), DSC perfusion also plays an important role in this setting demonstrated as distinct curves of percentage of signal intensity recovery (PSR), with GBM usually showing more than 50% of recovery to the baseline, much higher when compared with metastasis (due to absence BBB) (Fig. 8.74).

FIGURE 8.68 Glioblastoma multiforme, histopathologic specimens. A: Note typical areas of necrosis with a rim of densely arranged tumor cells (pseudopalisading) around the acellular necrotic debris. Other areas show a high density of pleomorphic cells interspersed with endothelial cell-proliferating neovascularization. B: At higher magnification, neoplastic cells have highly pleomorphic nuclei, multinucleated giant cells, and frequent mitotic figures.

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FIGURE 8.69 Classic glioblastoma. Axial fluid-attenuated inversion recovery (A–C), gradient-echo (D–F), and T1 postcontrast (G–I) images demonstrate a large right temporal mass with many characteristics of glioblastoma. This mass has central necrosis, areas of hemorrhage (as shown by low–signal-intensity areas on the gradient-echo images), and intralesional flow voids indicative of neovascularity (I, arrowheads). In addition, there is subependymal enhancement (H, white arrows). A daughter ring is also present (H, white arrowhead). Areas of nonenhancing tumor can separate the enhancing components in patients with glioblastoma.

FIGURE 8.70 Glioblastoma with characteristic features on conventional MRI. Note heterogeneous mass of tumor with vasogenic edema, low signal on T2 (A) indicating foci of hypercellular tumor, edema with tumor crossing corpus callosum, and thick irregular ring enhancement (B).

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FIGURE 8.71 Hypercellular glioblastoma. A large, heterogeneous hypercellular glioblastoma is of relatively low signal on T2 (A) and enhances significantly after intravenous contrast (B). Despite the marked hypercellularity of the tumor causing low signal on T2, there is only mildly restricted diffusion (C,D), typical of hypercellular tumors.

FIGURE 8.72 Glioblastoma with regions of restricted diffusion. A heterogeneous right frontal mass on T2-weighted (A) and postcontrast (B) images shows marked heterogeneity on the apparent diffusion coefficient map (C) with focal regions of markedly restricted diffusion seen as marked hypointensity. This finding has been reported to distinguish glioblastoma from lower-grade astrocytomas.

Regions that enhance correlate with areas of tumor tissue on pathology, and so clearly enhancement is helpful in guiding surgical biopsy; however, not all enhancing regions of tumor will necessarily be of similar histopathologic grade, and targeting regions of high CBV derived from perfusion MRI (Fig. 8.41) for biopsy has been advocated by some investigators as a means for identifying the most metabolically active portions of tumor and reducing the risk of undergrading. For the neuropathologist, it is ideal in fact for the biopsy specimen to include the enhancing ring and the adjacent necrosis, when present. Contrast-enhanced images should also be closely examined for subependymal or leptomeningeal– subarachnoid seeding.

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FIGURE 8.73 Change in configuration of an enhancing ring with time (glioblastoma). A: Axial T1-weighted magnetic resonance (MR) (800/20). B: Contrast-enhanced axial T1-weighted MR (800/20), 5-minute postinjection. C: Contrast-enhanced axial T1-weighted MR (800/20), 41-minute postinjection. A heterogeneous glioblastoma in the left frontal lobe (A) shows a thin regular ring of enhancement (closed arrows) on the 5-minute postinjection scan (B). Note the thickening of the ring (closed arrows) with modularity on the 41-minute postinjection scan (C). The enhancement of the tumor crossing the corpus callosum (B,C, open arrows) also thickens with time.

FIGURE 8.74 Multifocal glioblastoma—DSC perfusion. An extensive frontal mass demonstrating separate regions of enhancement is seen occasionally in glioblastoma. Structural images such as FLAIR (A), T2-weighted (B), SWI (C), and T1-weighted postcontrast (D) images help in defining the lesion and suggest the correct diagnosis. DSC perfusion imaging metrics such as percentage of signal recovery (usually >50%) and the rCBV values (E) allow the neuroradiologist to achieve a higher level of confidence in the correct diagnosis of multifocal GBM rather than metastases. (Courtesy of Lazaro Luis Faria do Amaral, MD; Sao Paulo, Brazil.)

There is a differential diagnosis for the imaging appearance of glioblastoma, particularly when only some of the “classic” MRI features (intratumoral neovascularity, hemorrhage, and necrosis) are identified. The differential diagnosis in untreated cases should include metastasis, anaplastic oligodendroglioma, and lymphoma. Even hemangioblastoma (see later in this chapter) can resemble a glioblastoma, due to its associated vessels, heterogeneity, enhancement, and edema. Abscess and other necrotizing processes can also be considered. Radiation necrosis can appear identical to glioblastoma or 480

recurrent tumor, as previously stated (Fig. 8.75). However, MRI can clearly narrow down this list considerably because (a) it is more sensitive for detecting multiple lesions, which would heavily favor metastases; (b) it can fully characterize the capsule of an abscess which is usually thin and exhibits low signal on T2-weighted images, with the center of a pyogenic abscesses showing marked diffusion restriction (170,171); (c) lymphoma is typically without any hypervascularity or hemorrhage and demonstrates more homogeneous low intensity on T2-weighted images; and (d) hemorrhagic neoplasms usually have a relatively specific appearance, which differs in many respects from cavernous angiomas or simple hematomas. Adjunctive MR techniques, like MRS and MR PWI, particularly for radiation necrosis and diffusion MR, may assist in refining the differential diagnosis. In cases in which biopsy is planned, these adjunctive techniques may guide the surgeon toward regions of highest grade, as suggested by elevated CBV or relatively high choline peaks on MRS (172,173).

FIGURE 8.75 Radiation necrosis, not tumor recurrence. Right parietal edema on fluid-attenuated inversion recovery image (A) with a focus of irregular enhancement (B) represented radiation necrosis, although metastasis and glioblastoma would appear identically.

The optimal chemotherapeutic regimen for glioblastoma has not yet defined, but adjuvant chemotherapy appears to yield a significant survival benefit in some studies (174). To date there is no consensus on which of the available therapeutic options should be considered as “standard of care” for patients diagnosed with recurrent GBM (monotherapy vs. combined, optimal use of anti-angiogenic drugs, protocol, etc.). During the last years, with the widespread use of new therapies, new phenomena of pseudoprogression (PsP) and pseudoresponse have emerged, which will be discussed later on this chapter. Gliosarcoma Gliosarcoma is a CNS tumor that contains distinct elements of both glioma and sarcoma, considered a GBM variant by the WHO. It is classified as a grade IV tumor and comprises only 1.8% to 2.8% of all cases of GBM, generally affecting adults in their fifth to seventh decades of life, mostly found in men (175). The tumors can also be categorized as primary (“de novo”) or secondary (previous history of radiation therapy) (176). Histologically, this tumor fulfills the criteria of GBM, but also exhibits a mesenchymal component with a wide variety of morphologies (177). MGMT methylation and IDH1 mutation are uncommon, as is the EGFR amplification, but the genetic profile is quite similar to the GBMs (178). Clinical symptoms are usually related to a rapidly expanding intracranial tumor, depending on its location. Although this entity shares so many aspects with GBMs, there are some important features that may help in differentiation between these two entities. Gliosarcomas show a temporal lobe predilection and are almost never found in the posterior fossa, although rare cases have been reported (176,177). On imaging exams, this tumor tends to appear as a large necrotic central area, associated with a thick and heterogeneous enhancing periphery, similar to a GBM. Prominent peritumoral edema/infiltration, calcification, hemorrhage, or cystic components have also been described (Fig. 8.76) (175,177,179). Unlike GBMs, these tumors have a well-recognized propensity to metastasize outside the CNS, most of them affecting lung and liver (177).

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FIGURE 8.76 Gliosarcoma. MR imaging—axial FLAIR (A), T2-weighted (B), T1-weighted (C), DWI (D), SWI (E), and T1-weighted postcontrast images—reveals a large lesion in the left frontal lobe, which exhibit a necrotic central area and a thick/heterogeneous ring-enhancing periphery, similar to a GBM. Note also the prominent peritumoral edema and infiltration, as well as the foci of calcification and/or hemorrhage at its periphery, better appreciated on susceptibility-weighted imaging (E, blue arrow).

Chordoid Glioma Chordoid glioma is a recently described tumor that has a typical location in the anterior third ventricle and hypothalamic region, with histologic features distinct from those of other glial tumors (180). This lesion has shown cords and clusters of epithelioid cells with mucinous background, with low-grade lymphoplasmacytic infiltrate, similar to chordoma or chordoid meningioma. However, there is avid staining for glial fibrillary acidic protein, a well-known marker for glial cells. In addition, ultrastructural analysis has shown features of specialized ependymal differentiation, suggesting an origin from the region of the lamina terminalis (181). This lesion has been classified a grade II neoplasm, generally affecting middle-aged patients and shows a strong predilection for the hypothalamus/anterior third ventricle region, with symptoms typically due to local mass effect (182). On imaging exams, this tumor usually appears as a hypothalamic/third ventricular mass which is isointense on T1-weighted MR images and slightly hyperintense on T2-weighted images, displaying a marked homogeneous enhancement after the contrast injection (Fig. 8.77) (180). T2-weighted images have demonstrated signal abnormalities extending into the proximal optic tracts bilaterally, and differentiation from optic pathway glioma can be difficult. Surgical resection, when possible, is the preferred initial treatment modality, and early data suggested a relatively benign behavior for this neoplasm. Angiocentric Glioma Angiocentric glioma is a recently recognized tumor, first described in 2005 and classified as a distinct neuroepithelial grade I neoplasm in 2007 by the WHO (183). The cortex and the subcortical white matter of the frontotemporal region are the most common sites for this tumor, generally presenting as a slow-growing lesion (184). This entity generally affects children and young adults presenting with drugresistant seizures (183,184). These tumors have similar pathologic features to infiltrating astrocytomas and ependymomas, and their rarity complicates accurate diagnosis (184). Histologically, they are characterized by elongated astrocytic cells forming rings around blood vessels. Tumor cells circumferential to the vessels predominant in low cellularity areas, whereas radial alignment with perivascular pseudorosettes was observed in more cellular regions (185). MRI tends to depict a 482

superficial well-delineated T2 hyperintense lesion, generally without contrast enhancement (Fig. 8.78). The surgical approach, with either a subtotal or gross total surgical resection, is the standard of care for these patients, and prognosis is good with successful surgery. Adjuvant radiotherapy may also play a role in select patients (183,184).

FIGURE 8.77 Chordoid glioma of the third ventricle. Sagittal T1-weighted precontrast (A), axial fluid-attenuated inversion recovery (B,C), and T1-weighted postcontrast sagittal (D) and axial (E) images demonstrate a heterogeneous signal intensity, homogenously enhancing mass (A,C, arrows) centered in the inferior third ventricle. Note the edema extending along the proximal optic tracts bilaterally (B, arrowheads). Histologic evaluation with hematoxylin and eosin staining (F) demonstrates that the tumor is composed of spindle and epithelioidlike cells with intervening myxoid matrix. The strong staining for glial fibrillary acidic protein (G) confirms the glial nature of this tumor, which is believed to arise from specialized glial cells in the lamina terminalis. (Pathologic pictures courtesy of John E. Donahue, MD.)

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FIGURE 8.78 Angiocentric glioma—imaging findings. Axial T2-weighted (A) and FLAIR (B) images show a heterogeneous, minimally hyperintense mass lesion (arrow) in the gyrus rectus of the left frontal lobe, no significant vasogenic edema. C: Sagittal T1-weighted image shows that mass (arrows) is slightly hyperintense relative to the brain parenchyma. D: Foci of calcification (arrows) within the mass are noted on the noncontrast computed tomography image. (Courtesy of Ayca Ersen, MD, and Suleyman Men, MD.)

Astroblastoma Cerebral astroblastoma is a rare neuroepithelial neoplasm primarily found in children and young adults, accounting for 0.45% to 2.8% of primary brain gliomas. No WHO grading is established at present due to its highly variable behavior, and it is currently classified as a neuroepithelial tumor of uncertain origin (186,187). Nonetheless, some neuropathologists distinguish between “low-grade,” which generally exhibit just a minimal cellular atypia, and “high-grade” astroblastomas (187). This lesion appears as a well-circumscribed relatively large supratentorial mass on imaging exams, demonstrating subtle calcifications in some cases (Fig. 8.79). The frontal and the parietal lobes are the most common sites, usually occurring close to the convexity (186). Surgical resection is the standard of care for these patients, with or without an adjuvant radiation therapy. Chemotherapy (temozolamide) may also be used for the anaplastic (“high-grade”) variants (186). Localized (Noninfiltrative) Astrocytic Tumors Localized astrocytic tumors have a common tendency to be well circumscribed and generally more differentiated than infiltrative astrocytomas, and they share a relatively favorable prognosis. The better outlook for patients harboring these lesions is due to a limited capacity for invasion and spread and a limited tendency to progress into more malignant forms. This group consists of PA, PXA, and subependymal giant cell astrocytoma. Pilocytic Astrocytoma This tumor represents one of the most benign forms of a glial neoplasm, classified as grade I by the WHO and is the most common astrocytoma in childhood, showing a strong predilection for the posterior fossa. In these patients, generally children and adolescents, presenting with an infratentorial mass, diffusion MRI may play a significant role in differentiation from other common neoplasms. Higher ADC values when compared to more aggressive tumors (such as medulloblastomas and ependymomas) are characteristic of this entity (188). Hemangioblastoma is another important entity included in the 484

differential diagnosis (see later discussion). When it is supratentorial, the PA most commonly arises in the optic nerve or diencephalon (chiasm/hypothalamus/floor of the third ventricle) (189), and may be one of the imaging findings in patients with type I neurofibromatosis. For further information on PAs, refer to “Pediatric Brain Tumors.” Tectal Glioma Brainstem gliomas are uncommon but can be found in adults, in patients with a median age of 30 to 35 years. In contrast to what occurs in the pediatric population, when gliomas occur in the adult brainstem, they behave similarly to supratentorial gliomas. One relatively rare type of brainstem glioma in adults, comprising less than 10% of adult brainstem gliomas, is the focal tectal glioma. These lesions are typically small and best seen on T2 or FLAIR images (Fig. 8.80). Often these are slightly exophytic into the quadrigeminal cistern. Symptoms are almost always due to local mass effect and include hydrocephalus from aqueductal obstruction, or Parinaud syndrome in larger lesions. Enhancement is unusual, and these lesions may sometimes be considered hamartomatous in nature (190). The presence of irregular areas of hemorrhage, necrosis, or enhancement should suggest a more aggressive neoplasm such as anaplastic astrocytoma or glioblastoma with tectal involvement. Studies have shown that lesions with tumor volumes of 2 to 4 cm3 tend to have a stable, benign natural history and may be hamartomatous, whereas those of larger sizes can have variable behavior, and surgical resection is not uncommonly needed (190). Continued imaging surveillance is indicated because some small- to medium-sized lesions can occasionally slowly enlarge, which might suggest a true low-grade glioma rather than a hamartomatous lesion (191).

FIGURE 8.79 Astroblastoma. CT (A,B) and sagittal T1-weighted (C), axial DWI with ADC map (D,E), T2*-weighted GRE (F), FLAIR (G), T2-weighted and T1-weighted contrast-enhanced images reveal a well-circumscribed and relatively large solid cystic mass located in the left temporo-occipital transition, which also demonstrates a region of calcification (F) and peripheral enhancement after the contrast injection (I).

Subependymal Giant Cell Astrocytoma The classic setting of subependymal giant cell astrocytoma (WHO grade I) consists of a wellcircumscribed lateral ventricular mass specifically in the region of the foramen of Monro, in a young adult with tuberous sclerosis (Table 8.12). The mass is truly a parenchymal astrocytic neoplasm that projects into the ventricle from a subependymal location—it is not a tumor of the ependyma itself. This slowly growing tumor is very rare outside of the clinical setting of tuberous sclerosis and is found in up to 10% of patients with the syndrome (169–170—previous) (192,193). It can be found as an incidental lesion in the clinical setting of tuberous sclerosis or as a mass causing symptomatic obstructive hydrocephalus during the first two decades of life. The lesion is often found in association with other subependymal hamartomas, and in fact this neoplasm shares many features of hamartoma on pathology. Although these lesions have classic findings on imaging studies, their neuropathologic features can be quite variable (Fig. 8.81). Calcification is extremely common. Treatment of subependymal giant cell astrocytoma is generally restricted to surgical removal, after which long-term survival rates are 485

excellent. Radiotherapy is sometimes necessary (194).

FIGURE 8.80 Tectal glioma in a 35-year-old man. Axial and sagittal fluid-attenuated inversion recovery (A,B) and sagittal T1 postcontrast (C) images demonstrate a T2 hyperintense, nonenhancing mass located in the tectum (A,B, arrows). This lesion had been stable for several years. Presumed tectal glioma.

TABLE 8.12 Intraventricular Masses

MR findings of subependymal giant cell astrocytoma hinge on the identification of the mass in its characteristic location along with the identification of other features of tuberous sclerosis (Figs. 8.82 and 8.83). There are basically four distinct intracerebral lesions seen in this syndrome (195): (a) hamartomatous cortical tubers, most commonly in the frontal lobes; (b) radially oriented transcerebral bands of heterotopic giant cells, accompanied by gliosis and dysmyelination; (c) subependymal heterotopic nodules; and (d) subependymal giant cell astrocytoma. Subependymal giant cell astrocytomas have been reported on MRI as hyperintense, somewhat heterogeneous masses on T2weighted sequences. Just as in the nonneoplastic subependymal nodules in these patients, central regions of marked hypointensity can be seen on T2-weighted MRI and on gradient-echo images due to susceptibility-induced signal loss from calcification and accompanying iron. Giant cell astrocytomas generally enhance with intravenous contrast, but the lack of enhancement cannot be used as exclusionary proof of this diagnosis. Pleomorphic Xanthoastrocytoma (PXA) PXA is a rare astrocytic solid and cystic neoplasm superficially located in the cerebral hemispheres, accounting for less than 1% of all astrocytic tumors, primarily found in young adults with a long history of seizures. The temporal lobe is the most common location. According to the latest WHO classification, PXAs represent grade II tumors histologically, but a small percentage demonstrate increased mitotic activity, with or without areas of necrosis, so they are designated as “PXA with anaplastic features” 486

(196). The lesion is considered a much less aggressive lesion than its histologic features would suggest (135). On pathology, the lesions are discrete superficial nodular masses overlying a large, fluid-filled cyst. Deeper parts of the lesion may show infiltration of the subjacent parenchyma. On microscopic examination, these lesions show considerable pleomorphism and cellularity and a notable absence of mitotic figures, necrosis, and vascular proliferation (135). The differential diagnosis can include glioblastoma and malignant fibrous histiocytoma, such that clinical features and MRI are essential to make the correct diagnosis. In the typical young adult age group that harbors these lesions, ganglion cell tumors should be the primary differential diagnosis under consideration.

FIGURE 8.81 Subependymal giant cell astrocytoma, microscopic sections. Features of these lesions associated with tuberous sclerosis consist of a diffuse proliferation of astrocytes within a fibrillary, partially vacuolated background (A). At higher magnification (B), note the heterogeneity of cells with small and very large astrocytic nuclei and abundant cytoplasm.

FIGURE 8.82 Subependymal giant cell astrocytoma. Axial T2-weighted (A), FLAIR (B), and T1 postcontrast (D) images demonstrate a large mass centered near the left foramen of Monro. Note also the multiple calcified subependymal nodules, better appreciated on T2*-weighted GRE imaging (C).

MR demonstrates a well-defined superficial solid mass with a large cyst immediately deep to the solid tissue (197), generally associated with inner table calvarial scalloping, although this feature is shared with other slow-growing peripheral tumors, such as gangliogliomas and dysembrioplastic neuroepithelial tumors (DNETs), and PAs (Figs. 8.85 and 8.86). While PXA usually demonstrates relatively lower ADC values in the solid hypercellular component when compared to low-grade astrocytoma (197), the morphologic features of the lesion are the key to the diagnosis. The solid component usually displays enhancement and is calcified about half of the time. Surgical excision alone 487

is generally the initial treatment for this relatively benign lesion, but a significant frequency of recurrence, with malignant transformation in 10% to 25% of cases, has been noted (135).

FIGURE 8.83 Giant cell astrocytoma in a patient with tuberous sclerosis. Axial fluid-attenuated inversion recovery (A), T2 (B), and T1 postcontrast (C) images demonstrate a large mass centered near the foramen of Monro. In addition, note the multiple subependymal nodules (A, arrowheads), as well as subcortical tubers (A, white arrows), which confirm the diagnosis of tuberous sclerosis. Enhancement of subependymal nodules can be seen and does not imply the presence of giant cell astrocytoma.

FIGURE 8.84 Pleomorphic xanthoastrocytoma (PXA). Axial FLAIR (A) and T2-weighted imaging (B) reveal a large left well-defined temporal mass, with a large cyst immediately lateral to the solid tissue. Axial (C) and coronal (D) T1weighted postcontrast images show prominent enhancement after administration of gadolinium in the solid component medial to the large peripheral cystic portion.

Tumors of Neuronal and Glial–Neuronal Composition Gangliocytoma and Ganglioglioma Most ganglion cell tumors are benign WHO grade I neoplasms consisting entirely or in part of mature neurons. The ganglioglioma is composed of both neural and glial elements and is a slow-growing tumor that affects mostly young adults or children. Most gangliogliomas are supratentorial, and the temporal lobe is the predominant site (198–202), but these tumors can arise in the cerebellum, brainstem, suprasellar region, and in spinal cord as well. On pathologic examination, gangliogliomas are well488

circumscribed tumors, typically cystic and often with focal calcification (Fig. 8.86) (18,200). Gangliocytoma is a far less common tumor diagnosed when only abnormal neurons are present (135,203). The distinction between ganglioglioma and gangliocytoma is often not sharp, either histologically or on MRI, and so the term ganglion cell tumor may be used (Figs. 8.87 and 8.88). As a group, ganglion cell tumors are relatively uncommon neoplasms, accounting for less than 10% (0.4% to 9%) of all CNS tumors, and are primarily seen in young adults (204,205). Even though this tumor represents an indolent neoplasm with a slow growth rate, there are reports of subarachnoid space spread (206), as well as tumor recurrence and malignant transformation (204,205). However, there is no classic imaging finding that would suggest a grade II or even anaplastic features (anaplastic gangliogliomas—grade III) (207). After surgery, recurrences are rare and there is good OS with degree of resection representing one of the important factors for prediction of outcome (205). This entity must not be confused with neuronal heterotopia, which represents a nonneoplastic region of normal gray matter in an abnormal location. Because small biopsy specimens of heterotopia may be confused with ganglion cell tumors by the pathologist on frozen section, the neuroradiologist plays an extremely important role in the differentiation of these two distinct entities. Rarely, ganglion cell tumors are associated with certain phakomatoses (i.e., NF1, NF2) and other entities (i.e., Peutz–Jeghers and Turcot syndrome) (205), and focal cortical dysplasia. Differentiation of ganglioglioma from focal cortical dysplasia can be a difficult task, especially as these two lesions may appear simultaneously in the same patient (210).

FIGURE 8.85 Pleomorphic xanthoastrocytoma (PXA). A large parietal mass is partially calcified and has a large cystic component on computed tomography (A). Note that the calcifications, despite being dense and extensive, are invisible on conventional T2 (B). Coronal T1 shows only patchy enhancement after gadolinium (C) in the solid

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component underlying the large peripheral cystic portion. D: Histopathologic specimen. Hematoxylin and eosin stain shows extreme nuclear and cytoplasmic pleomorphism, including large hyperchromatic nuclei and multinucleated cells and lymphocytic infiltrate.

FIGURE 8.86 Ganglioglioma, histopathologic features. Microscopic features of this slow-growing tumor include a well-circumscribed mass often with an extensive fibrocollagenous component (A). They typically contain neuronal cells with abnormal morphology, often binucleated “ganglion” cells (B, center). Neurofilament stain (C) is positive for cells of neuronal origin. Glial fibrillary acidic protein–positive astrocytes (D) indicate the most actively proliferating component of the tumor.

FIGURE 8.87 Ganglioglioma. A: Unenhanced CT (A,B) and MR imaging (C–H) show a peripherally located lesion with subtle calcifications, better appreciated on CT (A,B), but also depicted with T2*-weighted GRE (E) on MR imaging. The lesion demonstrates a solid cystic appearance with high signal on T2-weighted sequences (D,F,G), associated with a minimal enhancement on T1-weighted postcontrast images (C,H). (Courtesy of Bruno Siqueira Campos Lopes, MD—São Paulo, Brazil.)

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FIGURE 8.88 Solid ganglioglioma. A: Proton density–weighted magnetic resonance (MR) (3,000/30). B: T2weighted MR (3,000/80). A heterogeneous cortical–subcortical left frontal mass lesion is well defined and shows no associated high intensity in the adjacent white matter.

The diagnosis of ganglion cell tumor on MRI centers around the delineation of a superficial solid or partially cystic (38%) (200,202) mass lesion, preferentially located in the temporal lobe of a child or young adult. The signal intensity is nonspecific and is usually nonhomogeneously hyperintense on T2weighted images. Most gangliogliomas show some contrast enhancement (202). Heterotopias are exactly isointense to normal gray matter on all MR pulse sequences, whereas gangliocytomas and gangliogliomas are not. The only signal aberration one might see in association with heterotopia is increased signal subjacent to the lesion, presumably indicating gliosis or dysmyelination. The differential diagnosis on imaging studies in a child or young adult includes ganglioglioma, PA, and PXA, the three neoplasms that all commonly show a nodular mass in association with a macroscopic cyst. CT or gradient-echo imaging to detect calcification, a more common feature of ganglioglioma, may be useful in this distinction. Dysplastic Cerebellar Gangliocytoma (Lhermitte–Duclos Disease) Dysplastic gangliocytoma of the cerebellum, or Lhermitte–Duclos disease (LDD) (211), is seen as a large region, often holohemispheric, of ill-demarcated masslike thickening of cerebellar folia. It is considered a complex hamartoma or malformation rather than a true neoplasm (212). Although the lesion may present in childhood, it slowly enlarges over time and is usually discovered in adults. Its exact origin remains unknown, whether neoplastic, dysplastic, or hamartomatous (213). Nonetheless, mutations of the PTEN gene (germline loss of one allele with subsequent loss of the remaining allele) have been described and linked to this entity (214,215). It is associated with regional enlargement of the cerebellar stratum granulosum, absence of the Purkinje cell layer and progressive hypertrophy of the granular cell neurons with increased myelination on histopathology (213). LDD may occur in isolation; however, there is evidence that it is associated or possibly pathognomonic for Cowden disease, which is a multiple hamartomas syndrome with an increased risk for benign and malignant tumors, such as ductal carcinoma of the breast, endometrium, and thyroid cancer (216,217). MRI signal intensity patterns depict this extremely rare lesion as an intra-axial cerebellar mass on T2-weighted images (218) with enlarged cerebellar folia and heterogeneous hyperintense “stripes” of dystrophic change and CSF. It demonstrates minimal if any contrast enhancement (Fig. 8.89). Areas of calcifications may also be seen on T2*-weighted gradient recalled echo (GRE) images (211). Occasionally, infiltrative astrocytoma of the cerebellar hemisphere must be distinguished from this entity, and this is done by virtue of more homogeneous hyperintensity throughout the lesion in the case of astrocytoma (Fig. 8.90). In proper context, cerebellitis may also be considered as another differential diagnosis.

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FIGURE 8.89 Lhermitte–Duclos disease (dysplastic gangliocytoma of the cerebellum). A: Sagittal T1-weighted magnetic resonance (MR). B: Axial T2-weighted MR. C: Coronal T1-weighted MR after intravenous contrast. D–F: Microscopic sections from a similar case. A large expansile mass occupies most of the left cerebellar hemisphere (A,B). Note irregular stripes of alternating low and high intensity (A,B), probably related to abnormal myelination pattern, and lack of enhancement (C). On microscopy, note the hamartomatous hypertrophy of the granular layer neurons of the cerebellum, which acquire a superficial resemblance to Purkinje cells (D). Hypertrophied granular cell layer cells are of neuronal origin, expressing positive immunostaining with antibodies against neurofilament (E). An abnormal myelination pattern in the superficial layer of the cerebellar folia is shown (F) with myelin stain (Luxol fast blue).

Central Neurocytoma Central neurocytoma (WHO grade II) is a relatively benign intraventricular tumor (Table 8.12) that occurs typically in young- to middle-aged adults. The lesion is rare, comprising an estimated 0.1% of all primary tumors of the CNS (219), but accounting for nearly 10% of intraventricular neoplasms (220). The typical location is in the body or frontal horn of the lateral ventricle, arising either from the septum pellucidum, fornix, or the walls of the supratentorial ventricular system (subependymal layer) (220,221). As a relatively slow-growing tumor, it tends to have a prolonged clinical course, presenting with clinical findings related to the obstruction of the foramen of Monro (obstructive hydrocephalus), leading to decreased consciousness or even death (220,221). On gross pathology, central neurocytomas are well circumscribed and attached to the septum pellucidum or the lateral ventricular wall, often arising from the foramen of Monro. On microscopy, the tumor is made up of small, well-differentiated cells with features reminiscent of OD but with heterogeneous regions that can also mimic pineocytoma (PC), ependymoma, or even pediatric dysembryoplastic neuroectodermal tumor (Fig. 8.91) (222). 492

Imaging reveals heterogeneous nature of this tumor, with CT revealing cystic components as well as scattered and/or popcorn calcifications. Dense calcification is more suggestive of meningioma (Fig. 8.92). Nonetheless, MRI is the technique of choice for complete evaluation, revealing a solid-cystic neoplasm in the body/frontal horn of the lateral ventricle (220). The clusters of cystic components are well visualized with the use of T2 sequences, giving it a “Swiss cheese/soap bubble” appearance. Calcifications may also be demonstrated and this tumor usually shows moderate, heterogeneous enhancement on the T1-weighted postcontrast images (220). Conventional MRI is able to accurately characterize most intraventricular tumors by virtue of their specific neuroanatomic relationships, morphology, signal intensity pattern, and enhancement, but advanced methods may also be helpful in selected cases. DSC perfusion MRI may provide additional information on the vascularity of these neoplasms, even though it does not allow for differentiation between these entities. Nonetheless, lower rCBV values may favor the diagnosis of central neurocytoma rather than other intraventricular tumors, such as papillomas and meningiomas (223). As with PWI, MRS does not show a pathognomonic pattern according to prior studies, however, an increase in glycine (Gly) at 3.55 ppm may raise this entity as a possibility (220,224). Surgical removal with gross total resection remains the treatment of choice. Additionally, various radiotherapy techniques have been shown to be useful in cases of residual tumor after subtotal resection or tumor recurrence (225).

FIGURE 8.90 Pilocytic astrocytoma of the cerebellum, not Lhermitte–Duclos. A left superior cerebellar hemispheric mass on T2-weighted images (A,B,D) shows clear hyperintensity throughout the lesion, better appreciated on fluidattenuated inversion recovery images (A–D), distinguishing this infiltrative astrocytoma from the more benign Lhermitte–Duclos lesion. Note also the heterogeneous enhancement after contrast injection, as well as high values on ADC map (C). MR spectroscopy (F) reveals an increase on choline and lactate peaks, associated with a significant reduction of the N-acetyl aspartate.

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FIGURE 8.91 Central neurocytoma. An intraventricular mass attached to the septum pellucidum that is slightly heterogeneous but predominantly isointense to gray matter on T1-weighted (A) and T2-weighted images (B) and exhibits mild enhancement on T1-weighted postcontrast images (C–F).

FIGURE 8.92 Intraventricular meningioma with dense calcification and no significant enhancement. T1-weighted images before (A) and after (B) intravenous contrast show a nonenhancing mass within the body of the left lateral ventricle and the foramen of Monro. The entire mass is of rather low intensity on T2-weighted (C) and fluidattenuated inversion recovery (D) images and more anteriorly situated than most intraventricular meningiomas. The lack of enhancement is ascribed to the dense calcification within the matrix of the tumor, as shown by computed tomography (E).

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Extraventricular Neurocytoma (EVNCT) Extraventricular neurocytoma is a new and rare variant incorporated by the latest WHO classification (2007). Along with the central neurocytoma, it is considered a grade II neoplasm, with similar biologic behavior, radiographic and histopathologic characteristics. Location rather than histology is the only primary difference between these two entities (8,226). The histologic characteristics include fibrillary areas mimicking neuropil and collections of uniform round cells that have immunohistochemical and ultrastructural evidence of neuronal differentiation (8). As the most common location is at the periphery of the temporal lobes, as with other neuroglial tumors, this new variant should be included in the differential diagnosis of chronic drug-resistant seizures, affecting mainly young adults (8,226). As cited previously, imaging findings are similar to the classic “central neurocytoma,” showing a solid-cystic appearance, well-circumscribed margin, with predominance of hypointense signal on T1-weighted and isointense to hyperintense on T2-weighted imaging. This variant can also show a “swiss cheese/soap bubble” appearance on T2 images (8,226). Hemorrhage and calcifications may be present (8), and there is usually variable and heterogeneous enhancement on the T1-weighted postcontrast images, although nonenhancing lesions may occur as well (227). Subependymoma Subependymomas (WHO grade I) are unusual highly differentiated neoplasms that are considered variants distinct from ependymoma. These tumors are actually “mixed” in composition, consisting of astrocytes and ependymal cells (228). These tumors are sharply demarcated, lobulated, intraventricular masses (Table 8.12) arising from beneath the ventricular lining. They are noninvasive histologically and usually very benign in clinical course. They are most frequently found at autopsy as incidental findings with no production of symptomatology, even when they are large enough to fill the fourth ventricle, their most common site of occurrence (75%) (229). Subependymomas are usually seen in males, typically presenting between the fourth and sixth decades of life (230). This lesion is rarely found in children. They show no tendency to undergo anaplasia or disseminate through the CSF and are one of the only glial tumors that can be truly considered benign. Symptomatic subependymomas are more often related to the septum pellucidum, foramina of Monro, or cerebral aqueduct, where they can obstruct the flow of CSF and cause hydrocephalus. Although usually solid and relatively homogeneous, occasionally large subependymomas can show microcystic change, calcification, or hemorrhage. Necrosis is rarely seen on pathology. The MR diagnosis of subependymoma hinges on its periventricular location, with the most common sites being the foramen of Monro and the fourth ventricle, typically in an asymptomatic middle-aged or elderly man. Lesions related to the lateral ventricle are usually in contact with the septum pellucidum and therefore may be indistinguishable on CT from central neurocytoma, particularly because both of these tumors can calcify. Small masses are relatively homogeneous in signal intensity and hyperintense to brain on T2-weighted images; large lesions reveal intensities that mirror their pathologic heterogeneity and resemble ependymoma. According to Abdel-Aal et al. (231), the supratentorial neoplasms tend to have minimal or no enhancement on contrast-enhanced T1-weighted images (Fig. 8.93), while the infratentorial ones tend to enhance heterogeneously (Fig. 8.94). These tumors may also show increased perfusion and high values of rCBV, but this fact does not necessarily represent a dedifferentiation or high-grade pattern, likely simply reflecting multiple thick hyalinized intratumoral vessels rather than neoangiogenesis (231). The top differential diagnosis includes ependymomas, which usually exhibit an earlier peak of incidence (before the first two decades of life), choroid plexus tumors, giant cell astrocytomas, and meningiomas, as well as the recently described rosette-forming glioneuronal tumor (RFGT) that tends to affect younger adults. The age of presentation along with the imaging findings are essential for accurate diagnostic approach. Rosette-Forming Glioneuronal Tumor (RFGT) This recently confirmed new entity was first described as a possible unique and characteristic tumor by Komori et al. in 2002 (232). According to the last revision of the WHO, it is classified as a grade I glioneuronal neoplasm (232), associated with benign and indolent behavior. This tumor exhibits distinctive radiologic and histopathologic findings, with neurocytic and glial architecture. Neurocytic rosettes and perivascular pseudorosettes are formed by the uniform neurocytes and small round cells in the neurocytic component. The astrocytic component is quite similar and resembles a PA pattern 495

(232–236). RFGT affects primarily young adults, with a peak of occurrence around the second and third decades of life, also showing female predominance (2:1 ratio) (233). Although rare, this tumor has also been described in the elderly (237). As it is a slow-growing tumor, some diagnoses are made during routine brain examination, for a variety of clinical symptoms, headache being one of the most prevalent (233). When located in the fourth ventricle, RFGT can present with an obstructive hydrocephalus (234) or with a hemorrhagic transformation, which are associated with a poor outcome (Fig. 8.95) (235). Recently, the first case involving the cervical spine was also described by Anan and colleagues (238). MRI tends to reveal a well-circumscribed mass with both solid and cystic components, usually without associated perilesional edema. Calcifications are relatively common, but hemorrhage is an unusual feature. When present, the enhancement may be irregular. As cited above, it is important to evaluate possible extension to the neighboring structures (i.e., pons, vermis, midbrain, and cerebellar hemispheres). Satellite lesions may also be present (233,235,237).

FIGURE 8.93 Subependymoma. Axial T2-weighted (A), FLAIR (B, yellow arrow), T1-weighted postcontrast (C) and T2*-weighted GRE (D) images demonstrate a nonenhancing (E, blue arrow), slightly heterogeneous mass within the right lateral ventricle.

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FIGURE 8.94 Subependymoma of the 4th ventricle. Sagittal FLAIR (A), sagittal T1-weighted (B), and axial T2weighted (D) images reveal a slightly heterogeneous mass occupying the inferior aspect of the fourth ventricle, that exhibit subtle calcifications on T2*-weighted GRE (G) imaging and demonstrates mild to moderate enhancement (C). This lesion does not exhibit significant increase of rCBV on DSC perfusion (E).

FIGURE 8.95 Rosette-forming glioneuronal tumor. Sagittal T1-weighted (A), sagittal FIESTA (B), and axial FLAIR (C) show a heterogeneous lesion, hypointense on T1-weighted and hyperintense on T2-weighted images, involving the midline posterior fossa, with unusually irregular morphology but predominant involvement of the vermis, demonstrating nodular enhancement after contrast injection (D). On DSC perfusion (E), this mass does not show significant increase of rCBV. (Courtesy of Lázaro Faria do Amaral, MD, São Paulo, Brazil.)

Dysembrioplastic Neuroephitelieal Tumors (DNET) DNET is a slow-growing and usually benign neuroepithelial tumor, containing glial and neuronal components, which affects children and young adults with drug-resistant seizures. Most of these patients (80%) experience their first seizure episode before the third decade of life (239). DNETs along with other low-grade tumors, account for seizure etiology in 10% to 30% of these patients (240). DNET is 497

classified as a grade I neoplasm by the WHO (7), a fact that is supported by its indolent course, although some cases of malignant transformation and tumor recurrence have been described (241,242). Typical findings on hystopathology may be used to subcategorize DNETs into three distinctive forms: (1) simple—only specific glioneuronal components; (2) complex—associated with focal cortical dysplasia; and (3) nonspecific (243). Microscopic exam can reveal its complex cytoarchitecture, with glioneuronal component resulting in bulging of the affected cortex. Long-term follow-up is a useful imaging strategy (241–243). Along with other glioneuronal tumors, DNET shows a predilection for the gray–white matter junction, generally in the temporal lobe periphery, followed by the frontal lobe; however, it can occur anywhere in the brain (i.e., caudate nucleus, cerebellum, or pons) (239). Imaging examinations are able to delineate this lesion well, demonstrating a round hypodensity on CT, as well as adjacent calvarial inner-table remodeling (related to this slow-growing neoplasm). MRI is the standard of care for DNET evaluation, demonstrating an expansile, multicystic (“soap bubble”) lesion, which is usually hypointense on T1-weighted and hyperintense on T2-weighted images. Hemorrhage and calcifications are unusual (Fig. 8.96) (239). FLAIR images may reveal a thin rim of hyperintensity known as “hyperintense ring sign,” which is distinct and suggestive of DNET (244); additionally, 3DCISS/FIESTA may be useful as well, assisting in differentiation from enlarged perivascular spaces, which sometimes may mimic masses or neoplasms (cysts tend to exhibit the same signal intensity compared to CSF) (245,246). Hemangioblastoma Hemangioblastomas are rare vascular lesions classified as grade I by the WHO, which may appear throughout the CNS and demonstrate a strong propensity to involve the cerebellar hemispheres (251,252). Cerebellar hemangioblastoma is a benign neoplasm that comprises approximately 7% of posterior fossa tumors in adults (18). Despite its relative rarity, it is the most common primary intraaxial tumor in the posterior fossa in adults. Although it is a vascular tumor, hemorrhage is only rarely seen (252). There is a well-established relationship with von Hippel–Lindau (VHL) syndrome, which is detailed in Chapter 5 (Central Nervous System Manifestations of the Phakomatoses). The incomplete penetrance of this syndrome makes it difficult to accurately assess the incidence of hemangioblastoma in patients with this syndrome, but it has been reported to range from 35% to 60% (253). Of all patients with hemangioblastoma, between 4% and 40% meet criteria for VHL syndrome (254,255). These tumors peak in incidence during the fifth and sixth decades, except in VHL syndrome, in which they present in younger adults (254). Hemangioblastomas are usually solitary lesions; multiplicity is said to occur in 20% of patients with VHL syndrome and only rarely in otherwise-healthy patients. Multiple hemangioblastomas are also more common when they arise within the spinal cord (256).

FIGURE 8.96 Dysembryoplastic neuroepithelial tumor (DNET). A heterogeneous intra-axial mass located in the medial part of the left temporal lobe with striking “bubbly” appearance and marked hyperintensity on T2WI (A,B). There is no enhancement after the contrast administration (C).

Gross pathologic examination of hemangioblastomas reveals well-demarcated, frequently cystic masses with highly vascularized solid nodules within the wall of the cyst. Aside from the mural nodule, the cyst wall is not involved with tumor but is more often simply gliotic. The solid nidus is superficial and, in fact, virtually always abuts pia mater. Microscopically, in distinction from its gross appearance, the tumor is neither encapsulated nor well circumscribed, and it can invade cerebellar parenchyma. The mural nodule is a hypervascular mass of capillaries with intervening benign-appearing neoplastic stroma (Fig. 8.97). Four types of these lesions are demonstrated on MRI, with cystic lesion with a mural nodule representing the most common subtype. However, solid, microcystic, or even completely cystic 498

appearances are also encountered (Figs. 8.98–8.101) (251,252). Interestingly, morphologic changes may be seen during the follow-up of these patients, with solid lesions developing cystic components and consequently resulting in poorer outcomes, due to increased mass effect and associated symptoms (251). The goals of the preoperative imaging study are to make the specific diagnosis of hemangioblastoma, to identify correctly all lesions, and to delineate the vascular nidus. There can be no question that MRI is the most effective noninvasive imaging modality for accomplishing these goals (255), although it has not been established whether high-resolution, contrast-enhanced MRI is as sensitive as angiography for the detection of small lesions. MRI plays an important role in the characterization of these lesions, with the potential to delineate the nidus and to help in the differentiation from other infratentorial masses, such as PAs and cystic metastasis (257,258). The presence of a predominantly cystic lesion associated with a peripheral pial-based mural nodule of solid tissue, which shows an intense enhancement and facilitated diffusion on DWI, including large vessels within and/or at the periphery of the mass, are the typical findings allowing for correct imaging diagnosis (251,257). Recent investigations have studied the role of DSC perfusion in differentiation of hemangioblastomas from PA (257,258). Kumar and colleagues (257) have described a large increase in the rCBV in patients with hemangioblastoma (mean value was 7.7) compared with PA (mean value was 1.8), with a similar finding reported in a previous study (259). Additionally, this inherent characteristic (high rCBV) may also help in differentiation of hemangioblastomas from metastases (259).

FIGURE 8.97 Hemangioblastoma, gross and histopathologic features. A gross specimen (A) shows correlates of heterogeneity seen on magnetic resonance, with vascular regions admixed with solid nodular portions of tumor. Histologic examination reveals numerous vascular channels lined by plump endothelial cells. Vascular structures often form large blood-filled cysts (B). At higher magnification (C), foamy lipid-laden stromal cells with clear cytoplasm are seen admixed with endothelial cells. Red blood cells are present within the lumen of the numerous delicate vascular structures.

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FIGURE 8.98 Proteinaceous cyst in extremely vascular hemangioblastoma. A markedly heterogeneous cerebellar mass is seen on sagittal T1-weighted image (A), with solid, cystic, and vascular signal intensities. On proton density– weighted images (B,C), the cyst is hyperintense to cerebrospinal fluid. T2-weighted images (D,E) reveal a heterogeneous solid component that is mainly isointense to gray matter. Note the large vascular flow voids on all images at the periphery of the tumor and within the solid portion. Edema in the left uncus is noted (C,E). After intravenous contrast (F,G), solid components enhance markedly; the cyst wall shows no enhancement. Large veins also enhance (G). Additional left temporal lobe enhancing hemangioblastoma is also clearly depicted (G).

Surgical resection is considered curative, but recurrence is common after incomplete excision of the tumor. The rate of recurrence is reduced significantly if the vascular nidus itself is removed rather than merely the cystic portion (260). After surgical excision, newly documented lesions may truly represent new lesions rather than recurrence in patients with VHL syndrome.

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FIGURE 8.99 Hemangioblastoma, posterior fossa in a patient with known von Hippel–Lindau disease. Sagittal T1weighted image (A) shows a mass in the cerebellum (white arrows), with an adjacent cystic area (white arrowheads). Also note multiple flow voids (black arrowheads). Axial T2 (B,C), fluid-attenuated inversion recovery (D,E), T1 precontrast (F,G), and T1 postcontrast (H,I) images demonstrate the mass with both cystic and solid components. Also note multiple other smaller lesions best seen on postcontrast images (H,I, arrowheads).

PINEAL REGION TUMORS Pineal gland neoplasms are uncommon tumors, with an estimated incidence of less than 1% of all intracranial tumors (Table 8.13) (18). The clinical presentation usually develops along one of the three scenarios: hydrocephalus, due to aqueductal compression; Parinaud syndrome of tectal compression (palsy of upward gaze, pupillary reflex impaired with light but preserved with accommodation, and failure of convergence); or endocrinologic abnormalities associated with suprasellar involvement (e.g., precocious puberty in males with germ cell tumors) (261). These tumors can be divided into two major groups: germ cell tumors and tumors derived from pineal parenchymal cells. Pineal region glial cell tumors (e.g., astrocytomas, gangliogliomas, or glioblastomas) and meningiomas usually extend from adjacent brainstem or tentorium and only rarely originate from the stroma of the pineal gland itself. Pineal cysts, on the other hand, are remarkably common as incidental findings. 501

FIGURE 8.100 Hemangioblastoma, cerebellar vermis with extensive edema. A: Sagittal T1-weighted magnetic resonance (MR) (400/20). B: Axial T1-weighted MR (550/20). C: Axial T2-weighted MR (2500/90). D: Axial T1weighted MR (600/30), with contrast enhancement. E: Coronal T1-weighted MR (600/30), with contrast enhancement. Characteristic MR features include large tumor vessels (A, arrows), solid (1) and cystic portions (2) (A–C), and dense enhancement of the solid component (D,E, 1) after contrast administration. The enhancing mass abuts the pial surface (E). Note high-intensity edema associated with the lesion (C) and tonsillar herniation from mass effect (A).

MRI has allowed for a marked improvement in the preoperative evaluation of benign and malignant pineal masses, as well as a distinction of the true pineal lesions from parapineal masses impinging on the pineal gland. Imaging of the entire neuroaxis with MRI with intravenous contrast is necessary when malignant pineal lesions are suspected, given the high frequency of metastatic dissemination via subarachnoid space (262). Despite excellent lesion characterization on MRI, there is controversy in the recent literature regarding characteristic imaging patterns of the common pineal region tumors (262–264). Unfortunately, approximately 10% of all the pineal lesion biopsies are either nondiagnostic or result in incorrect diagnosis, due to the complexity and high vascularity of these masses and frequent insufficient tissue obtained (secondary to deep location with crucial adjacent vascular and brain structures) (263). Two new entities have recently been described in this region, papillary tumor of the pineal region (PTPR) and pineal parenchymal tumor of intermediate differentiation (PPTID).

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FIGURE 8.101 Solid supratentorial hemangioblastoma, need for contrast administration. Questionable or invisible abnormalities on fluid-attenuated inversion recovery (A) are clearly shown to represent three separate intensely enhancing (B) hemangioblastomas in cerebellar hemispheres of a patient with von Hippel–Lindau syndrome. Also note the tiny intramedullary enhancing hemangioblastoma in the cervical spinal cord of this patient (C,D, arrow).

TABLE 8.13 Pineal Region Tumors

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FIGURE 8.102 Suprasellar germinoma with seeding on fluid-attenuated inversion recovery (FLAIR). The suprasellar mass on sagittal (A) and coronal (B) images enhances intensely (C,D) after contrast. Although the lesion is inseparable from the optic chiasm and hypothalamus on these images, the added depiction of the subarachnoid space abnormality (E,F), particularly well seen on FLAIR (F) as high intensity within the sulci, prompts the first consideration to be germinoma because these lesions have a known predilection to disseminate.

There are two major goals of presurgical MRI evaluation in patients with already documented pineal region masses: (1) detection of a decompensated (acute) hydrocephalus to be treated as an emergency and (2) planning of the surgical approach, choosing a stereotaxic biopsy in cases with high suspicious of germinoma (extremely radiosensitive neoplasm) versus invasive definitive surgery, recommended in patients with pineal parenchymal tumors (PPTs) (262). Given the diagnostic and treatment challenges described above, the neuroradiologist plays an important role in delineation and characterization of these lesions as well as in providing crucial information for surgical planning. Germ Cell Tumors Despite the somewhat problematic categorization of pineal tumors, it is well documented that most are of germ cell origin. Several different tumors constitute the family of germ cell neoplasms, including germinoma; the malignant nongerminomatous germ cell tumors, including embryonal carcinoma, choriocarcinoma, yolk sac carcinoma, and mixed types; and teratoma, both immature and mature (133). Germ cell tumors of the CNS generally develop in the midline, most frequently in the pineal region, followed by the suprasellar area (Figs. 8.102–8.105) and the fourth ventricle. Laterally situated basal ganglionic germ cell tumors are less common but are seen more often in patients of Asian descent. Germinomas are the most common germ cell tumor and also are the most common pineal mass (18,265,266). These tumors commonly present with a long prodrome of endocrinopathies, particularly growth failure and diabetes insipidus, and less often hydrocephalus or Parinaud syndrome. They can 504

also be associated with the development of precocious puberty in males (267); however, the precise explanation for this remains elusive. The pineal germinoma peaks in incidence at puberty, and most patients are in their first three decades of life, and may be seen in association with several genetic syndromes (Klinefelter, Down, and NF1). There is a striking male predominance of over 90% of patients with pineal germinoma (18). It is not clear why this does not apply to suprasellar germinomas, although other (e.g., ganglionic) intracranial germ cell tumors are also more common in males. Although these tumors are highly prone to seed the subarachnoid space and invade adjacent brain parenchyma, they are markedly radiosensitive and demonstrate very high survival rates, even in the presence of widely disseminated metastases (18). Spontaneous regression is extremely uncommon, but has been documented the literature, with persistent controversy regarding its etiology (268). Intratumoral hemorrhage is a relatively frequent pathologic finding (18).

FIGURE 8.103 Pineal and suprasellar germinoma. The suprasellar nodularity and pineal mass on unenhanced T1weighted images (A,B) enhance with nodular solid features after contrast (C,D).

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FIGURE 8.104 Pineal germinoma. A: Sagittal T1-weighted magnetic resonance (MR) (600/20). B: Axial T2-weighted MR (3,000/90). C: Axial T2-weighted MR (3,000/90). D: Sagittal T1-weighted MR (600/17), with contrast enhancement. An intrinsic pineal mass (A–C, closed arrows) displaces the superior colliculi (A, open arrow). Note the homogeneous low intensity on T2-weighted images (B,C) and high intensity in the thalami (C) and midbrain (B), indicating parenchymal invasion. The mass enhances diffusely (D, arrows) after contrast administration. E: Histologic specimen of germinoma exhibits large polygonal cells with distinct boundaries and large spherical nuclei containing nucleoli, admixed with small, mature lymphocytes.

Pineal germinomas are usually well-circumscribed, relatively homogeneous lesions that are inseparable from the pineal gland. CT may demonstrate the characteristic feature of calcifications engulfed by tumor, in contradistinction to pineal cell tumors which may show “scattered calcifications.” It is important to emphasize that germinomas may also demonstrate cystic components, which is of importance to the referring physician, as such lesions often have a decreased response to radiation therapy (264). In a recent study, Awa et al. (264) described that basal ganglia extension (“butterfly sign”), combined with a thick rim of peritumoral edema, is a useful finding in preoperative differentiate germinomas from the other entities in the pineal region. The second most common pineal germ cell tumor is a teratoma (Fig. 8.106). These neoplasms have a wide variation in their degree of histologic maturity and consequently demonstrate a variable biologic behavior and clinical course. They usually occur in an earlier age group than germinoma, with most seen in the first decade of life. Because these lesions are derived from all three germinal layers, they can contain hair, teeth, bone, and fat on pathologic examination (18). According to the 2007 WHO Classification of Tumors of the Central Nervous System, teratomas are a type of nonseminomatous germ cell tumor, and can be subdivided into mature (dermoid cyst), immature, and teratoma with malignant 506

transformation (7). They are virtually always partially cystic and commonly hemorrhagic (18), usually displaying a heterogeneous appearance on imaging due to the variable contents.

FIGURE 8.105 Suprasellar and pineal germinoma with hemorrhage. A: Sagittal T1-weighted magnetic resonance (MR). B: Sagittal T1-weighted postcontrast MR image. C: Axial gradient echo. D: Axial T2-weighted image. MR imaging shows a large irregular mass located in the pineal region, displaying a prominent enhancement on T1weighted postcontrast image (B). Note the intratumoral hemorrhage on the T1-weighted image (A, yellow arrow) and on the T2*-weighted GRE. There is also significant involvement of the pituitary stalk, which enhances heterogeneously after the contrast agent administration (B, blue arrow). (Courtesy of Bruno Siqueira Campos Lopes, MD, São Paulo, Brazil.)

FIGURE 8.106 Pineal teratoma. A: Sagittal T1-weighted magnetic resonance (MR) (600/20). B: Axial T1-weighted MR (600/20). C: Axial T2-weighted MR (2,800/80). An inhomogeneous, partially high-intensity pineal mass (A,B,

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arrows) represents a fat-containing teratoma. The fatty portion of the mass parallels the intensity of subcutaneous fat (A–C).

Embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mixed germ cell tumors are much less common and have worse prognoses due to their higher degree of malignancy. These lesions are very frequently hemorrhagic. Diagnosis is sometimes made without biopsy, by the finding of elevated human chorionic gonadotropin or α-fetoprotein in serum or CSF. The imaging findings are nonspecific; however, a recent retrospective study by Lv et al. (269) reported characteristic choriocarcinoma imaging features, such as heterogeneous signal intensity with markedly hypointense areas on T2weighted images, hemorrhage and heterogeneous, ringlike, or intratumoral nodular enhancement. When this findings are seen in a young patient with serologic results (serum HCG/β-HCG levels) supporting this hypothesis, a biopsy may be avoided. Survival rates appear to be improving with combined modality treatment, including craniospinal irradiation and chemotherapy; nonetheless, the disease is fatal and there is no established treatment (269). Pineal Cell Tumors Primary neoplasms of the parenchymal cells of the pineal gland, known as PPT, typically arise from pineocytes or their precursors and are therefore distinctly different from other pineal region tumors (262), accounting for approximately one-third (30%) of all tumors in this region (270). PPTs are heterogeneous entities and their classification has been a controversial issue in the last few decades. At present, the WHO, as of its last update in 2007, recognizes three major categories of PPTs with four grade subtypes, related to their behavior and malignant potential, including grade I PC, grade II/III PPTID and also grade IV PB (262). These neoplasms supposedly occur as a broad spectrum and different grades may also coexist within the same tumor, as has been recently reported (271,273) in a case of a low-grade PPT (PC) that underwent transformation into a secondary PB. As these entities may share most of the imaging findings, it is essential to take into account demographic and clinical data. The patient’s age should be considered, as adult patients usually present with benign tumors, whereas children are frequently affected by more aggressive tumors (262). PC is more often a tumor of middle-aged and older adults. These tumors are well-defined lesions that generally do not infiltrate brain. PCs are usually less cellular than PB and demonstrate cells with more cytoplasm (18). These are solid lesions rather than cystic on pathologic examination, so the demonstration of a cystic pineal mass should prompt the radiologist to consider simple pineal cyst rather than this neoplasm. These tumors show a slow more benign course when they demonstrate more neuronal differentiation but are aggressive malignancies with very poor survival rates in their less differentiated form (18). PPTID is a newly recognized rare entity that as intermediate features between the grade I (PC) and the grade IV (PB) PPTs. They were categorized by the WHO in 2007 into two subgroups, with different prognoses, according to the number of mitoses and degree of neuronal differentiation (low-grade PPTID/grade II or high-grade/grade III). According to the literature, PPTID has a slight female preponderance, most frequently found in adults during the third and fourth decades of life (8,272). Imaging findings and histopathologic characteristics have been described in the last few years as sharing those of other PPTs (Fig. 8.107), with no pathognomonic features, presenting as midline, usually circumscribed mass located in the pineal region; scattered or central calcifications; some degree of restricted diffusion (variable ADC values) and iso-to-low signal intensity on T2-weighted images and heterogeneous enhancement after contrast injection (8,262,272). PB (grade IV neoplasm) (Fig. 8.108) is typically found in children, is a highly cellular and infiltrative tumor composed of poorly differentiated immature cells with very scant cytoplasm. It often shows focal hemorrhage and microscopic necrosis. This tumor appears histopathologically similar to medulloblastoma and other primitive undifferentiated neoplasms but may exhibit retinoblastomatous differentiation, sometimes Flexner–Wintersteiner rosettes, in which neoplastic cells with cytoplasmic extensions surround a small lumen. PB is more likely to be a large and heterogeneous mass, exhibiting irregular borders with brain invasion. Hyperdensity on CT scan and areas of restricted diffusion with lower ADC values, as well as iso- or hypointensity on T2-weighted images may be seen on MRI (262). PBs tend to disseminate early through the subarachnoid pathways, with leptomeningeal and subependymal seeding often found at the time of initial diagnosis. A rare variant of PB is the “trilateral retinoblastoma,” the term used for a PB in a patient with bilateral retinoblastoma (273). This is most often an inherited syndrome, and the diagnosis should be sought in any patient with bilateral retinoblastoma. 508

The specific diagnosis of histopathologic type in pineal cell tumors is often not possible (Fig. 8.109). MR depicts pineal neoplasms as lobulated solid tumors that may enhance intensely with contrast (Fig. 8.110). As the tumor arises from pinealocytes in the gland central region and not from cells in neighboring structures, “scattered”/exploded calcifications (tumor mass compressing intrinsic pineal calcifications) may be seen in the periphery, detected by CT and MRI and also playing a role in the differentiation from the GCTs. Unfortunately, in some cases, germinoma can appear identical to PB on MR scan. It is important to emphasize that cystic lesions may represent pineal cysts in most cases. Signal intensity is another important feature and can help in the differential diagnosis, which usually reflects the cellular density of these entities (pineal neoplasms). PB generally shows relative cytoplasm paucity and is essentially isointense to gray matter on T2-weighted images, a pattern shared by other PNETs. PPTID and PC, with a higher degree of cytoplasm when compared to PB, have relatively higher signal intensity on T2-weighted images. Papillary Tumor of the Pineal Region Described in 2003 as a distinct entity, this rare neuroepithelial tumor that exhibits ependymal differentiation and typically arises from specialized ependymocytes of the subcomissural organ (one of the circumventricular organs), formally incorporated in the last WHO classification (270), and considered a grade II or III neoplasm by most neuropathologists (8). This neoplasm is generally located in the lining of the posterior commissure or pineal region, affecting middle-aged patients, with peak incidence in the third and fourth decades (mean age—32 years) and a moderate 5-year survival rate (73%) (8,274). CSF dissemination seems to be rare; however, its clinical behavior is characterized by frequent local recurrence (274). Macroscopically, this tumor resembles a PC; however, these tumors are easily distinguished microscopically by the presence of a papillary architecture with pseudostratified columnar epithelium (8). Although only a few publications are available, in some cases, T1 hyperintensity appears to represent a characteristic finding (Fig. 8.111). These tumors usually present as a large and well-circumscribed lesions with marked enhancement following contrast injection (270).

FIGURE 8.107 Pineal parenchymal tumors of intermediate differentiation (PPTID). MR imaging reveals a midline, circumscribed mass located in the pineal region (A); displaying mild degree of restricted diffusion (E) and iso-to-low signal intensity on T2-weighted image (C), associated with heterogeneous enhancement after the contrast injection (B). In this case, calcifications were not seen on T2*-weighted GRE imaging (D). (Courtesy of Bruno Siqueira Campos Lopes, MD, São Paulo, Brazil.)

Pineal Cysts 509

Pineal cysts are common as incidental necropsy findings, reported to be present in up to 40% of routine autopsies. These incidental nonneoplastic glial lesions went virtually unnoticed before the advent of MR with direct sagittal imaging in evaluating possible brain pathology. Even large pineal cysts with apparent compression of the dorsal midbrain are usually asymptomatic, but occasionally pineal cysts can bleed internally or be so large that they may be a cause of aqueductal compression with secondary hydrocephalus and gaze disorders (275,276). The role of the neuroradiologist in this entity is to distinguish the pineal cyst from pineal neoplasm and to recognize the former as a benign and probably noncontributory factor to the patient’s clinical symptomatology.

FIGURE 8.108 Pineoblastoma. Noncontrast CT (A) and MR imaging (B–E) reveal a heterogeneously hyperdense large, lobulated mass lesion in the pineal region, which exhibit areas of low signal on T2-weighted imaging (B) and some degree of restricted diffusion on DWI (C), associated with a heterogeneous enhancement after the contrast agent administration (E). (Courtesy of Bruno Siqueira Campos Lopes, MD, São Paulo, Brazil.)

The MR diagnosis of a pineal cyst is often based mainly on morphology rather than simply signal intensity. It can be small and lie within a small portion of the gland, or it can replace the entire structure. The contents of the pineal cyst are homogeneous and are either isointense to CSF or diffusely hyperintense, especially notable on the proton density–weighted image. The divergence of the signal intensity from that of normal CSF should not alarm the radiologist and in fact is the most common pattern noted (277). The relative hyperintensity of the cyst fluid may relate to factors such as isolation from flow (compared with ventricular CSF), high protein content, or even old hemorrhage and does not signify tumor. The pineal cyst usually does not enhance intrinsically if scanning is performed immediately after injection of contrast, but surrounding residual pineal tissue will because there is no BBB in pineal capillaries. The size for which follow-up imaging has been recommended varies between 1.0 and 1.5 cm, although far larger lesions, even those with mass effect on adjacent structures, should not confuse the neuroradiologist as being anything other than benign cysts in the vast majority of cases (278,279). Moreover, other studies have shown fairly stable pineal cysts with mild changes in size (280). It is probably reasonable to recommend a single follow-up in those limited number of cases in which there is uncertainty as to the diagnosis, but the overwhelming number of pineal cysts need no follow-up (Fig. 8.112).

COLLOID CYSTS Colloid cysts are rare, congenital, benign lesions, comprising less than 2% of intracranial tumors. However, they represent 15% to 20% of all intraventricular pathologies (Table 8.12) and 55% of third ventricle masses (281–283). These lesions are distinctive because of both their characteristic 510

morphology and their specific location at the anterosuperior aspect of the third ventricle, between the columns of the fornices. They represent the most common type and location of neuroepithelial cysts (284), which can also occur in choroid plexus, within the lateral ventricle, subarachnoid space, and even brain parenchyma. Most are found or detected in adults, and those discovered in the pediatric population tend to exhibit a rapid development (285). They represent epithelial-lined mass lesions, with lining resembling pulmonary epithelium, a fact that suggests an endodermal origin, rather than neuroepithelial (281). Colloid cysts become problematic when they occlude the foramina of Monro and cause hydrocephalus, which may be intermittent and positional. Young- to middle-aged patients present with headache, sudden transient paralysis of the lower extremities, incontinence, personality changes, and dementia, the latter possibly related to forniceal compression. Hemorrhagic transformation is extremely rare, with just a few cases reported in the literature (282,283). The main cause for concern regarding this lesion is its location rather than size (281), although occlusion of the foramina of Monro generally occurs with cysts larger than 1 cm (282), with hydrocephalus or even sudden death as possible outcomes (281,282). For this reason, these lesions should be treated (simple shunt placement, open surgeries, and percutaneous approaches). The neuroendoscopic transcallosal procedure is most commonly performed at present (285).

FIGURE 8.109 Ganglion cell tumor, pineal. T2-weighted (A) and fluid-attenuated inversion recovery (B) images show a homogeneous, rather low–signal-intensity mass involving the pineal gland. No enhancement is seen (C) after contrast. This appearance may also be seen in pineocytoma.

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FIGURE 8.110 Pineocytoma. Sagittal T1-weighted image (A) shows intrinsic pineal mass filling the pineal cistern and compressing the vermis. Axial proton density–weighted image (B) shows a homogeneously hyperintense mass without edema in adjacent brain. In a different case, pineocytoma enhances homogeneously (C). Histologic specimens (D,E) show bland uniform clusters of cells arranged around acellular amorphous areas, occasionally in a large “rosette” formation. In some areas, the lobular pattern of the normal pineal gland is preserved.

MRI with thin sections and/or volumetric sequences provides an exact location of this lesion, which usually appears as relatively hypointense on T2-weighted imaging. Most of these cysts exhibit high signal on T1-weighted images, depending on its contents (especially water, protein, and cholesterol) (Fig. 8.113). CT exam usually depicts a round, well-circumscribed lesion in the anterosuperior aspect of the third ventricle, slightly hyperdense to CSF (281). These lesions have variable contents (protein, cholesterol, old blood, hemosiderin, CSF, and various ions) which may change their MR appearance over time, possibly related to hemorrhagic or xanthogranulomatous changes, as the mucinous component (its principal constituent) has not been found to undergo modification (281,285). Other cysts contain clear serous fluid, similar to CSF and differing only slightly with regard to total protein content. A thin wall is nearly always discernible and represents the epithelial lining. Unless there is solid enhancement of the lesion rather than the commonly found slight peripheral enhancement, there is almost never a question about the diagnosis.

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FIGURE 8.111 Papillary tumor of the pineal region (PTPR). A: Sagittal T1-weighted magnetic resonance (MR). B: Axial T1-weighted postcontrast image. C: Sagittal T1-weighted postcontrast MR images. D: Axial T2-weighted image. MR imaging shows a well-circumscribed lesion in the pineal region, displaying marked heterogeneous enhancement following contrast injection (B and C). Note also inherent T1 hyperintensity seen in some areas (A, white circle) which appears to be a characteristic finding of these tumors. (Courtesy of Bruno Siqueira Campos Lopes, MD, São Paulo, Brazil.)

Beyond diagnosis, the neuroradiologist may play an important role in predicting outcome of treatment by determining possible cyst content and viscosity (281). Although Tamura et al. recently reported successful neuroendoscopic drainage of a low T2 signal colloid cyst (283), typically the more viscous cysts with low T2 and high T1 signal are associated with lower success rate, and alternative treatment such as an open-surgery resection may be considered (281).

PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA Lymphomatous involvement of the CNS may appear as two different entities: (1) secondary CNS involvement by systemic lymphoma or (2) PCNSL, when the disease is confined to brain, leptomeninges, eyes, or spinal cord, at the time of diagnosis (286–288). The secondary metastatic form is the most common, which varies in frequency and is highly dependent on the histologic subtype (286). Metastatic lymphoma manifests in CNS as leptomeningeal spread (cranial nerves, spinal cord, or spinal roots) in two-thirds of the patients, and presents as parenchymal disease in the remaining one-third of the patients generally corresponding to the initial presentation of PCNSL (286). In metastatic lymphoma of the CNS, it is exceptional for parenchymal masses to be seen without leptomeningeal involvement (18). PCNSL is a relatively uncommon entity which remains a challenging diagnosis, corresponding to 1% to 5% of all brain tumors and approximately 1% of the non-Hodgkin’s lymphomas (NHLs), nearly all of them presenting as diffuse large B-cell lymphoma (DLBCL) (286,288), with T-cell lymphomas being rare (289). When Hodgkin’s lymphoma involves the brain parenchyma, it is almost always concurrent with systemic disease or with dural attachment (290). During the last few decades, significant increase of PCNSL in immunocompetent patients was noted, in all age groups and without a gender predilection, a fact that cannot be ascribed just to the impact of new technology (286,291). Immunocompromised patients have increased risk for PCNSL; however, the incidence in this population has declined in the last few years due to the introduction of the HAART therapy (286). The site of origin of PCNSL is controversial as CNS has no endogenous lymphoid tissue or lymphatic circulation. In immunocompetent patients, these are believed to represent DLBCL and they are strongly associated with Epstein–Barr virus 513

in immunocompromised patients (292). Even though lymphomas usually demonstrate characteristic imaging features, at present, no imaging finding has been identified that has the ability to unequivocally differentiate between primary and secondary involvement (286). Hence, clinical information, epidemiology, and histology are essential to raise and confirm this possibility, especially in patients with acquired or congenital immunodeficiency syndromes.

FIGURE 8.112 Pineal cyst. A: Sagittal T1-weighted magnetic resonance (MR) (600/20). B: Axial proton density– weighted MR (3,000/35). C: Axial T2-weighted MR (3,000/90). D: Axial T1-weighted magnetic resonance imaging (800/30), with contrast enhancement. A round homogeneous mass in the pineal (A–C, closed arrows) compresses the superior colliculi (A, open arrow) in an asymptomatic patient. The mass is only slightly higher in intensity than cerebrospinal fluid on the proton density–weighted image (B). Note the minimal dorsal enhancement (D, arrows), representing residual normal pineal parenchyma, choroid, or veins. E,F: Histologic specimens of a small pineal glial cyst demonstrates the nature of this common finding that is derived from cystic degeneration within the glial element of the pineal gland.

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FIGURE 8.113 Colloid cyst. Axial fluid-attenuated inversion recovery (FLAIR) (A), sagittal T1 (B), axial T1 (C), and coronal T1 postcontrast (D) images demonstrate a smoothly lobulated mass located at the foramen of Monro. Note the small amount of transependymal flow seen on the axial FLAIR images. E: Histologic specimen of a colloid cyst (different patient) shows the cystic structure lined by a single layer of flat cuboidal to low columnar, often ciliated cells filled with periodic acid-Schiff–positive amorphous material.

PCNSL is a densely cellular neoplasm with a high nuclei-to-cytoplasm ratio frequently diagnosed in patients aged 45 to 70 years, affecting mainly superficial and/or periventricular regions and usually exhibiting a marked BBB dysfunction, often in contact with ventricular or meningeal surfaces (286,293). Leptomeningeal spread is a relatively common feature, often undetectable by CT (294) which is typically visualized on postcontrast MRI, with the FLAIR sequence being most sensitive. The supratentorial compartment (predilection for the frontal lobes and deep gray matter) is involved in more than half of patients at initial presentation (289). The clinical outlook is dismal in PCNSL after radiotherapy alone; greater than 60% of patients relapse in the brain, with median survival of 12 months (295). High-dose methotrexate has been incorporated in the past years and is currently a part of standard therapy (with or without whole-brain irradiation) which according to some reports, has prolonged median survival (2 to 4 years) when compared with radiotherapy alone; however, optimal management has not been fully established at this time (288). Differentiation of PCNSLs from other intracranial masses is of high clinical relevance because treatment and management strategies are quite different, especially compared to glioblastomas (296). MRI is essential for the complete evaluation of suspected PCNSLs. Although patterns are extremely variable in focal involvement, particularly in patients with AIDS, features associated with high cellularity tend to be demonstrated, both on CT and MRI, typically appearing as iso- to hyperdense mass on CT scan and exhibiting iso- to hypointense signal on T2-weighted images. However, lymphoma can also be hyperintense on T2-weighted and FLAIR images. Additionally, low ADC values within contrastenhancing lesions is also seen, being one of the hallmarks of hypercellular tumors, findings that may play an important role in the posttreatment surveillance, guiding management, and predicting patient outcomes (Figs. 8.114 and 8.115) (297,298). After the contrast injection, single or multiple relatively homogeneously enhancing parenchymal lesions typically in periventricular location may be seen in both immunocompetent and immunocompromised patients (Fig. 8.116). However, in immunocompromised patients, centrally necrotic lesions (Fig. 8.117) with irregular rim and bizarre enhancement can be present, and have been reported in up to 75% of patients who have acquired immunodeficiency syndrome (AIDS) (286,288). The extent of edema on MRI is generally less than that seen with primary 515

gliomas or metastases of similar size. Additionally, calcifications or hemorrhage are quite unusual, although hemorrhage is more common in HIV patients (286). Knowledge of immune status of the patient (immunocompetent or immunocompromised) is important for the radiologist in this setting, allowing for a more accurate differential diagnosis (296).

FIGURE 8.114 Lymphoma—multifocal involvement. MR imaging—sagittal T1-weighted (A), axial T2-weighted (B), and axial T2*-weighted GRE (C)—reveals well-defined cortical-subcortical enhancing (D) masses, adjacent to the cortex and pia. These lesions also display a typical low signal on T2-weighted imaging (B) and show evidence of restricted diffusion (E), confirmed by the low values on ADC map (F) due to hypercellularity.

The differential diagnosis of such imaging findings includes several entities, depending on the appearance of the lesion, and immune status of the patient: Immunocompromised patients (HIV): If one sees a single deep lesion having relatively homogeneous intensity similar to that of gray matter, dense contrast enhancement, and minimal edema, the classic description for the entity, the most likely diagnosis is PCNSL. However, multiple parenchymal masses are often empirically treated with antitoxoplasmosis agents, due to its higher prevalence in this population, and followed for radiographic and clinical response (4 to 6 weeks) in the absence of tissue diagnosis (286,289,293). The advanced imaging methods may be helpful in the differentiation between these two entities. Important findings highly suggestive of lymphoma include the presence of subependymal spread (299), absence of calcification, and MRS demonstrating elevated peaks of lactate (Lac), as well as a moderate choline (Cho) peak increase (Fig. 8.118) (286). MR perfusion of PCNSL may also show an elevated or normal rCBV (Fig. 8.119), compared with relatively diminished rCBV in toxoplasmosis (286). Hemorrhage is also very common in cerebral toxoplasmosis, particularly after treatment, and, if present, argues against lymphoma. Thallium-201 chloride scan has been successfully used to make this differentiation, where lymphoma usually exhibits an increased uptake as compared to infectious diseases such as toxoplasmosis (300).

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FIGURE 8.115 Lymphoma crossing the corpus callosum. Upper row—axial T2-weighted (A), axial T1-weighted postcontrast (B), and DWI (C) images demonstrate a large, homogeneously enhancing mass involving the splenium of the corpus callosum. The restricted diffusion is more typical of lymphoma than glioblastoma.

FIGURE 8.116 Lymphoma in acquired immunodeficiency syndrome (AIDS) with subependymal enhancement. Bilateral ganglionic periventricular masses (A,B) are isointense to gray matter on the T2-weighted image (B) and show extensive edema in this AIDS patient. After intravenous contrast (C,D), only partial enhancement is seen. Note the subependymal spread along the left frontal horn (C), highly suggestive of lymphoma.

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FIGURE 8.117 Lymphoma in acquired immunodeficiency syndrome (AIDS)—use of DWI and ADC values. MR images —axial T2-weighted (A), DWI (B), ADC map (C), and T1-weighted postcontrast (D,E)—demonstrate periventricular masses associated with extensive perilesional edema, as well as signs of restricted diffusion and low values on ADC map, consistent with hypercellular lesions. Note the subependymal spread along the right occipital horn (E, blue arrow), which is highly suggestive of lymphoma.

FIGURE 8.118 Lymphoma. Axial T2-weighted (A) and FLAIR (B) images show a hypointense lesion located in the right frontal lobe, surrounded by moderate edema. Note the characteristic hyperintensity on DWI (C) and heterogeneous enhancement after the contrast injection (D). On MR spectroscopy, mild elevation of choline peak and reduction of N-acetyl aspartate are seen, as well as an marked elevation of lipids/lactate peaks.

Non-HIV and immunocompetent patients: In non-AIDS patients, other lesions are also in the differential diagnosis. If a focal-enhancing parenchymal mass is accompanied by enhancement along the perivascular spaces, especially with adjacent meningeal enhancement, lymphoma and sarcoidosis should always be considered in the same differential diagnosis (Fig. 8.120). Capillary telangiectasia typically shows lacelike enhancement on MRI and is nearly isointense to gray matter, but this asymptomatic lesion should not have any mass effect and is characteristically in the pons. Exceptionally rare 518

infiltrative disorders, including amyloidosis and CNS Whipple disease can also present with deep brain or brainstem masses that are hypercellular and enhance in the setting of cognitive decline.

FIGURE 8.119 Lymphoma—DSC perfusion evaluation. Axial T1-weighted postcontrast (A) and rCBV color map from DSC perfusion MRI (B) exhibit the typical pattern found in patients with lymphomas, with slight increase of rCBV compared to the contralateral white matter.

FIGURE 8.120 Neurosarcoidosis along perivascular spaces. Subtle hyperintensity in right frontal white matter on the T2-weighted image (A) is clarified by intravenous contrast, after which clear enhancement is noted bifrontally in a pattern indicative of infiltration along Virchow–Robin spaces (B) in this pathologically proven case of sarcoidosis.

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The classic “butterfly” appearance of an enhancing mass crossing the corpus callosum may be seen with PCNSL and other lesions, including neoplasms like glioblastomas and metastases as well as inflammatory disorders, such as encephalitis or demyelinating disease. In these cases, multiparametric evaluation may be helpful. Lymphomas, like all hypercellular tumors, tend to display homogeneously restricted diffusion with lower ADC values (296) and less elevation in rCBV (DSC perfusion) and rCBF (ASL perfusion) when compared to high-grade gliomas and nonhypercellular metastases (296,301), with the presence of lactate on spectroscopy, along with an almost complete absence of NAA and increase in choline (289). Hemorrhage is rare in patients with PCNSL (296). Demyelinating disease may also appear as a lesion that crosses the corpus callosum, and may be included in the differential diagnosis, although solid homogeneous enhancement would not fit with demyelinating disease. Encephalitis should have significantly restricted diffusion, usually without the homogeneous enhancement of lymphoma. Recently, Farrell et al. reported that ultra-small superparamagnetic iron oxide (USPIO) nanoparticles may be useful in the diagnosis of these entities (297). It should be noted that dramatic resolution of lymphomatous masses has been reported after steroid administration, with striking regression of brain lesions and elimination of previous enhancement; however, this unusual phenomenon has also been reported, although very rarely, in patients with other entities. Posttransplant lymphoproliferative disorder (PTLD) represents a rare and highly morbid condition affecting chronically immunocompromised patients, mainly after solid organ transplants, where a group of B cells grows out of control, manifesting as a spectrum of lymphoproliferative disorders, ranging from benign hyperplasia to highly invasive malignant lymphoma (303). According to the WHO, four types of PTLD are described: (1) premalignant lymphoid hyperplasia; (2) polymorphic lymphoma; (3) monomorphic lymphoma; and (4) other lymphoproliferative disorders (304). Regardless of precise histology, mortality rates are well over 50%. EBV and CMV positive status, patient age, transplant duration, and aggressive immunosuppression regimen, together with the graft type, are some of the important risk factors described (304). PTLD neoplasms are actually relatively common tumors in the posttransplant setting, being the most common cause of cancer-related mortality after solid organ transplantation. CNS involvement tends to occur later than non-CNS PTLD (304), usually after the first few years, when inflammatory and infectious disorders are more common. The CNS is involved in up to 30% of cases of PTLD, and in many of these, the disease is confined to the CNS (contrasting with NHL, in which only around 1% of cases show isolated CNS involvement). CNS involvement is a poor prognostic sign (305). When the brain is involved, lesions are typically multiple and enhancing and can appear identical to typical lymphoma, which reflects hypercellular masses often with accompanying leptomeningeal or subependymal involvement, exhibiting a predilection for the deep gray matter and periventricular regions (304). In these patients, infection is the other major lesion to consider (Fig. 8.121). This entity may also involve other sites in the brain (Figs. 8.122 and 8.123). Because immunosuppression required to preserve graft function results in impairment of T-cell immunity and allows for uncontrolled proliferation of EBV-infected B cells, the treatment of PTLD centers on reduction of that same immunosuppression. In addition to reducing the immunosuppression, surgical resection or the use of localized radiation therapy has been of value in some patients with PTLD, but chemotherapy has been of limited value.

METASTATIC DISEASE Metastatic spread of tumor to the brain and its coverings from extracranial sites is a relatively common occurrence that represents a frustrating therapeutic problem for the physician and an emotionally and physically debilitating event for the patient. It is well known that cancer is the second most common cause of death in developed countries, only following cardiovascular diseases (306). At the same time, while the numbers of malignancy cases are increasing, important advances have occurred in several diagnostic and treatment modalities for these patients that have improved survival. Additionally, gradual aging of the population and an associated increase in overall incidence of neoplasms (which generally affect patients in the fourth to seventh decades of life), as well as earlier detection of neoplastic lesions, have resulted in a marked increase in the number of patients diagnosed with metastases. Approximations from literature reports concerning the incidence of metastases range vary, but intracranial metastases are found in about one-fourth of all patients who die from cancer. Intracranial metastases accounts for 170,000 new cases each year in the United States alone (307).

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FIGURE 8.121 Posttransplant lymphoproliferative disorder. A small right frontal lesion with extensive edema which hypointense appearance on T2-weighted (A) and restricted diffusion on DWI and ADC map (B,C), consistent with a hypercellular lesion, and ring enhancement seen on pre- and postcontrast T1-weighted imaging (D–F).

FIGURE 8.122 Posttransplant lymphoproliferative disorder #2. Hypothalamic–chiasmatic location of a PTLD, which also exhibit hypercellular appearance on T2-weighted (B) and DWI (C), with a ring enhancement on T1-weighted postcontrast imaging. Note the elevated peaks of lipid/lactate on MR spectroscopy (E).

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FIGURE 8.123 Posttransplant lymphoproliferative disorder. A small right parietal lesion with edema (A) shows a significant increase in size after 1 month (B). The hypercellular appearance on T2 (B) and diffuse enhancement (C) are typical of cerebral lymphoproliferative disorders and appear identical to lymphoma.

The role of the radiologist includes both detection and specific diagnostic characterization of these lesions, while providing important information regarding the anatomic location and relationship with neighboring structures. It is also well established that these lesions are the most common intracranial tumors in adults, outnumbering primary brain tumors and occurring in approximately 15% to 40% of all cancer patients (308,309). Although brain metastases are likely to coexist with other sites of metastatic disease, symptoms secondary to intracranial metastases antedate the primary diagnosis of cancer in 45% of surgical cases (310). Most intracerebral metastases at diagnosis are multiple, regardless of the site of origin; however, there is a high incidence of solitary metastasis, with estimates ranging from 30% to 50% and are especially common in melanoma, lung, and breast carcinoma (18,311,312). Therefore, the fact that an intracerebral mass lesion is solitary should not mitigate the consideration of metastasis as the diagnosis. With the emergence of sophisticated radiosurgery, the detection of cerebral metastases is critical to patient management. In many cases, the patient may be asymptomatic, and the metastatic lesions are found incidentally on screening tests. Moreover, although brain metastases are likely to coexist with other sites of metastatic disease, the symptoms from brain metastases antedate the primary diagnosis of cancer in 45% of surgical cases (310). The most common symptoms that lead to the diagnosis of brain metastasis include headaches (88%), confusion (36%), hemiparesis (35%), seizures (29%), visual problems (27%), vertigo (24%), vomiting (22%), and aphasia (17%) (290). From surgical and CT studies, roughly 80% to 85% of metastases are located in the supratentorial compartment (310,313,314). The sine qua non of intracerebral metastases is enhancement of intra-axial masses with edema (Fig. 8.124). Early metastatic foci are commonly found at the gray matter–white matter junction, a feature shared by all hematogenously disseminated embolic disease. This distribution has been ascribed to the dramatic narrowing of the diameter of arterioles supplying the cortex as these vessels enter the white matter (18). As noted by Henson and Urich (315), tumor emboli measuring 100 to 200 μm in diameter are often found lodged in the 50- to 150-μm lumina of arterioles. Additionally, the metastatic deposit may disseminate to the calvarium or dural membranes and impinge or invade the adjacent brain secondarily. As imaging techniques have improved and became widely available during the last years, smaller, clinically silent lesions are detected at an earlier stage; however, the optimal screening protocol with contrast-enhanced MRI remains an important subject for discussion. The incidence of intraparenchymal lesions, the most common form of metastatic disease in the intracranial compartment, varies by stage and histology, with the most common in order of decreasing incidence being lung and breast cancers, followed by melanoma, gastrointestinal and genitourinary cancers (307). For many patients that present with brain metastases, the survival rates still remain poor, although aggressive management is effective in both symptom palliation and prolongation of life. Treatment modalities for the management of brain metastases include surgery, radiation therapy, and chemotherapy. Whole-brain radiation or stereotactic radiosurgery may be used. Chemotherapy may be used alone or with concurrent radiation as a radiosensitizing agent. Over the past decade or so, radiosurgery with Gamma-Knife and CyberKnife have become options for single tumors less than 3.5 cm in surgically inaccessible areas and for patients who are not surgical candidates (307). It has been well documented that MRI with intravenous contrast is more sensitive than CT for this diagnosis (312,316), so all candidates should be imaged by MRI prior to such treatment consideration Metastases are characteristically surrounded by extensive edema (Fig. 8.125), often extending far 522

from the site of a relatively small metastatic focus. However, edema does not exhibit a direct relationship with either the size of the metastasis or the patient clinical status and this imaging feature is obviously not pathognomonic, and may appear in other patients with inflammatory or infectious diseases. Additionally, metastases to gray matter, especially the cerebral cortex, can have no associated edema (Fig. 8.126). For this reason as well as an overall lack of sensitivity, a normal noncontrast CT does not exclude metastases to the brain. The edema associated with brain metastases is classified as vasogenic (318), where the major mechanism of edema formation is an underlying disturbance in vascular permeability, so that plasma proteins and other macromolecules pass freely into the extravascular space and consequently into the interstitial extracellular space (319). MRI is able to detect the typical focal lesions from the associated edema with contrast administration, although there are no pathognomonic features associated with metastases. Lesions are often separable from edema on T2-weighted images as the metastasis is typically a focus of variable signal intensity, in an area of high-intensity edema, which is usually prominent and follows white matter boundaries, like fingerlike projections with intervening unaffected cortex. Generally, vasogenic edema does not fully cross the corpus callosum unless the associated lesion is actually in the corpus callosum (Fig. 8.127) nor does it involve cortex, features that often help to distinguish these lesions from primary infiltrative brain malignancies; however, metastases can occur in the corpus callosum and location alone should not preclude the diagnosis.

FIGURE 8.124 Metastatic lung carcinoma—typical pattern of distribution. A–F: Axial T1-weighted postcontrast images reveal multiple supra- and infratentorial foci of metastatic disease found at the gray–white matter junction. (Courtesy of Victor Hugo Rocha Marussi, MD, São Paulo, Brazil.)

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FIGURE 8.125 Extensive metastases unsuspected without intravenous contrast. Cognitive changes in an elderly man with extensive white matter abnormality on fluid-attenuated inversion recovery (A,B) suggest chronic ischemic changes. Unsuspected metastases underlying the white matter abnormality are revealed after contrast enhancement (C,D).

T1WI with and without contrast agents, T2WI, FLAIR, and gradient-echo scans are the standard MRI sequences used in the characterization of these tumors; however, the imaging features are usually nonspecific, regardless of site of origin, and appear to be extremely variable in signal. There are several specific pathologic changes in metastases that influence the MR appearance of these lesions, and these findings seem to be best delineated by conventional T2-weighted images rather than FLAIR. Areas of nonhemorrhagic cystic necrosis appear as irregular regions of CSF-like intensity surrounded by the nonnecrotic portion of the lesion. Necrosis, on the other hand, has also been shown to shorten relaxation times (12), which may be due to release of intracellular, naturally occurring paramagnetics (e.g., iron or copper) or due to free radical peroxidation (320). Intratumoral hemorrhage, which occurs in just less than 20% of metastases (319,320), is readily detected by MRI. The exquisite sensitivity for the detection of hemorrhage on MR images can give clues to the primary site of origin because some metastases (most notably melanoma, small cell lung carcinoma, thyroid cancer, choriocarcinoma, and renal cell carcinoma) have a particular tendency to bleed. Furthermore, a detailed analysis of signal intensities in these cases can lead to the diagnosis of underlying tumor as the etiology of the intracranial hemorrhage (20). Specificity is also provided by MRI in the evaluation of melanoma metastases because pathologically documented nonhemorrhagic melanotic lesions are hyperintense on T1-weighted images and isointense on T2-weighted images (24). Other lesions that can show signal patterns suggestive of their site of origin include mucinous adenocarcinomas (e.g., colon), in which characteristic hypointensity is seen on T2-weighted images standing out from hyperintense edema (Fig. 8.37). Gradient-echo images distinguish between hemorrhagic metastases with acute blood and mucinous metastases, even though both lesions are low signal on T2 images, because the dramatic hypointensity of hemorrhage on GRE, always present if blood is the cause of the low signal on conventional T2 images, is not found if mucin is the cause of low signal on T2.

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FIGURE 8.126 Enhancing cortical metastasis in a patient with other chronic lesions. A: Proton density–weighted magnetic resonance (MR) (3,00035). B: T2-weighted MR (3,000/90). C: T1-weighted MR (600/20), with contrast enhancement. Although long–repetition time images (A,B) show multiple areas of abnormality, the postcontrast scan (C) reveals only one metastatic lesion (C, arrows). Note that the metastasis is not detectable on the precontrast proton density–weighted image (B) due to its cortical location and consequent lack of edema.

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FIGURE 8.127 Tissue characterization on T2-weighted images versus fluid-attenuated inversion recovery (FLAIR), metastases. Periventricular metastases with edema are seen on T1-weighted (A), FLAIR (B), and T2-weighted (C) images. Irregular enhancement is confirmatory after contrast (D). Note that internal signal characteristics indicating necrosis and other features are obvious on T2-weighted images (C), despite the homogeneous, nondescript appearance on FLAIR (B).

An increased rCBV within the contrast-enhancing lesion associated with a decreased or normal value in the peritumoral edema is the hallmark of the metastatic disease on DSC perfusion MRI, reflecting the relative sparing of the adjacent white matter, when compared to infiltrating primary brain tumors (323). Another feature that may help in the differentiation using DSC PWI is PSR, which tends to be lower than 50% in metastatic lesions (169). Spectroscopy tends to have nonspecific findings, such as slightly elevated choline peak, reflecting the high cellular turnover, and decreased or absent NAA and creatine levels. Lactate and lipids may be found in some necrotic areas. In the peritumoral region, there is a similar pattern to the one characterized with perfusion imaging, demonstrating intermediate elevation of choline levels compared to marked elevation in high-grade gliomas as well as moderately lower FA values on DTI, reflecting the lesser degree of infiltration in adjacent white matter (92,324). Values of rCBV and ktrans may also be helpful in the postradiosurgery follow-up imaging, although threshold values for highly accurate differentiation between tumor response, recurrence, and radiation necrosis have not been validated at this time (308). The patterns of enhancement on MRI include solid, nodular, and ringlike. Close attention must be paid to the ring enhancement characteristics which while similar to the one observed in high-grade gliomas, differs significantly from that seen in benign conditions. Malignant neoplasms generally demonstrate a thick, irregular, or nodular rim enhancement, as opposed to the regular, even, thin, and smooth rim enhancement in benign conditions like abscess, enhancing subacute hematoma, and other nonneoplastic entities. However, exceptions occur; in particular, adenocarcinoma metastases can appear as thin-walled ring-enhancing lesions (Fig. 8.128).

FIGURE 8.128 Ring enhancement, metastases versus abscesses. Although most metastases are irregular and thick walled on enhanced studies, adenocarcinomas (A) and occasionally other tumors can be remarkably similar to the classic thin-walled, ring-enhancing lesions of abscesses (B).

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Regarding the temporal sequence of metastatic tumoral enhancement, it appears that no uniform pattern exists. In any given patient, most metastases enhance dramatically on the immediate postcontrast scan, but other metastases in the same patient and from the same tumor may only appear on delayed scans (Fig. 8.129). We also recognize that higher doses of contrast agent reveal more metastases on MRI. However, added cost and possible toxicity generally eliminate the use of high-dose gadolinium in practice. Finally, all these findings must be correlated with all the clinical data available, to optimize the diagnostic evaluation and establish the most accurate differential diagnosis.

FIGURE 8.129 Evanescent enhancement in cortical metastases. A: Proton density–weighted magnetic resonance (MR) (3,000/35). B: T2-weighted MR (3,000/90). C: Contrast-enhanced computed tomography (CT). D: T1-weighted MR (800/20), 3 minutes after contrast enhancement. E: T1-weighted MR (800/20), 15 minutes after contrast enhancement. F: T1-weighted MR (800/20), 45 minutes after contrast enhancement. Precontrast long–repetition time images (A,B) and contrast-enhanced CT (C) are normal. On initial postcontrast MR (D), left frontal cortical metastasis is seen (D–F, closed arrows) and persists on the 15-minute postcontrast scan (E) and the 45-minute postcontrast scan (F). Note transient visualization of a second metastasis only on the 15-minute postcontrast scan (E) in the right frontal cortex (E, open arrow).

RADIATION EFFECTS 527

Postoperative hyperintensity, hemorrhage, or encephalomalacia may persist for a great length of time after tumor resection. There are several features of recurrent tumors and radiation effects of which the radiologist should be cognizant. Unfortunately, microscopic recurrent or residual tumor cannot be realistically excluded with any macroscopic imaging tool, and even histopathology needs adequate tissue sample volumes and clinical correlation to make the diagnosis. Radiation effects may occur at different times during or after therapy, and three phases have been described: acute (during radiation), subacute, or early-delayed (up to 12 weeks after radiation ends) and late (months to years after therapy) (325). Vasodilatation, disruption of the BBB, and edema are usually present in the acute and subacute phases, in which new or increased contrast-enhancing lesions in the irradiated tumor area may be seen (325). During the late phase, necrosis secondary to blood vessel damage and brain edema secondary to increased capillary permeability predominate. It is self-limited and is generally not problematic unless significant mass effect demands surgical decompression. On pathologic examination, it is a coagulative necrosis without much tissue reaction, presumably due to the ischemic nature of the event (135). Necrosis from radiation is usually found around the original tumor bed because that is where the radiation was directed. Problematically, recurrent glioma is also typically noted in the immediate vicinity of the original lesion (154). In addition, radiation necrosis and recurrent tumor can frequently coexist. Radiation necrosis and vascular changes from radiation (Fig. 8.130) can occur sooner than the typical 1-year interval (154); in fact, acute radiation encephalitis can have a disrupted BBB and enhance dramatically on MRI. The MR assessment for recurrent tumor, therefore, is based on either focal mass lesion recurrence on serial scans or anatomic pattern or new enhancement in or around the site of the original tumor in comparison with the baseline postoperative scan (usually obtained 4 to 6 weeks after surgery). Unfortunately, one still cannot differentiate radiation necrosis from recurrent tumor by MRI alone in many cases. Two new patterns of brain parenchymal changes that further confound posttreatment imaging have emerged with recent advances in GBM treatment (surgery followed by radiotherapy with concurrent temozolomide (RT/TMZ), and then maintenance temozolomide for at least 6 months), and with introduction of bevacizumab for recurrent glioblastomas (325,326). PsP is a subacute treatment-related reaction with or without clinical deterioration, occurring after completion of chemoradiation treatment in patients with high-grade brain tumors which is usually detectable on MRI within the first 3 to 6 months of chemoradiation, most frequently found in patients with methylated MGMT; however, occurrence beyond this time limit has been reported (325,327). PsP is most likely induced by a pronounced local tissue reaction with an inflammatory component, edema, and abnormal vascular permeability, corresponding to a new or enlarged contrast-enhancing lesion which is followed by improvement or stabilization without any further treatment as seen on MRI examination. The accurate diagnosis of PsP is essential to avoid modifications of effective therapies or unnecessary intervention for GBM patients (324). Unfortunately, at present, the only reliable method for distinguishing PsP and early progression of disease is to perform follow-up examinations (326), although MR with DSC perfusion imaging, DCE permeability imaging, along with DTI, DWI, spectroscopy, and anatomic features may play a role in aiding with differentiation of recurrent tumor from PsP (Fig. 8.131). However, these methods have not yet been validated in prospective clinical trials. Frequently, conventional MRI shows similar findings both in PsP and true progression, a fact that has been well demonstrated by Young et al. (328) who retrospectively analyzed 11 MRI features in 321 glioblastoma patients’ posttreatment, where of all the established conventional findings, only the subependymal enhancement was a reliable predictor for early progression.

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FIGURE 8.130 Radiation necrosis after treatment for glioblastoma, utility of magnetic resonance (MR) spectroscopy. Axial T2 (A), fluid-attenuated inversion recovery (B), T1 precontrast (C), and T1 postcontrast (D) images demonstrate a right parietal mass adjacent to the lateral ventricle. On these image sequences, alone, it would not be possible to separate radiation necrosis from recurrent tumor. Multivoxel MR spectroscopy (E,F) demonstrates markedly elevated lactate peaks with no dominant choline peaks, consistent with necrosis rather than recurrent tumor. This was pathologically proven to be radiation necrosis.

FIGURE 8.131 Pseudoprogression. Axial T1-weighted postcontrast images. Follow-up T1-weighted postcontrast MRI of a GBM patient following chemoradiation demonstrates transient increase in enhancement in the left temporal lobe that resolves during follow-up.

Pseudoresponse is another term coined after introduction of bevacizumab, an antioangiogenic (antiVEGF agent) for recurrent glioblastomas. This therapy tends to produce a rapid reduction in the enhancing component within hours or days after beginning of therapy, a fact that suggests a change in vascular permeability rather than a true tumor reduction. On MRI, the neuroradiologist must be aware of this possibility and scrutinize all the structural sequences, especially the T2-weighted images, which may show expansion or stable appearance of the abnormal hyperintense areas, suggestive that only BBB “normalization” has occurred rather than true tumor response (325). Finally, it must also be acknowledged that the importance of entities like PsP and pseudoresponse during postchemotherapy follow-up imaging is still uncertain at the time of this writing. The fact is that the role of antiangiogenic agents is far from settled. In a recent study comparing 458 patients receiving bevacizumab plus RT/temozolomide to 463 patients receiving placebo plus RT/temozolomide (329), no significant difference in OS was found between drug versus placebo at 1 or 2 years. Moreover, the drug group had more Grade 3 or higher adverse events than placebo patients, and overall adverse events were found more often with the drug than with placebo. Indeed, the importance and uses of antiangiogenic treatment in GBM is not fully written yet.

EXTRA-AXIAL TUMORS 529

Meningeal Tumors Meningiomas Meningiomas arise from meningothelial (arachnoidal) cells of the leptomeninges (7) and are the most common primary nonglial intracranial tumors (330), representing 35.8% of all primary brain and CNS tumors, as well as 53.8% of nonmalignant neoplasms (163); however, their occurrence is undoubtedly higher as many asymptomatic meningiomas are found at routine autopsy (331). According to the last WHO update in 2007 (7), meningiomas could be classified as grade I to grade III neoplasms (Fig. 8.133), based on their histologic features. WHO grade I are unlikely to show aggressive behavior and do not meet any of the criteria for a higher-grade lesion based on morphologic criteria, and are subdivided into a number of subtypes with transitional, meningothelial, and fibroblastic seen most frequently (332). Malignant meningiomas (WHO grade III) represent a less common aggressive form (only 1.5% of all meningiomas), which comprised such variants as anaplastic, papillary, and rhabdoid meningiomas which are associated with higher rates of recurrence. Grade II neoplasms are characterized by mixed clinical behavior. Additionally, the 2007 WHO classification has also introduced brain invasion as a criterion in distinguishing between benign meningiomas (grade I) and grade II or III meningiomas.

FIGURE 8.132 Pseudoresponse. Following bevacizumab treatment, a recurrent GBM demonstrates significant decrease in contrast enhancement.

FIGURE 8.133 Intra-Sylvian meningioma. Sagittal T1-weighted (A) and axial T2-weighted (B) magnetic resonance (MR) show an extra-axial intra-Sylvian mass nearly isointense to gray matter. After contrast (C), dense and homogeneous enhancement with associated dural tail is clearly seen. Multiplanar MR is valuable here in providing precise anatomic localization before surgery. A histologic section (D) from a similar meningioma shows typical whorl formation and a syncytial arrangement of cells.

Meningiomas mostly affect people in the middle and late decades of life. There is a strong female 530

predilection, with a female-to-male ratio of about 2:1 (333). Meningiomas are rare in childhood, accounting for no more than 2% of intracranial tumors (334). Childhood tumors are more apt to prove malignant than are those in the older population group (335). There is a strong association between neurofibromatosis (NF) type 2 and multiple meningiomas, in which younger patients are affected (335) (see Acoustic Schwannomas). In these patients, the acroninim and mneumonic “MISME” (multiple inherited schwannomas, meningiomas, and ependymomas) more accurately describes the disorder. Meningiomas have a distinct predilection for certain intracranial locations, although they may occur in any area where meninges exist or there are cell rests of meningeal derivation (18). Approximately 50% of convexity meningiomas are parasagittal or attached to the sagittal sinus. Other favorite sites include the dura adjacent to the anterior Sylvian fissure region, the sphenoid wings, tuberculum sellae, perisellar region, and olfactory grooves. They may also arise from the optic nerve sheath intraorbitally or extend into the optic foramen from a tuberculum sella tumor. In the posterior fossa, they frequently arise from the petrous bone in the cerebellopontine angle, the clivus, the tentorial leaf, and the tentorial free margin. Meningiomas are usually broad based and firmly attach to the adjacent dura (Fig. 8.4) but can arise without any dural attachments apparently from pial meningeal cells. These pial-based meningiomas may be found in the depths of the Sylvain fissure (Fig. 8.133) or may present intraventricularly, usually in the lateral ventricle but occasionally in the third and fourth ventricles arising from either the tela choroidea or arachnoidal cell rest within the stroma of the choroid plexus. Studies using high–field-strength magnets have indicated a detection rate comparable to that of contrast CT (337,338) and an overall superiority of MR in determining the tumors’ extra-axial location and in defining intrinsic tumor vascularity, arterial encasement, venous sinus invasion, and marginal areas of extension. Compared with white matter, meningiomas on T1-weighted images are almost always hypointense, with an occasional tumor being isointense or hyperintense. On T2-weighted images, meningiomas are usually hyperintense to the cerebral white matter in those portions that are not heavily calcified (Fig. 8.134). The degree of hyperintensity is, however, widely varied on these sequences. Meningiomas demonstrating hypointensity on T2-weighted images are associated with fibroblastic or mixed variety with predominant fibroblastic elements (Fig. 8.135). According to Kim et al, the T2WI can be used to estimate tumor hardness preoperatively (339), which could be an important prognostic factor, such as the presence of the visual impairments caused by intrasellar meningiomas. Meningiomas may develop rare histologic variants that may have unique intensity correlates on MR. One example is the lipomatous meningioma (18) (Fig. 8.136) which is considered to be a form of metaplastic meningioma (340). In this unusual lesion, there is metaplastic transformation of meningioma cells into adipocytes, with the cytoplasm containing large fat droplets composed of triglycerides. These meningiomas appear markedly hyperintense on T1-weighted images and become hypointense on T2-weighted sequences. Another fatty cell change occurring in meningiomas is of the xanthomatous type. It most frequently develops in the angioblastic variety but may also be encountered in syncytial and fibroblastic types. This change is usually patchy within the tumor but may be more confluent. The cells with this change contain multiple small droplets composed of cholesterol and other lipids (18).

FIGURE 8.134 Posterior inferior falx meningioma. Axial T2-weighted image. Tumor is hyperintense (arrows) to both white matter and gray matter and extends across the falx to the opposite side.

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FIGURE 8.135 Hypointense meningioma. Densely calcified computed tomography shows a densely calcified extraaxial mass consistent with meningioma (A). The lesion shows marked hypointensity on MR (B,C), particularly on the T2-weighted image (C). After contrast, significant central enhancement is seen (D), which could not have been noted on computed tomography due to the calcific density of the lesion. Histologic section of a similar meningioma (E) shows the proliferation of cells containing bland, round to oval nuclei in a mesenchymal collagenized matrix. A characteristic feature of meningiomas is the tendency to form concentric whorls (F). When whorls degenerate and calcify, the result is concentric calcified structures called “psammoma bodies.”

Most meningiomas (84% in one series) demonstrate a heterogeneous intensity pattern on T2-weighted images (337). Tumor heterogeneity can be related to the presence of several factors: tumoral vascularity, cystic foci, calcifications, and an inherent speckling and mottling of uncertain etiology. Tumor vascularity has been identified in approximately one-third of cases and is revealed as punctate and curvilinear hypointensities within the mass on both T1- and T2-weighted images. The “mother-inlaw” sign (Fig. 8.137) is named for a homogeneous prolonged tumor blush and the “sunburst”/“spokewheel” appearance related to the coexistence of both pial and meningeal feeders, represent the typical angiographic findings depicted on digital subtraction angiography (DSA) (341). Vascular supply can be also evaluated using ASL, MR perfusion imaging, and MRA, which can provide specific information regarding the origin of the arterial branches feeding the tumor (342). Cystic foci 532

develop from coalescence of cystic spaces in the microcystic and angioblastic varieties of meningioma. They appear on T1-weighted images as smooth, rounded hypointensities. They become hyperintense on T2-weighted images. Their intensity pattern tends to follow that of CSF in the cisterns and ventricles. The cysts are usually small; however, larger cysts with the same characteristics may develop and have a tendency to be located more peripherally in the tumor. Rarely, the entire meningioma becomes cystic and creates confusion on imaging. Calcifications, when apparent on MR, appear as coarse, irregular regions of hypointensity on both T1- and T2-weighted sequences (Fig. 8.138). Cystic foci and calcifications may be identified in approximately 20% of these tumors. These regions appear as fine or coarse foci, respectively, of mixed high and low signal intensity. This pattern is probably related to the varied cellular histology within each meningioma.

FIGURE 8.136 Lipomatous meningioma the left sphenoid wing. A: Axial noncontrast computed tomography demonstrates a markedly hypodense mass in the left frontal temporal region containing multiple isodense irregular nodular areas. B: Sagittal T1-weighted image without contrast through the tumor mass. The tumor is markedly hyperintense, being similar to orbital and scalp fat. It contains multiple irregular isointense foci. C,D: Axial long– repetition time (TR)/short–echo time (TE) (C) and long-TE (D) images demonstrate that the tumor is heterogeneously hyperintense on the long-TR/short-TE (C) and heterogeneously hypointense on the T2-weighted image (D). A chemical shift artifact from the fat–water interface is present and demonstrated as a hypointense rim in the posterior portion of the tumor (solid white arrows) and a hyperintense rim at the anterior margin of the tumor (open white arrows). It is more pronounced in panel D due to reduced bandwidth. Note the hyperintense cerebrospinal fluid cleft evident at the posterior tumor border (black arrows) behind the hypointense chemical shift artifact in panel D.

As already stated, several criteria help to establish the extracerebral localization of the meningioma, and these criteria represent the keys to the diagnosis. A broad dural-based margin is strongly suggestive, but not definitive, for this localization. Bony hyperostosis and/or invasion are highly suggestive of an extra-axial origin (Fig. 8.139). CT is still considered useful in characterization of hyperostosis due to an adjacent nonmalignant meningioma, as well as for detection of bony lytic changes related to WHO II/III meningiomas (343). However, close attention to detail often reveals hyperostosis associated with these lesions on MR (Fig. 8.140). This finding adds significant specificity to the diagnosis, since hyperostosis is virtually unique to meningioma and not found in lymphoma or metastases, lesions that otherwise can appear identical to meningioma. In some cases, the differentiation of hyperostosis associated with an en plaque meningioma (Fig. 8.141) from a primary intraosseus meningioma represents a significant challenge (344). The most important and highly specific characteristic for extra-axial localization is the identification of various anatomic interfaces interposed 533

between the tumor surface and the brain surface. Four different anatomic interfaces may be identified with MR: pial vascular structures, CSF clefts, brain cortex, and dural margins (Table 8.1). The interfaces are frequently not found along the full tumor–brain margin but in most instances are sufficient to make a highly reliable determination of extra-axial localization.

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FIGURE 8.137 Left sphenoid wing meningioma. Tumor vascularity (black solid arrows), arterial vascular rim (white solid arrows), venous vascular rim (white open arrows), entrapped internal carotid artery (black open arrows). A: T1weighted axial image through the center of a tumor that is hypointense to both white and gray matter. Tumor vascularity (also B–D, I, J) remains hypointense on all imaging sequences before and after gadolinium injection. Vascular rim vessels are small, rounded, and curvilinear signal voids at the interface of the tumor with the brain (also B–E, I, J). The entrapped internal carotid artery remains hypointense on all imaging sequences pre- and postgadolinium administration (also B,C,E,I). B,C: Axial long–repetition time/short–echo time (B) and T2-weighted (C) images at the same level as panel A. The tumor is hyperintense to white matter and isointense to gray matter in both panels B and C and reveals an inhomogeneous intensity pattern related to tumor vascularity and intrinsic mottling. The B cerebrospinal fluid cleft (white arrowhead) containing vascular rim vessels is isointense in panel B and hyperintense in panel C. D: Sagittal T1-weighted image demonstrates tumor vascularity and both arterial and venous vascular rim structures. E: Sagittal T1-weighted image at the level of the carotid siphon reveals an entrapped internal carotid artery and both arterial and venous vascular rim vessels. F: Lateral left carotid arteriogram reveals tumor vascularity, an entrapped internal carotid artery, and a middle cerebral artery elevated over the superior margin of the tumor stain. G: Venous-phase lateral left carotid arteriogram demonstrates tumor blush and marginal venous vascular elements. H: Postcontrast axial computed tomography reveals homogeneous tumor enhancement but no visualization of tumor vascularity, entrapped internal carotid artery, vascular rim, or cerebrospinal fluid cleft. I: Postgadolinium axial T1-weighted image demonstrates heterogeneous tumor enhancement, rounded hypointensities of entrapped internal carotid artery, arterial vascular rim vessels, and tumor vascularity. Venous vascular rim vessels are obscured by the gadolinium. J: Postgadolinium coronal T1-weighted image through the tumor demonstrates diffuse heterogeneous enhancement, linear hypointensities of tumor vascularity, and marginal hypointensities of elevated middle cerebral artery vascular rim elements.

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FIGURE 8.138 Calcified convexity meningioma. A: Sagittal short–repetition time (TR)/echo time (TE) image demonstrates a 1.5-cm, dural-based parietal mass (arrow) with a lobulated region of marked hypointensity occupying the majority of the central portion of the tumor. B: Axial long–TR/TE image demonstrating a similar lobulated central hypointensity within the left parietal tumor (arrow). The peripheral soft tissue portion of the tumor is obscured by the high intensity of the enlarged surrounding subarachnoid space. C: Coronal postgadolinium-enhanced short–TR/TE image demonstrates peripheral enhancement of the tumor. There is a reduction in the size of the central hypointensity due to gadolinium enhancement of the outer portion of the calcified tumor region. Enhancement of a small tail of dural thickening extending inferiorly is observed (arrow).

FIGURE 8.139 Large frontal convexity meningioma growing through the calvarium with lytic and hyperostotic bony

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change. A: Sagittal T1-weighted image demonstrates large, slightly hypointense frontal convexity mass with punctate and linear tumor vascularity (solid white arrows), a vascular rim (open black arrow), and accordionlike compression of marginal convolutions (solid black arrows). A large nodule of tumor has grown through the calvarium and presents as a scalp mass. There is a thickened signal void of the inner table at the anterior aspect of the tumor nodule that is growing through the skull (open white arrows). B: Coronal T2-weighted image demonstrates marked tumor hyperintensity. Complete destruction of the bony tables of the skull has occurred, with the tumor penetrating through into the scalp. At the lateral margin of the intracalvarial tumor there is thickening and increased hypointensity of that portion of the skull that indicates an osteoblastic hyperostotic reaction (solid black arrows). Again note accordionlike compression of inferior convexity cortical convolutions (open black arrows). C: Histologic section of bone trabeculae (pink bands) admixed with whorls of neoplastic meningothelial cells replacing the bone marrow. This represents meningioma invading bone rather than simply secondary hyperostotic change.

FIGURE 8.140 Evidence of hyperostosis on MRI. Large left middle cranial fossa extra-axial mass with vascular cleft and extracranial extension is isointense to cortex on T2 (A) and enhances homogeneously after intravenous (IV) contrast (B). Uncal herniation and hydrocephalus are notable secondary findings. Note significant hyperostosis of left temporal bone (arrows, B), making the diagnosis of meningioma almost certain.

FIGURE 8.141 Meningioma en plaque, contrast enhancement characteristics. Coronal T1-weighted (A) and axial T2weighted (B) images show hyperostosis of the right sphenoid wing with marked hypointensity. After contrast (C), only a thin rim of extra-axial enhancement is seen, despite the extent of the lesion.

Pial blood vessel interfaces appear as punctate and curvilinear signal voids on all sequences at or along one or more margins of the tumor with the brain. When brain edema is present, the vascular rims 537

may occur at the junction of the uniform high intensity of the brain edema on T2-weighted images and the more heterogeneous lower intensity of the tumor. For those tumors located at the base of the brain or in the proximal portions of the Sylvian and interhemispheric cisterns, displaced larger brain arteries are likely to be identified at the interface. Meningiomas tend to develop large marginal draining veins located at their brain surface interface. These veins are most likely the large marginal vascular structures seen with the more peripherally located meningiomas and at tumor–brain interface locations, where large arteries would not be expected to be seen (e.g., in the large basally located tumors). CSF interfaces are also identifiable in about 80% of meningiomas on MR. They appear as highintensity clefts on T2-weighted sequences relative to the adjacent tumor and brain (Fig. 8.4). CSF clefts generally follow the intensity pattern of the ventricular and subarachnoid fluid but may be of slightly higher intensity due to the relative isolation of these thin CSF spaces from pulsation effects. In addition, on T2-weighted images, a thin isointense band representing the brain cortex separates the CSF clefts from the edema. Vascular rims may be seen to lie within regions of the CSF clefts (Fig. 8.4). The dural margin interface is seen primarily in meningiomas of the cavernous sinus. It appears as a low-intensity rim on all imaging sequences covering the lateral margin of the tumor and separating it from the adjacent temporal lobe. Not infrequently the tumor may be seen invading this dural margin and abutting the adjacent brain. Meningiomas along the falx and tentorium may also be seen invading into and through the dura to its opposite side (Fig. 8.16). Note that intra-axial brain tumors almost never invade dura unless there has been previous surgery. Metastatic brain tumors may occasionally grow exophytically from the brain and invade the dura. In these lesions, however, no brain–tumor interface will exist. Brain cortex interface between tumor mass and white matter is best seen on T2weighted images when there is white matter edema (Fig. 8.10). It may, however, be identified on T1and T2-weighted images when there is no white matter edema. Another anatomic characteristic indicative of extra-axial localization that can be recognized with MR consists of arcuate bowing and compression of adjacent cortex in an onion skin–like configuration beginning at the margin of the tumor (Fig. 8.4). Large intracerebral masses located at or near the surface of the brain do not show a similar anatomic alteration. Extra-axial masses compress adjacent portions of the brain together, whereas intra-axial masses, even when they are located near the surface, tend to spread parenchymal areas apart.

FIGURE 8.142 Morbidity after resection of unrecognized invasive meningioma. Preoperative image after contrast (A) retrospectively showed highly irregular margin of enhancing tumor (arrows, A), which should have raised suspicion of brain invasion. Postoperative defect shows no significant residual tumor (B) but diffusion-weighted image (C) reveals obvious acute postoperative cerebellar infarction.

Perhaps the most important radiologic finding to clarify in patients with meningioma is the presence or absence of brain invasion. The recognition of brain invasion is critical to surgical management of the patient, because generally a meningioma cannot be readily removed if it has invaded brain parenchyma without risking venous or arterial brain infarction (Fig. 8.142). In meningiomas and all other extra-axial masses, the presence or absence of brain invasion must be commented on by the radiologist. The key MR findings of brain invasion include (1) tumor in contact with edematous white matter, indicating an intra-axial component; (2) an irregular, interdigitating interface between the tumor and the underling brain; and (3) enhancement inside the perivascular spaces (Fig. 8.143). Although suggestive of higher WHO grade, nonmalignant meningioma can invade the brain parenchyma, as can lymphoma, metastatic disease, and primary malignant meningeal tumors. MR can often depict important vascular phenomena related to meningiomas. Internal tumor vascularity (Fig. 8.138) and arterial encasement (Fig. 8.144) are well demonstrated on MR and are usually not detectable with CT (337,345) because on CT these vessels usually exhibit nearly the same contrast enhancement as the meningioma. With MR, tumor vascularity and encased arteries with rapid flow usually remain hypointense on all imaging sequences even after the administration of contrast 538

agent. MR is also superior to CT in demonstrating venous sinus invasion (335). Venous sinus invasion is demonstrated on MR by the partial or complete obliteration of the sinus flow void with a soft tissue mass (Figs. 8.4 and 8.145). The intensity of the tissue within the venous sinus is usually similar to that of the adjacent tumor mass and can be appreciated on both T1- and T2-weighted sequences. Sagittal and transverse sinus invasion is best demonstrated with coronal imaging, whereas cavernous sinus involvement may be identified in either the coronal or axial planes. MRA or other MR flow techniques may improve the sensitivity of this determination.

FIGURE 8.143 Invasion of brain by extra-axial meningioma. Right frontal mass is associated with extensive edema (A) and shows a thick extra-axial rind of enhancement (B). Irregular lobulated interface with brain and enhancement within perivascular spaces (arrows, B) proves lesion is invading brain.

FIGURE 8.144 Cavernous sinus and prepontine meningioma with internal carotid artery encasement. Axial T2 (A) and T1 postcontrast images (B) demonstrate a T2 hypointense mass centered in the left cavernous sinus with a small prepontine component. Note the anterior displacement and a slight narrowing of the flow void of the cavernous segment of the left internal carotid artery. A lateral view maximal intensity projection from a magnetic resonance angiogram (C) demonstrates smooth narrowing of the left internal carotid artery. The primary differential diagnosis here based on the T1 and T2 characteristics would be lymphoma, but the smooth narrowing of the carotid artery favors meningioma over lymphoma.

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FIGURE 8.145 Heavily calcified meningioma with venous sinus compromise. Sagittal T1-weighted images (A,B) show an extra-axial mass compressing underlying brain parenchyma in the midline. Magnetic resonance venogram (C) shows a marked diminution of caliber but still patency of the superior sagittal sinus in that region. Axial T2weighted (D,E) images show marked hypointensity of a calcified mass with impingement into the adjacent superior sagittal sinus (E), also revealed by postcontrast image (F). Dura with multiple calcified meningiomas at necropsy (G). (Courtesy of Dr. N. K. Gonatas, Hospital of the University of Pennsylvania, Philadelphia, PA.)

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FIGURE 8.146 Tentorial meningioma with dural and transverse sinus invasion. T1-weighted (A), long–repetition time (TR)/short–echo time (B), and T2-weighted (C) coronal images at the same level demonstrate a slightly hypointense mass (A), which becomes moderately heterogeneously hyperintense on long-TR images (B,C) arising adjacent to the inferior aspect of the right lateral aspect of the tentorium. Intradural invasion of the tumor can be identified between the two tentorial leaves, with partial destruction of the inferior leaf, which has lost its normal hypointensity (black arrow). The tumor has spread laterally into the region of the transverse sinus and abuts directly on the inner table of the skull. Angiography showed that the sinus occlusion was incomplete because a small residual lumen remained at this location. Note also the small, rounded signal void on the medial aspect of the tumor mass, representing a vascular rim vessel (white arrow). The intensity of the tumor that has invaded the dura and transverse sinus is similar to that of the extradural component.

Transdural invasion is equally well demonstrated with MR (Fig. 8.146) and CT. Tumor may be demonstrated crossing from one side to the other through the tentorium cerebelli, falx cerebri, or cavernous sinus. Contrast enhancement is usually not required to demonstrate this finding with MR. Bony hyperostosis is also equally well demonstrated with MR and CT (Fig. 8.4). Meningioma calcification (Fig. 8.138) is unquestionably less well defined with MR than with CT. Gradient-echo imaging improves the sensitivity for the detection of calcifications; however, specificity for this finding is clearly less than on CT. Calcification, however, is not critical to the diagnosis in most cases unless the patient also harbors a primary malignancy that can metastasize to dura. Brain edema develops in approximately 50% of meningiomas. It is more common with large lesions but may be extensive even with small meningiomas (Figs. 8.147 and 8.148). Its exact cause has not been determined. Some studies have indicated that its presence is significantly correlated with either the meningioma blood supply at least in part derived from cerebral pial arteries or with venous drainage to cortical veins (346). Although varying amounts of edema may be present with any of the meningioma cell types, fibroblastic and transitional cell tumors have been reported to have only mild to moderate degrees of edema. Severe edema tends to be associated with meningiomas of the syncytial or angioblastic cell types (347). The degree of edema was found to be a helpful predictor of meningioma histology for meningiomas that were isointense to the cortex on T2-weighted images. Of tumors in this group that demonstrated moderately severe edema, they were mainly of the purely syncytial type or of a mixed type with significant syncytial components. The terminology of meningiomas containing abundant vascular elements has long been the subject of debate. The WHO classification of nervous system tumors, which is widely accepted among neuropathologists, considers hemangioblastomas and hemangiopericytomas of the meninges to be 541

separate entities that should not be classified under meningiomas. Therefore, meningiomas that show features of increased vascular elements, or transitional forms of meningeal tumors with elements of both classic meningiomas and the other vascular tumors, are considered angiomatous (rather than “angioblastic”) variants of meningiomas (Fig. 8.149). Regardless of the classification used, angiography of all the vascular meningeal tumors generally demonstrates extensive tumor vascularity, staining, and rapid tumor circulation with enlarged early draining veins. Tumor blood supply from brain pial arteries may be a predominant feature. Cyst formation is also common and focal and diffuse hemorrhage can occur (Figs. 8.150). Calvarial Invasion. Although meningiomas may cause hyperostosis of the inner table without bony invasion, many en plaque and some globular convexity and basal meningiomas extensively penetrate the skull, causing marked thickening of the bone along with osteoblastic reaction. MR will usually demonstrate this bony change as well as the layer of soft tissue tumor adjacent to the inner table of the skull. Some meningiomas arise from arachnoid cell rests in the diploic space. In these tumors an intracranial component may not be present. Regions of soft tissue tumor within the bony thickening can be identified more readily with MR than with CT. Occasionally, bony invasion produces a lytic bony reaction (Fig. 8.5). Some tumors may extend throughout a table of the skull and present primarily as a scalp mass. Although bone destruction may appear aggressive, this finding does not correlate with malignant degeneration.

FIGURE 8.147 Intraosseous meningioma with a small extraosseous component. A: Contrast-enhanced axial computed tomography reveals a marked bony hyperostosis in the right temporal parietal region without any soft tissue extraosseous component. B: Coronal T1-weighted image demonstrates marked hypointensity of a bony hyperostosis involving the inferior temporal parietal region and extending below the tentorium into the inferior occipital bone region on the right side. A small extraosseous, extracerebral soft tissue mass that is isointense can be identified adjacent to the superior lateral leaf of the tentorium. It is marginated from the brain by a vascular rim vessel (black arrow). Also note the slight soft tissue thickening between the two leaves of the lateral aspect of the tentorium and the slightly higher-intensity soft tissue mass in the region of the transverse sinus (white arrows). C: Axial long– repetition time/short–echo time image demonstrates a signal void of marked bony hyperostosis in the right temporal parietal region, which appears mainly to involve the inner table. There is a thin rim of hyperintense tissue on its inner aspect, most likely representing en plaque dural tumor (white arrows) and a focal nodular high intensity encroaching on the lateral aspect of the right temporal lobe (black arrow), representing the extraosseous tumor nodule evident in panel B.

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FIGURE 8.148 Small convexity meningioma with extensive brain edema. Coronal T1-weighted image (A) and axial T2-weighted image (B) demonstrate a 2.5-cm-high convexity rounded mass outlined by vascular rim vessels (white arrows) from adjacent brain. The mass abuts slightly against the inner table of the skull, which demonstrates a thickened hypointensity representing bony hyperostosis extending a short distance peripherally (black arrows) from the tumor base. There is extensive edema throughout the right frontal and parietal white matter.

FIGURE 8.149 Right inferior temporal angioblastic meningioma. A: Axial noncontrast computed tomography reveals a

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multicystic, hyperdense right temporal lobe tumor extending to the midline with evidence of brainstem compression and displacement of the third ventricle to the left. The mass was considered most likely intra-axial on computed tomography. B: Axial T1-weighted image through the temporal fossa reveals the tumor to be mildly hyperintense to both gray and white matter. Multiple small and slightly larger, mildly hypointense regions are present within the substance of the mass. Small, rounded signal voids are evident at the anterior and posterior margins of the tumor (white arrows), representing vascular rim vessels. C: T2-weighted axial image at a level similar to panel B. The background intensity of the tumor that was slightly hyperintense in panel B has become mildly hypointense. The multiple mildly hypointense foci in panel B have become hyperintense. On the long–repetition time/short–echo time image (not shown) these foci were isointense, suggesting a cystic nature. The medial margin of the tumor mass extends into the perimesencephalic cistern and is directly compressing the right cerebral peduncle (arrows). D,E: Axial T1-weighted (D) and T2-weighted (E) images through the tumor at a higher level than panels B and C. Cystic foci are larger and extend close to the tumor surface. A markedly hyperintense region is present in the posterior portion of the tumor in panel D and remains hyperintense in panel E, suggesting the presence of subacute hemorrhage into a cystic focus. Rounded and curvilinear hypodensities within the tumor substance in both panels D and E indicate prominent tumor vascularity (black arrows). F: Sagittal T1-weighted image through the right temporal lobe demonstrates an inferior tumor margin abutting directly on the petrous ridge and sphenoid bone (black arrows). The hemorrhagic and multiple hypointense cystic foci are evident, as is a single marginal vascular rim vessel posteriorly (white arrow).

FIGURE 8.150 Meningioma presenting as subdural hematoma. T1-weighted (A) and T2-weighted (B) images show a mixed-signal subdural hematoma with an irregular focus of more acute blood. Edema posterior to the acute hematoma is also noted (B). After intravenous contrast (C), irregular enhancement is seen along the posterior margin of acute blood. At surgery, hemorrhage with underlying meningioma was found.

Advanced MRI techniques such as perfusion and spectroscopy are usually of little value in making the diagnosis in patients with typical imaging findings of meningioma. Not surprisingly, perfusion studies have found that CBV maps show the highest values for angiomatous type and lowest for fibrous meningiomas (348). Additionally, PSR, a less complex alternative measure of microvascular permeability that can be derived from the DSC MRI signal intensity–time curve, may also exhibit less 544

than 50% of recovery when compared to the baseline, due to the absence of BBB. ASL perfusion and DCE perfusion will also generally depict increased rCBF (cerebral blood flow) and ktrans value, respectively. Dural metastases are sometimes indistinguishable from meningiomas using conventional MRI, unless calcification or hyperstosis can be identified, features unique to meningioma. It has been suggested that PWI may occasionally be helpful for this differentiation, with low rCBV suggesting the diagnosis of metastasis and high rCBV being more indicative of meningiomas (349). Intraventricular Meningiomas. Meningiomas may arise from arachnoid cells of the tela choroidea or from cell rests within stroma of the choroid plexus. These most commonly occur in the lateral ventricles, particularly in the region of the glomus (Table 8.12). The MR characteristics of these lesions are similar to those of meningiomas in other locations. Clinically, they are usually silent until they become large enough to block that portion of the ventricular system causing trapping and dilation of the more distal portions. Meningiomas can usually be differentiated from choroid plexus papillomas both clinically and with MR. Lateral ventricular choroid plexus papillomas develop mainly in young children, with meningiomas usually appearing in the middle-aged and elderly population. Meningiomas have a smooth margin and are generally oval in configuration (Figs. 8.151 and 8.152), whereas papillomas frequently demonstrate very nodular, heterogeneous, irregular surfaces. Papillomas also usually present with diffuse hydrocephalus and not just dilation of the trapped ventricular segment. Although papillomas are more frequently very heterogeneous, intraventricular meningiomas can also show significant heterogeneity and extensive edema. Therefore, the location of the lesion and the age of the patient are the two most valuable clues to the diagnosis. Meningiomas and Contrast Enhancement. There is strong uptake of contrast by essentially all meningiomas, which usually produces marked homogeneous tumor enhancement (350–352). Contrast enhancement on MR is almost always identifiable, even when meningiomas are densely calcified. Enhancement may be either central or ringlike. This enhancement relates to the fact that meningioma capillaries have no BBB. Intravenous contrast is useful in demonstrating and defining the borders of symptomatic small lesions that compress or infiltrate around cortical neural structures such as the optic nerves and other cranial nerves, which may be occult on nonenhanced MR. The anatomic boundaries of larger lesions that may be isointense to brain are clearly definable on T1-weighted enhanced scans. Enhanced scans, however, may obscure some vascular rim interfaces, particularly those that are venous in nature. Slow-flowing veins enhance with gadolinium, hiding their presence due to intensity similar to that of the enhancing tumor. The most striking finding of contrast-enhanced MR in meningiomas is dural enhancement adjacent to the lesion. En plaque meningiomas and globular convexity and basal meningiomas may infiltrate adjacent dural surfaces for several centimeters. Recognition of this infiltration can be of significant importance in surgical planning for complete tumor removal (353). Although high-resolution MR can occasionally demonstrate marginal dural thickening without contrast, gadolinium administration is clearly useful in defining the extent of dural thickening and thereby provides a valuable clue to the diagnosis. Pachymeningeal enhancement is not specific for meningioma; rather, it indicates involvement by any adjacent mass, whether the mass is meningioma, metastases, or invasive intra-axial brain tumor. Regardless of the precise etiology of the dural thickening and enhancement, its determination in continuity with the margins of an intracranial tumor adds another valuable MR diagnostic feature of tumors. Although quite nonspecific when meningeal enhancement is present, the absence of meningeal enhancement is highly valuable in eliminating a meningeal tumorlike meningioma from consideration. Contrast administration is also extremely valuable in detecting residual and recurrent meningiomas postoperatively. Tumor–brain interfaces are frequently obliterated postoperatively, and postsurgical changes in the surrounding brain often further obscure the recurrent tumor. Although enhancing dural thickening is almost universally present after surgery, it usually appears as a thin, smooth, enhancing membrane. Recurrent tumor is revealed as a lobulated, thick, gadolinium-enhancing mass that protrudes into the intracranial compartment. Meningioangiomatosis (MA). MA represents an uncommon malformative or hamartomatous lesion involving the meninges and cortex, with unclear pathogenesis. In rare cases, MA has been reported to coexist with meningiomas and it be associated with neurofibromatosis type II (354). MA can be a difficult diagnosis to make based on imaging findings alone; however, diagnosis may be suspected in a patient with a characteristic history and presentation (children or young adults with headaches and seizures), and the presence of a calcified mass on imaging exams, that usually appears as an ill-defined mass with an heterogeneous enhancement with associated edema (355). 545

FIGURE 8.151 Intraventricular meningioma. Axial T2 (A), gradient echo (B), T1 precontrast (C), and postcontrast (D) images demonstrate an intraventricular mass in the atrium of the right lateral ventricle. Note foci of hypointensity on gradient-echo image, representing calcifications. The location, appearance, and enhancement characteristics in this adult patient make intraventricular meningioma the most likely diagnosis, which was surgically confirmed.

FIGURE 8.152 Intraventricular meningioma. Pregadolinium (A,B) images show a somewhat heterogeneous mass within the right lateral ventricular atrium. Note the significant edema associated with the lesion. The lobulated mass

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densely and fairly homogeneously enhances after intravenous contrast (C). Brain sections from an autopsy (D) demonstrate the marked intratumoral heterogeneity of an intraventricular meningioma. (Courtesy of Dr. N. K. Gonatas, Hospital of the University of Pennsylvania, Philadelphia, PA.)

Radiation-Induced Tumors. A late complication following cranial irradiation is the formation of tumors, most of which are meningeal. Both benign and malignant meningeal neoplasms can occur decades after radiation therapy, most notably in a pediatric patient treated with whole-head radiation for acute lymphoblastic leukemia. When the original lesion is malignant, new tumors are typically seen toward the end of the first decade after treatment, whereas in the setting of treated benign disease, the delay is typically longer. In addition to meningiomas, meningeal sarcomas and other rare meningeal tumors can be found in this setting. A smaller incidence of malignant gliomas has also been described after radiation treatment for a variety of lesions. The rare entity of radiation-induced tumor (Fig. 8.153) should only be suspected if a new meningealbased mass develops many years after irradiation of any primary lesion; in most cases, the original lesion will have been a glioma or other nonmeningeal tumor. Because surgery and the original lesion have already distorted the anatomy in the region, an awareness of the possibility and the use of intravenous contrast are essential in delineating these lesions.

FIGURE 8.153 Radiation-induced tumor. Twenty-eight years after radiation treatment for pituitary adenoma, this patient presented with a large hypercellular mass (A,B) with diffuse enhancement (C,D) adjacent to the clinoid process and cavernous sinus associated with an adjacent cyst intimately associated with the middle cerebral artery. Surgical resection proved hemangioendothelioma.

Malignant meningiomas are rare and difficult to diagnose because there is often considerable discrepancy between their biologic behavior (i.e., outcome) and their histologic features. Although similar to malignancies in some cases, the “typical” imaging findings such as heterogeneous enhancement, margin irregularity, surrounding edema, bone destruction, and “mushrooming” are not sufficiently helpful in differentiation between low- and high-grade meningiomas (356). In this regard, advanced imaging techniques seem to be helpful, as has been reported recently. In 2008, Nagar et al. (357) found lower mean ADC values and normalized ADC ratios in atypical/malignant meningiomas. This finding is consistent with histopathologic features of malignant tumors (e.g., increased cellularity). Another recent study showed a statistically significant inverse correlation between the tumor marker Ki67 proliferation index and an ADC cut-off value in atypical meningiomas (sensitivity 29%, specificity 94%, PPV 67%, and NPV 75%) (358). In addition, Ki-67 index was also found to be positively correlated 547

with maximum rCBV value in atypical anaplastic meningiomas (359). DSC perfusion imaging has also been used to evaluate the perilesional edema of malignant meningiomas. Zhang and colleagues (360) found a statistically significant difference of maximal rCBV and relative mean time to enhance (rMTE) values between the associated peritumoral edema in benign and malignant meningiomas. These findings are supported by the evidence of an increased VEGF expression in ECs in the parenchymal edema surrounding anaplastic meningiomas, as previously reported by Yoshioka et al. (361). The criteria for their diagnosis are, therefore, of somewhat limited value, and a true incidence is difficult to ascertain. It has been noted that malignant meningiomas occur more frequently in males. Burger and Scheithauer (154) divided meningiomas into three groups, using both the level of histologic differentiation and the degree of aggressiveness to adjacent brain tissue: (a) typical benign meningioma; (b) atypical meningioma, having a strong tendency to recur but lacking histologic criteria of frank anaplasia; and (c) rare overtly malignant meningioma. While some authors have stated that brain invasion (Fig. 8.4), with deep expansile penetration of perivascular spaces with or without pial disruption, constitutes by definition a malignant meningioma, this definition is not uniformly accepted (see earlier discussion). True invasion of underlying parenchyma is usually accompanied by prominent reactive gliosis and edema. Malignant meningiomas have a distinct tendency to evoke marked brain edema, but this is commonly found in benign meningioma, whether invasive or not. Although most malignant meningiomas are only moderately anaplastic, unequivocal anaplasia on microscopy is a definite criterion for malignancy (18). Metastatic disease from meningioma is a clear indication of malignancy. Because of problems with definitions, the recurrence rate and survival for patients harboring these lesions are difficult to assess. Generally, these lesions often result in multiple surgical procedures and radiotherapy with uncertain results. On MR, the diagnosis of malignant meningioma is virtually impossible to make preoperatively due to the considerable overlap of the features of these lesions with simple benign meningioma (bone destruction, brain edema), unless one detects metastatic spread. Lymphoma Lymphomas may be primary within the CNS or associated with systemic involvement and present an important differential diagnosis when visualizing extra-axial brain lesions. CNS involvement is frequent in individuals with systemic lymphoma. About one-third of these individuals develop secondary brain or spinal involvement (362). Primary CNS lymphomas account for 2.2% of all primary brain tumors, with a mean age at diagnosis of 65 and are extremely rare in childhood (363). In the vast majority of these cases (PCNSL), which was discussed earlier this chapter, supratentorial brain parenchyma will be involved either by a single or multifocal tumor lesions, whereas primary leptomeningeal seeding is less common (364). Leukemic meningeal involvement, most often seen in the setting of acute lymphocytic leukemia, may be apparent at diagnosis in 3% to 5% of the cases or in 5% to 7% during relapse (365). Similar to leptomeningeal involvement by metastatic solid tumors, lymphomatous meningeal involvement presents with a similar spectrum of signs and symptoms, for example, signs and symptoms associated with cranial nerve dysfunction; however, MRI has a dramatically lower sensitivity in detecting lymphomatous meningeal disease. Specifically, Pauls et al. (366) reported sensitivity for MRI as high as 84.6% for the diagnosis of leptomeningeal involvement by solid tumors, with sensitivity as low as 20% for patients with leukemia and 37.5% for patients with lymphoma. The tumor most commonly involves the arachnoid membrane and may be present focally or diffusely throughout the CNS (18). There is frequent secondary invasion of the brain, with tumor extending along the Virchow–Robin spaces. The tumor may also locally invade the dura from the arachnoid membrane in both the primary and secondary varieties and can occasionally present as large, discrete dural masses. Rarely, the tumor may extend beyond the dura into the skull and extracranial compartment (Fig. 8.154). Subarachnoid involvement is usually not identified with CT (367,368). Frequently, it is not even evident on routine MRI; however, in some cases it may manifest as high signal in subarachnoid space along the surface of the brain on FLAIR images. There may be secondary invasion into the underlying parenchyma. The lesion may be obscured on T2-weighted sequences because of the high intensity of the adjacent CSF, which may have similar intensity to that of the tumor. Thinner plaques of subarachnoid tumor are more likely to be identified after the administration of contrast, such as Gd-DTPA, and, more recently, with FLAIR images, which are highly sensitive to disease in the subarachnoid space (Figs. 8.155 and 8.156) (55). Thin streaks of high intensity may be identified over the surfaces of the brain and along the cranial nerves (369). On T1-weighted images the tumor is usually isointense to the 548

adjacent brain surface but is usually outlined by the surrounding CSF. On FLAIR, the tumor may be isointense or hyperintense to the adjacent brain. On T2-weighted sequences it may be iso- or hyperintense but is frequently hypointense to the adjacent brain due to its high cellularity. After contrast administration on T1-weighted images, diffuse homogeneous enhancement develops. Contrastenhanced images usually reveal more extensive meningeal spread than was evident on nonenhanced images.

FIGURE 8.154 Lymphoma with extracranial component. Coronal T1 (A) and T2 (B) show relatively homogeneous extra-axial mass over convexity with large extracranial component. Note subtle erosive change in calvarium and a question of marrow abnormality.

FIGURE 8.155 Lymphomatous meningitis, posterior fossa. Isolated enhancement of leptomeningeal regions in the posterior fossa are characteristic of any basilar region meningitis, whether inflammatory, infectious, or neoplastic, as in this case of lymphoma.

Differentiation from en plaque meningioma may be difficult but is suggested by its diffuse dural extension, subarachnoid extensions, and more frequent multicentricity. Like many meningiomas, lymphoma is typically of relatively low signal intensity on T2-weighted images (i.e., isointense to gray matter), reflecting its hypercellularity. This signal pattern is also seen in prostate metastases and sarcoidosis, making it virtually impossible to distinguish among these entities by MR alone; CTdocumented calcification, however, would be virtually specific for meningioma in the untreated patient. The enhancement of perivascular spaces adjacent to an intra-axial mass indicates subarachnoid space tumor spread and should prompt consideration of lymphoma (see previous discussion on this chapter— Primary Central Nervous System Lymphoma).

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FIGURE 8.156 Fluid-attenuated inversion recovery (FLAIR) sensitivity versus contrast-enhanced T1-weighted magnetic resonance, leukemic meningitis. Although subtle enhancement can be seen on conventional contrastenhanced images in scattered sulci (A), FLAIR images (B) demonstrate much more extensive bilateral abnormal high signal within the subarachnoid space, revealing leukemic meningitis.

Sarcoidosis Intracranial involvement occurs in about 15% of patients with known sarcoidosis. Primary CNS involvement may also rarely develop (370,371). Intracranial involvement manifests two patterns. Most commonly, the disease appears as a granulomatous leptomeningitis, but it may also manifest as multiple diffuse parenchymal lesions or as a single intracerebral mass. The leptomeningeal disease may secondarily involve the adjacent brain surface by infiltration along the perivascular spaces. The disease may also present as a dural-based mass. On MR, T1-weighted images in leptomeningeal disease frequently demonstrate isointense thickening of the subarachnoid space on the brain surface that may extend into the sulcal regions. This may be focally present in one region of the subarachnoid space or may be evident diffusely throughout the brain. On T2-weighted images, the lesion not infrequently appears hypointense, most likely secondary to the compact cellular nature of the granulomatous process (Fig. 8.157). There may be edema in the adjacent portions of the brain, which suggests infiltration along the Virchow–Robin spaces into the parenchyma or small-vessel vasculitis from the disease. After contrast administration, the subarachnoid granulomatous process demonstrates diffuse homogeneous enhancement, which more clearly outlines its extent than on noncontrast images. Lesions in this location may be indistinguishable from meningiomas or dural-based lymphomatous disease, and so clinical correlation and biopsy are essential for accurate diagnosis. Extra-axial Metastases Extra-axial intracranial metastases are common in clinical practice. The most common type of metastatic tumor to spread to dural sites is breast carcinoma, followed by lymphoma, prostate carcinoma, and neuroblastoma (311). Metastases to the skull are seen as focal lytic or blastic lesions of both the inner and outer tables of the calvarium on either plain films or CT. These lesions typically lack a well-defined sclerotic border, which, if present, suggests benignity. Occasionally, metastatic lesions to the skull are expansile and even hemorrhagic, especially from renal cell or thyroid carcinoma. MR depicts calvarial metastases as focal regions of abnormal low signal intensity (isointense to gray matter) on T1-weighted images, which are relatively easily seen as distinct from the high intensity of normal fatty marrow (Fig. 8.158). Note that these lesions can be obscured on MR by enhancement after intravenous contrast, and so precontrast images must be obtained if calvarial metastases are suspected. The intracranial epidural extent of skull metastases and the presence of subdural disease are well documented by both CT and MR. The role of the radiologist in these cases is mainly correctly to discern extra-axial disease from superficial cortical intra-axial lesions. It can also be helpful to distinguish epidural from subdural masses. Both modalities usually demonstrate epidural tumor as the characteristic biconvex mass that displaces brain parenchyma away from the inner table. Epidural metastases in adults are almost invariably secondary to metastatic tumor in the adjacent skull and are usually associated with primary carcinomas of the breast, lung, prostate, or kidney (311,312,372). Pathologically, metastatic foci are focal and well-defined masses invading the dura or skull and extend to the surface of the brain, but occasionally these lesions are diffuse. Despite the intimate relationship of the dura to the bony calvarium and the leptomeninges to the pachymeninges, these structures present significant barriers to contiguous spread of malignant tumors. On the other hand, however, none are absolutely impenetrable, and, in fact, it is not rare to find plaques of metastatic tumor on the inner side of the dura in necropsy specimens (18). The major feature of epidural disease that allows distinction from subdural tumor is the neoplastic involvement of overlying calvarium, a nearly universal finding in epidural metastases. Recent implementations of fast spin-echo MR techniques, unfortunately, result in intradiploic tumor deposits and normal marrow becoming isointense on “T2-weighted” images. Therefore, fat-suppressed postcontrast imaging should be performed in these cases. Subcutaneous (subgaleal) extension of metastatic tumor centered in the skull is easily depicted by both CT and MR. MR also allows better definition of the dura itself. Note that displaced gray matter (i.e., cortex) is identifiable between the mass and subcortical white matter (Fig. 8.159) when an extra-axial lesion is present. MR is superior at depicting several signs and structures that are not only pathognomonic of extra-axial disease, but also allow specific identification of the involved compartment: (a) the identification of a CSF or vascular cleft between the lesion and normal brain, (b) 550

direct visualization of the displaced dura and its relationship to the mass (especially after intravenous contrast), and (c) the documentation of displaced cortical veins, which lie between the extra-axial lesion and the brain. Signal intensity patterns on MR are usually not specific in the evaluation of types of extra-axial tumor because most metastases are slightly hypointense to cortex on T1-weighted images and are slightly hyperintense on T2-weighted images. This does differ somewhat from the most typical pattern described in meningiomas, which are classically nearly isointense to cortex on all sequences (337). Unfortunately, some metastatic lesions, particularly those of small cell primary neoplasms, are isointense to gray matter on MR. It is not uncommon for subdural metastases to invade brain parenchyma. Other nonneoplastic lesions, such as sarcoidosis or even empyema, can appear identically to metastases on MR studies. Signal intensity patterns are helpful, however, in separating extra-axial hemorrhage from tumor because the various stages of extra-axial hemorrhage have relatively specific intensities (373). Intravenous contrast agents might increase the detection of neoplastic causes of extraaxial hemorrhage. Bone invasion would indicate a neoplastic etiology of the mass. It is likely that the sensitivity of MR increases with the use of contrast agents for small extra-axial metastases, as is the case for other extra-axial lesions.

FIGURE 8.157 Sarcoid of the pial membrane with brain invasion. A,B: Axial postgadolinium-enhanced, T1-weighted images demonstrate thick, irregular enhancement in the interhemispheric fissure with featherlike invasion into the medial cortical surfaces bilaterally (A, arrows) and extension into sulci (B, arrows). C,D: T2-weighted axial images at approximately the same levels as panels A and B, respectively. Gadolinium-enhancing tissue in panels A and B is slightly hypointense (arrows) to normal cortical tissue intensity. The hyperintensity of underlying white matter bilaterally is more extensive than enhancing tissues in panels A and B, suggesting the presence of secondary brain edema.

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FIGURE 8.158 Metastases, thyroid. A huge destructive extra-axial skull base mass is both expansile and hemorrhagic on T1 (A,B) and T2 (C) images, characteristic of thyroid carcinoma metastases.

FIGURE 8.159 Epidural metastases. A: T1-weighted magnetic resonance (MR) (600/20). B: T2-weighted MR (3,000/90). C: T1-weighted MR (600/20) with contrast enhancement. An extra-axial mass is centered in bone and extends both extracranially and intracranially, implying its epidural site of origin. The mass is delineated by a vascular cleft (A–C, open arrows) between the lesion and brain. Also note the intervening cortex interposed between the mass and the underlying high-intensity edematous white matter on the T2-weighted image (B), proving an extra-axial location. The involvement of diploic fatty marrow is seen as a replacement of normal high intensity on precontrast T1weighted image by low-intensity tumor (A, closed arrows). Note that the distinction among tumor, normal marrow, and subcutaneous fat is obscured after contrast administration.

It is believed that subdural tumor implants are more likely to result from direct hematogenous seeding rather than transgression of dura from epidural tumor (374). Although most evidence points to the arterial route as the path of transport of extracranial neoplasms to their intracranial site of spread, some authors (375) suggest that, especially in the case of subdural metastases, the epidural plexus of spinal veins plays a role in the spread of prostate carcinoma into the dural and subsequently cerebral veins, a hypothesis originally suggested by Batson (376). Symptomatology from epidural or subdural metastases is usually due to direct compressive effects of underlying brain parenchyma, and so location again determines the neurologic deficit. Other, less common sequelae of these lesions include venous thrombosis, which can occur either as a result of tumor invasion itself into the dural sinus or from venous compression and stagnation. A rare consequence of dural metastases is pachymeningitis interna 552

hemorrhagica, which entails subdural hemorrhage in association with diffuse dural metastases. Subdural hematomas due to dural metastases are usually bilateral and are most often due to breast carcinoma (18) but have been reported with many neoplasms, including prostate carcinoma and melanoma. Subdural metastatic lesions, in contrast to subdural fluid collections (e.g., hematoma, hygroma) often appear very similar in intensity and shape to epidural metastases. These lesions are solid masses of neoplastic tissue and do not necessarily have the typical crescentic appearance of subdural hematomas because they do not merely passively fill the potential space of the subdural compartment.

FIGURE 8.160 Dural-based and subarachnoid metastasis, breast carcinoma. Axial T2 (A), fluid-attenuated inversion recovery (FLAIR) (B), T1 postcontrast (C), and coronal T1 postcontrast (D) images demonstrate both dural-based (C, arrow) and leptomeningeal metastasis in this patient with breast carcinoma. Note the abnormal subarachnoid space signal on FLAIR images.

Leptomeningeal metastasis or leptomeningeal carcinomatosis (Figs. 8.160 and 8.161) is seen in solid and hematologic neoplasms and progresses by seeding, growth in the pia-arachnoid compartment and dissemination of metastatic cells along this compartment (via CSF). Arachnoid layer involvement results from either a dural-based centripetally growing metastasis or centrifugal extension from an already invaded pia mater (377). Subarachnoid space may be invaded by hematogenous spread through either the arterial circulation, through the Batson’s venous plexus in retrograde fashion, or along the spinal or cranial nerves and via the perivascular lymphatics. Alternatively, direct involvement from an intra-axial mass may occur, with high-grade or a low-grade tumor (378), when located in closed proximity to the ventricular system (meduloblastoma, ependymoma) or the subarachnoid space (377,379,380). Tumor spread may follow the nerve pathways, in both directions, either from periphery to the neuraxis and vice versa. The term “leptomeningeal carcinomatosis” implies a solid tumor source of metastatic cells propagation either a primary brain tumor or a secondary tumor, for example, breast, whereas “leukemic or lymphomatous meningitis” refers to meningeal involvement in the setting of hematologic neoplasms (380). Both entities occur in about 4% to 15% of cancer patients (381), while less than 2% of patients with a primary brain tumor will develop a leptomeningeal carcinomatosis (382). Breast cancer is the most common (12% to 35%) solid tumor associated with leptomeningeal seeding, followed by lung cancer (10% to 26%) and melanoma (5% to 25%) (379). Rarely (20% of leptomeningeal metastases), leptomeninges represent the first metastatic site; however, in the vast majority of cases, intra-parenchymal metastases, and less frequently, dural metastases coexist (379,381). Special attention should be paid in the evaluation of patients treated with bevacizumab (Avastin, Genetech/Roche). Kleinschmidt-DeMasters et al. investigation in 2009, took note of prior studies raising suspicion of secondary effects of bevacizumab with apparent promotion of late onset parenchymal multifocal tumor spread (383–386), and reported that in two patients it altered the radiographic characteristics of leptomeningeal carcinomatosis and, though not unequivocally, this agent may have positively influenced the tumor spread (387). A more recent study conducted by Wick and colleagues (388) showed evidence contrary to this hypothesis, arguing that patients not on bevacizumab 553

had a similar risk of spread at recurrence or progression of high-grade glioma.

FIGURE 8.161 Extensive carcinomatous meningitis, fluid-attenuated inversion recovery (FLAIR), and contrastenhanced images. FLAIR images (A) show extensive involvement of the posterior fossa and right occipital mass. After contrast, axial (B), and coronal (C) images show obvious enhancement along surfaces of the posterior fossa and along cisterns.

In terms of sensitivity, contrast-enhanced MRI has been recognized as a superior diagnostic tool when compared to CT (377). On postcontrast T1-weighted images, pia-arachnoid enhancement may be diffuse or focal and is usually described as a wavy “serpentine” pattern because it outlines sulci and basilar cisterns and it may have different appearances: thick, lumpy–nodular, or thin and linear (389). Nevertheless, these findings are not to be considered pathognomonic as many other leptomeningeal disorders may have such appearance, although avid, nodular enhancement seems to be more typical of tumor seeding (389). Accordingly, enhancement of cranial nerves or spinal roots might also take place. In addition, hydrocephalus and oozing of CSF through the ependymal lining into the parenchymal interstitium may ensue (377,390). Leptomeningeal disease in a patient with a positive history of neoplastic diseases may manifest with the sole finding of communicating hydrocephalus. Cortical/CSF interface may be investigated by a high-resolution T2-weighted sequence with concurrent saturation of fat signal in order to enhance the natural contrast (391). Given the small size of cisternal segments of the cranial nerves, the use of high-definition sequences such as the MP-RAGE or the RAGE is needed as they are better for detection and characterization of such abnormalities (391). There is some variance of opinion regarding the use of contrast-enhanced FLAIR sequences versus the conventional postcontrast T1-weighted images for detection of leptomeningeal carcinomatosis as studied in numerous investigations (55,392–397). Paramagnetic properties of gadolinium compounds cause T1 relaxation time shortening, resulting in hyperintensity on T1-weighted images. Additionally, in leptomeningeal carcinomatosis and in inflammatory meningitis, CSF shows a higher concentration of proteins and cellular elements, leading to higher T1 spin-echo signal, and interfering with the signal nulling on inversion recovery sequences such as FLAIR. This phenomenon is responsible of the lack of suppression of CSF signal and hyperintensity on FLAIR. This effect is maximized by the use of intravenous contrast (398). However, it should be noted that, high CSF signal on FLAIR image may be due to several artifacts (399). Which of the two sequences is the best in evaluation of leptomeningeal involvement remains controversial. Three-dimensional FLAIR sequence may be also used in this setting. While it may be advantageous in diverse pathologic processes when compared with the 2D FLAIR, Kakeda (400) recently described some pitfalls of this technique reporting that leptomeningeal metastasis appear less conspicuous on 3D FLAIR. Nerve Sheath Tumors Vestibular schwannomas are relatively frequent tumors, accounting for 7% to 8% of all primary intracranial neoplasms and represent 70% to 80% of all CPA (cerebellopontine angle) cistern lesions, followed by meningiomas and epidermoid cyst (401). The peak incidence is around the fourth and sixth decades, without gender predilection. They are frequently seen in association with neurofibromatosis 554

type 2, where they are typically bilateral and also reveal concomitant meningiomas (50% of the cases) (402). They may arise from any portion of the eighth nerve, but in most cases this tumor develops in the Schwann sheath of the inferior vestibular nerve in the internal auditory canal (IAC) (401). Subsequently, the mass usually grows slowly, eroding the posterior wall of the IAC and forming a round mass in the cerebellopontine angle (CPA) (“ice cream on cone” appearance) (401). Histologically, vestibular schwannomas are circumscribed and encapsulated tumors composed of two distinct types of tissue: Antoni type A tissue has a compact texture composed of interwoven bundles of bipolar spindle cells and Antoni B has a loose texture containing tumor cells (Fig. 8.162). There is frequently mucinous and microcystic change in the type B tissue. Large cysts may develop from confluence of smaller cystic areas (Fig. 8.163). Most of them are small and round lesions that tend to enhance homogeneously, considered as Antoni type A; Antoni type B lesions are usually larger (>25 mm) and present with heterogeneous enhancement after the contrast agent injection, delineating central areas of necrosis and microcystic changes. MR is considered the gold standard in the evaluation of unilateral neurosensorial hearing loss (403), with CT imaging primarily used to exclude IAC enlargement and/or a mass in the CPA. MRI plays an important role in the preoperative and postoperative evaluation, providing detailed anatomical information and differential diagnosis. These lesions are usually mildly hypointense on T1 and hyperintense on T2-weighted images, appearing with a markedly low signal or filling defect on T2weighted high-resolution MR cisternography (Fig. 8.164). These newer, high–spatial-resolution, thinsection, heavily T2-weighted images, allow also an excellent depiction of the contents of the CPA and visualization of the seventh and eighth nerve complexes (401). Aside from the classic IAC–CPA schwannomas, small and purely intracanalicular schwannomas may also be detected (Fig. 8.165), and may present with extension to the cochlea or vestibule (404). Meningiomas remain as one of the main differential considerations, and new sequences (FIESTA, PRESTO) allow for improved detection and characterization of these lesions. Meningiomas, as relatively benign and slow-growing lesions, tend to cause hyperostosis in the petrous ridge, exhibit subtle calcifications, and may show the typical “dural tail” sign, a feature that may also be seen with VS. On the other hand, VSs usually invade and enlarge the IAC, eroding the posterior wall. However, none of these findings are pathognomonic. Recently, Tomogane et al. (405) described that using the PRESTO sequence, tiny microhemorrhages may be detected in almost all of the schwannomas, but in none of the meningiomas which may help in this differentiation. Another feature that may help in this differentiation is the signal intensity within the labyrinth. With thin-section T2 imaging, low signal in this location may reflect protein produced by the schwannoma, which is also associated with nonobstructive hydrocephalus (406). As cited above, radiologist plays an important role in surgical planning and should provide the following information: (1) size of the tumor; (2) the distance between the lateral edge of the intracanalicular portion of the tumor and the fundus (hearing prognosis and surgical approach); (3) intralabyrinthine signal intensity (extension to cochlea and vestibule); and (4) identification of the facial nerve and its position relative to the vestibular schwannoma (401). Additionally, the postoperative follow-up imaging is also important to evaluate for residual or recurrent lesion with enhancement pattern guiding the neurosurgeon in establishing surveillance evaluations (407).

FIGURE 8.162 Histologic features of acoustic schwannoma. Acoustic neurinomas are histologically like any other schwannoma of the peripheral nerves. Note a biphasic pattern of growth with “Antoni A” dense areas and “Antoni B” loose areas (A). The cells are spindly and occasionally are lined around a nuclear-free area, called a “Verocay body” (B).

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FIGURE 8.163 Acoustic schwannoma with cystic changes. Unenhanced T1-weighted and T2-weighted images (A,B) reveal a large cerebellopontine angle mass with associated cysts. After contrast (C), most of the mass that extends far into the internal auditory canal is noted to be cystic.

FIGURE 8.164 Cerebellopontine angle and intracanalicular vestibular schwannoma. Thin-section, heavily T2weighted axial (A) and axial T1 precontrast (B) and postcontrast (C) images demonstrate a right cerebellopontine angle vestibular schwannoma. Note the intracanalicular component of the mass well seen on the T2-weighted images (A, white arrowhead).

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FIGURE 8.165 Intracanalicular acoustic schwannoma. Axial thin-section T2 (A) and postcontrast axial (B) and coronal (C) images demonstrate an isolated intracanalicular vestibular schwannoma (arrows). Note the excellent depiction of the lesion on the T2-weighted images, in comparison with the normal, thin contralateral cranial nerve VII and VIII complexes with adjacent cerebrospinal fluid.

Schwannomas may also occur along other cranial nerves, with those on the trigeminal nerve next in frequency to eighth nerve tumors, comprising about 0.2% of all intracranial tumors (408). The tumors of the fifth cranial nerve are seen along the course of the nerve, involving its prepontine cisternal segment and/or its extension into the Meckel cave at the petrous apex and the cavernous sinus. Cavernous sinus invasion and adherence to vital structures with inadequate tumor exposure are the major impediments to total tumor resection (409). On imaging exams, these lesions demonstrate intensity characteristics similar to those of vestibular schwannomas. Undoubtedly, this specific neuroanatomic location along the fifth nerve pathway is the key to the diagnosis (Fig. 8.166); however, other entities may mimic this condition, such as inflammatory (sarcoidosis), metastatic, and lymphoproliferative diseases (see Skull Base chapter for a more complete discussion). Maldevelopmental Cysts and Tumors Arachnoid Cysts There are many possible etiologies for the development of arachnoidal cysts. Some are acquired secondary to an inflammatory reaction in the subarachnoid space related to an episode of leptomeningitis, head trauma, or primary subarachnoid hemorrhage, or are associated with brain tumors that are extra-axial or on its surface. A large number, however, are the result of congenital abnormality in the development of the arachnoid membrane (410,411). The increasing use of MRI has allowed for frequent diagnosis of these lesions, with a prevalence estimated as less than 5% in both children and adults, most of them occurring in the middle cranial fossa (Fig. 8.167) (412). The arachnoid cysts in the middle cranial fossa are frequently associated with what is believed to be primary hypogenesis of the temporal lobe (413). Other locations include the frontal convexity region and cisterns in the suprasellar, quadrigeminal, and foramen magnum region (Fig. 8.168). They can also be within the ventricular system. They are frequently asymptomatic but become symptomatic when they compress the brain sufficiently to cause headache and obstruction of the CSF pathways, resulting in hydrocephalus. Arachnoid cysts frequently cause erosion and expansion of the overlying portion of the calvarium. They do not develop calcifications in their walls and demonstrate no contrast enhancement (414). The superficial brain vasculature is displaced inward and may be outlined against the inner cyst wall. Intensity usually follows almost exactly that of CSF (413–415): low intensity on T1-weighted images, isointensity on long-TR/short-TE images, and hyperintensity on T2-weighted images. FLAIR is particularly useful in arachnoid cysts because the signal should be completely suppressed if the contents represent CSF. Pulsation artifacts may occasionally be seen within the larger cysts and are revealed as focal streaks of hypointensity on the T2-weighted series. The superficial brain vasculature is displaced inward and may be outlined against the inner cyst wall.

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FIGURE 8.166 Trigeminal nerve schwannoma. A: Axial T1-weighted image demonstrates an isointense 1-cm mass in the pontine cistern on the left side (white arrow), with a tongue of tumor extending forward into the region of the Meckel cave (open white arrow). B,C: Axial long–repetition time/short–echo time (B) and long–echo time (C) images at approximately the same level as panel A. The mass in the cistern and Meckel cave becomes heterogeneously hyperintense (black arrows), containing punctate and linear bandlike areas of slight hypointensity. D,E: Postgadolinium axial images at approximately same levels as panels A–C. There is heterogeneous enhancement of the tumor with relative lack of enhancement in regions that were hypointense in panels B and C. The mass in the cistern is occupying the position of the fifth cranial nerve, with the normal fifth nerve seen on the right side (E, white arrow).

Neuroenteric Cyst Neurenteric cysts, also called enterogeneous cysts, are rare and benign congenital lesions caused by failure of separation of neuroectodermal and endodermal elements during the first weeks of embryogenesis (416,417). These lesions are three times more common in the spine, and when located in the brain, they are most frequently found in the posterior fossa. The clinical symptoms are related to its size and location, as well as with the effects on the neighboring structures (headache, intracranial hypertension). On imaging exams, a single well-circumscribed lesion is seen in the midline anterior to the brainstem. It typically exhibits a slight hyperintensity on T1-weighted images, characteristic for this entity (Fig. 8.169). Contrast enhancement and/or calcifications are not common features. The main differential diagnoses are other intracranial cysts that may occur in this location, such as dermal inclusion cysts (dermoid and epidermoids) and parasitic cysts (neurocysticercosis). Epidermoid Cysts Intradural epidermoid cysts are rare and congenital lesions of ectodermal origin characterized by a stratified epithelial capsule containing laminated keratin debris (418). Although epidermoid cysts are rare lesions, they are important in the CPA (Fig. 8.170) where they represent 5% of lesions, following schwannomas and meningiomas (401). The tumor grows slowly and is soft and very pliable, conforming to the shape of the adjacent brain and CSF spaces in which it is growing. Although congenital in nature, they usually do not present clinically until the third or fourth decade, and may present with cranial nerve deficits, such as trigeminal neuralgia, or with other less common symptoms such as a brain stem infarct (due to the stretching of basilar artery branches). The intradural lesions are frequently located in the cisterns of the CPA, supra- and parasellar regions, and middle cranial fossa, as well as in the cisterna 558

magna. On CT the lesions are hypodense and do not enhance with contrast material. They are difficult to differentiate from arachnoid cysts based on their density; however, their external surface is usually lobulated in configuration compared with the smooth surface of an arachnoid cyst. There may occasionally be focal calcifications in their walls. In contrast to arachnoid cysts, epidermoids tend to engulf and surround vessels and cranial nerves, whereas arachnoid cysts displace such structures.

FIGURE 8.167 Arachnoid cyst with skull remodeling and signal heterogeneity due to fluid motion. Sagittal (A) and coronal (B) T1-weighted images show a huge extra-axial mass with enlarged remodeled middle cranial fossa (B) that extends into the posterior fossa. Intralesional heterogeneity on T1- and T2-weighted images (C) is due to motion of the fluid within the arachnoid cyst.

FIGURE 8.168 Arachnoid cyst of quadrigeminal cistern. A,B: Sagittal T1-weighted (A) and coronal T2-weighted (B) images demonstrate a large extracerebral collection in the region of the quadrigeminal cistern that has similar intensity to that of ventricular fluid, being hypointense in panel A and hyperintense in panel B. The mass compresses the superior vermis inferiorly (A, white arrows; B, black arrow) and the posterior third ventricle and upper aqueduct (A, open white arrows), which, however, remain patent because no hydrocephalus is present.

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FIGURE 8.169 Neuroenteric cyst—two different cases. Sagittal T1-weighted images show T1 hyperintense masses ventral to the brain stem.

FIGURE 8.170 Right cerebellopontine angle epidermoid cyst. Axial T2 (A) and fluid-attenuated inversion recovery (FLAIR) (B) images demonstrate a slightly heterogeneous lesion on the FLAIR image that is isointense with cerebrospinal fluid (CSF) on the conventional axial T2-weighted image. The thin-section, heavily T2-weighted (C) image performed for cranial nerve assessment shows the lesion to be heterogeneous in comparison with normal cisternal CSF and has a slight mass effect on the adjacent pons and trigeminal nerve. On the precontrast T1weighted image (D), there is minimal internal signal, but it is difficult to see the lesion (arrow). Postcontrast image (E) demonstrates no internal enhancement. Diffusion-weighted image (F) demonstrates markedly reduced diffusion in the lesion, making the diagnosis and visualization of the lesion obvious.

On T1-weighted MR images, epidermoid tumors demonstrate subtle hypointensity compared to CSF. There is usually mild inhomogeneity of low intensity, with some patchy regions of isointensity within the lesion. On T2-weighted sequences, the tumors show marked hyperintensity similar to or greater than that of CSF, with significant heterogeneity of the signal intensity (419–421). The low-intensity signals within the tumor hyperintense pattern are probably the result of the cellular debris and solid cholesterol crystals within the cysts. On MRI, epidermoids are distinctly different from the arachnoid cysts, being virtually never isointense to CSF on FLAIR sequence. In addition, DWI demonstrates a markedly restricted diffusion within epidermoids, simplifying the diagnosis and helping its visualization. MRS may also play a role in the diagnoses, displaying an increased peak of lactate in these tumors 560

(418). Rarely intraparenchymal lesions may also occur, demonstrating the same imaging appearance as the extra-axial lesions (422). Another unusual pattern may be seen on MRI, referred to as white epidermoid, in which rich protein content results in reversed signal intensities on MR scan, exhibiting high signal intensity on T1-weighted images and low signal intensity on T2-weighted images. Dermoid Cysts Dermoid cysts or tumors are rare and benign lesions constituting less than 1% of all the intracranial lesions (423). They arise from inclusion of ectodermoidal elements in the neural groove at its time of closure, and as the epidermoid cysts are classically described as dermal inclusion cysts. Nonetheless, the presence of hair follicles, sebaceous and sweat glands in the cyst wall distinguishes dermoid cysts from epidermoid cysts (424). Not uncommonly there is a persistent defect in the overlying skin, with a sinus tract extending into the intracranial portion. Microscopically, these cysts may contain elements from all layers of the skin. Much of the wall of the cysts may be lined (as in epidermoid tumors) by stratified squamous epithelium supported by an outer collagen layer. Calcification may develop in the portion of the walls, and there may be bone and cartilage within some of the cysts (18). The clinical symptoms are due to the mass effect over the adjacent structures (headache, seizures, and hydrocephalus) or related to cyst rupture into the subarachnoid space (aseptic meningitis). On CT imaging, a dermoid cyst usually present as hypodense lesions displaying fat density areas, without significant enhancement, and are usually seen near the midline. Dermoid cysts typically demonstrate a marked hyperintensity on T1-weighted MR images due to their fatty content, which consists of triglycerides and unsaturated fatty acids (Fig. 8.171) (425). The hypointensity of the mass on T2-weighted images may be seen throughout or within one or more loculations within the lesion. Other portions of the cysts may demonstrate a pattern consisting of inhomogeneous hyperintensity, similar to epidermoid tumors, so the term dermal inclusion cyst is preferred when describing these entities on imaging exams. Subarachnoid rupture demonstrates droplets and streaks of high intensity within the subarachnoid cisterns around the tumor and along the cerebral convexities (Fig. 8.171). Within the ventricles a fat–fluid level develops in the anterior superior portions. A chemical shift artifact is frequently projected into the lesion on long-TR sequences. On T1-weighted sequences, a high-intensity fluid level is present anterior to the hypointensity of CSF, whereas on long-TR sequences an intermediate and low-intensity fluid collection is observed anterior to the high intensity of the CSF.

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FIGURE 8.171 Ruptured dermoid right temporal horn. A: Axial computed tomography at the level of the temporal horns demonstrates a markedly hypodense lesion of the right temporal horn extending anteriorly to the sphenoid wing (black arrow). There are focal calcifications in its medial and lateral walls (white arrows). B: Noncontrast coronal T1weighted image at the level of the temporal horns demonstrates a lobulated, markedly hyperintense mass in the right temporal horn (black arrow). Within the lateral aspect of this lesion are small nodular areas of iso- and hypointensity (open black arrow). C: Coronal T2-weighted image at same level as panel B reveals the right temporal horn mass to be heterogeneously isointense, with the superior rim revealing mild hypointensity. The lateral portion, which in panel B demonstrated focal hypointensities, demonstrates more marked hyperintensity in this image (arrow). D,E: Axial proton density–weighted (D) and T2-weighted (E) images through region of the lateral ventricles. Fluid levels are evident in the anterior aspects of both frontal horns. In panel D, high-intensity collections are present anteriorly that become mildly hypointense in panel E (solid black arrows). In both panels D and E, there is a markedly hypointense band on the posterior margin of these collections (open black arrows) that represents chemical shift artifact, proving the fatty nature of these collections.

Subarachnoid Lipomas Neither hematomas nor true neoplasms, these lesions arise from a congenital abnormality of the leptomeningeal membranes (meninx primitiva), occurring usually in the midline, along the pericallosal cistern, and more than half (55%) are associated with a brain malformation, with agenesis or dysgenesis of the corpus callosum being most frequent (426). Lipoma’s size and location usually correlate with severity of this developmental abnormality (427). Large lesions in this location are known as corpus callosum lipomas (428). They may also be found in the quadrigeminal, chiasmatic, perimesencephalic, CPA, and Sylvain cisterns (429). The lesions are frequently incidental and asymptomatic but may cause compression of the brain with obstructive hydrocephalus when enlarged or may infiltrate around the cranial nerves, producing focal symptoms. The pericallosal lipomas fall into two different patterns: curvilinear and tubulonodular types (427). The curvilinear type (Fig. 8.172) appears as a thin structure in the posterior aspect of the pericallosal cistern which is usually smaller than 1 cm and is associated with dysgenesis of corpus callosum. The tubulonodular variant (Fig. 8.173) represents a large midline lipoma with extension into the ventricles, agenesis of the corpus callosum, and arterial dysplasias in the intralipomatous segment. On MRI, they present as a high signal on T1-weighted images either uniformly or containing isointense nodules and bands representing the nonlipomatous elements within the lesion (430). On T2-weighted sequences, the lesion becomes hypointense and frequently more heterogeneous. There may be a pathognomonic chemical shift artifact evident.

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FIGURE 8.172 Curvilinear type of pericallosal lipoma. Thin, elongated, and curvilinear structure along the corpus callosum margin that appears hyperintense on T1-weighted image (A), as well as on axial FLAIR (B), associated with signal attenuation on fat suppressed T2- and T1-weighted sequences (C,D). Also note the dysgenesis of the corpus callosum (splenium and posterior body).

CONCLUSION After more than 25 years of experience using 1.5-T MR for the evaluation of brain masses, there is no longer a question about its value in diagnosis and management of brain tumors. Beyond the fundamental anatomic localization of these lesions, significant correlation is found between histology and signal intensity patterns in many cases. Combining anatomic MR with physiologic methods, including fMRI using task-activation studies, diffusion and perfusion MR, MRS, and in select cases positron emission tomography has clearly had an impact on patient management in many individual cases. It remains the case, however, that despite all of the sophisticated diagnostic tools and advances in treatment, brain tumors represent one of the only cancer categories for which overall mortality rates have not significantly improved over recent decades, according to US National Cancer Statistics. More than ever, thorough knowledge of neuroanatomy, neuropathology, and pathophysiology is essential for the neuroradiologist to play a significant role in improving the diagnosis and management of these difficult cases.

FIGURE 8.173 Tubulonodular type of pericallosal lipoma. B: Sagittal T1-weighted image shows a large midline hyperintense mass that demonstrates signal attenuation on the T1-weighted postcontrast fat-suppressed sequences (D). There is also associated agenesis of the corpus callosum. The anterior cerebral arteries course through this lobulated lesion, a feature that is better characterized on T2-weighted (A,C) and T1-weighted postcontrast (D) images.

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ACKNOWLEDGMENT Mark S. Shiroishi was partially supported by SC CTSI (NIH/NCRR/NCATS) (Grant #KL2TR000131).

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9 Pediatric Brain Tumors Robert A. Zimmerman and Larissa T. Bilaniuk

INTRODUCTION Tumors of the central nervous system (CNS) in pediatric patients are the second most common form of neoplasia (1). They are exceeded only by hematologic malignancies such as leukemia. Brain tumors arising during childhood account for 15% to 20% of all primary brain tumors. The location of brain tumors in children has long been divided into those that are located infratentorially and those that are located supratentorially. Prior to the advent of modern neuroimaging with computed tomography (CT) and, more recently, magnetic resonance imaging (MRI), it was thought that infratentorial tumors were more common than supratentorial tumors (2). With the greater sensitivity of CT and MRI for the detection of small cerebral tumors, the incidence has become recognized as being equal, if not slightly in favor of the supratentorial tumors. Aside from location, the histology of pediatric brain tumors is quite different from that seen in the adult population. In adults, metastases, meningiomas, and malignant gliomas are the most frequent tumors. In the pediatric population, aggressive tumors of embryologic origin such as primitive neuroectodermal tumors (PNETs) are relatively frequent, as are low-grade glial tumors of astrocytic differentiation. Moreover, certain tumors that are not uncommon in the pediatric age group are exceedingly rare in the adult population. Hematogenously disseminated metastases are extremely unusual in the pediatric population, but dissemination throughout the subarachnoid space can be rather common, depending on histopathologic type. The overall incidence of pediatric brain tumors is between 25 and 40 per million, with a male-tofemale ratio of 1.2 to 1. Tumors of astrocytic origin comprise 40% to 55% of the total, or 16.8 per million; PNETs 20% to 30%, or approximately 5 per million; and ependymomas 10% to 15%, or approximately 2.2 per million. Whereas most pediatric brain tumors appear to arise de novo without an underlying genetic cause or predisposition, certain genetic conditions do have a predisposition to the development of brain tumors. The most common of these conditions is neurofibromatosis type I, in which optic gliomas affect 5% to 15% of patients by age 20 years (3–5). In tuberous sclerosis, giant cell tumors also arise with significant frequency (6). Other genetic conditions that predispose to intracranial neoplasms include Gorland syndrome, basal cell nevus syndrome, Turcot syndrome (in which one-fourth of all cerebral neoplasms are PNETs), and tumors associated with neurofibromatosis type II (7). The signs and symptoms of a CNS tumor with which an infant or child presents depend in part on the age of presentation but are often nonspecific relative to the type of tumor and relate more to its neuroanatomic location and secondary effects. Infants frequently present with an enlarging head circumference, nausea, and vomiting. Children may present with seizures or focal neurologic deficits such as hemiparesis. Tumors that develop in hormonally sensitive locations such as the hypothalamus may give evidence of disturbed endocrine function manifested by diabetes insipidus, growth failure, or precocious puberty. Tumors that involve the visual pathways often present as visual problems or impaired ocular motility.

IMAGING EVALUATION FOR PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS Although MRI is universally recognized as the most sensitive technique available, CT is very often the initial technique used because of its availability and the rapidity of the examination. With the current generation of CT scanners, multislice studies (64 to 128 slices) often take seconds, providing thin 578

sections and relatively high resolution. The study of a brain tumor patient should include both pre- and postcontrast enhancement to determine whether hemorrhage, calcification, or contrast-enhancing tumor is present. If an MRI is scheduled to follow, then a pre-enhancement CT only may suffice. It should be understood that MRI is neither sensitive nor specific for calcification, so the only reliable way to detect calcification is by CT scanning. Although the CT scan may be adequate for the diagnosis and localization of a tumor mass, it may not be sufficient for characterization of the tumor type, for delineation of the tumor and its spread to the degree that can be done with MRI. CT scans are considered as a precursor to the MRI examination, if they are used at all. The basic, routine MRI for the evaluation of the pediatric brain tumor depends in part on tumor location and size. In case of tumors of suprasellar and pituitary regions, there is a necessity for thin sections. In general, a sagittal and axial T1, axial and coronal T2, and axial and coronal fluid-attenuated inversion recovery (FLAIR) are performed prior to the injection of gadolinium contrast material. If clinically indicated, based on the suspicion of hemorrhage or calcification being present, a T2 gradientecho susceptibility or a susceptibility-weighted imaging (SWI) scan can be performed before the injection of contrast material. Following the injection of contrast material, all three planes are obtained with T1 weighting. At the Children’s Hospital of Philadelphia, we favor the use in at least one plane (usually the axial) of fat saturation with T1-weighted imaging after the injection of contrast material. At the lower field strength of 1.5 Tesla (T), we use magnetization transfer sequences to increase the sensitivity to enhancement on our postcontrast images. At 3 T, we do not use magnetization transfer but do use fat saturation in at least one plane. Prior to the contrast injection we routinely perform arterial spin labelling (ASL) for assessment of cerebral blood flow, which is increased in the more vascular and more malignant tumors. Diffusion imaging is included on all evaluations of the CNS, including all cases of brain tumors. The diffusion imaging is performed as the last part of the examination because the pulse sequence tends to have a louder noise level and may awaken the sedated child. Depending on the neurosurgical approach to brain tumors at the institution where the child is being studied, navigational images may be acquired at the time of the initial MRI examination or later, prior to surgery. The navigational study includes axial postcontrast-enhanced T1 and T2 1-mm-thick slices obtained through the entire head at zerodegree angulation to the orbitomeatal line. The neurosurgeon can use these to plan the surgical approach and define the least hazardous pathway prior to surgery. Additional procedures that may be employed in the evaluation of the pediatric brain tumor by MRI include proton spectroscopy and task activation functional MRI when the tumor may be in or near a sensitive region, such as speech or language area, visual center, or motor cortex. These additional studies provide information about the risks involved and aid in planning the operative approach. Diffusion tensor imaging with fiber tracking can provide specific information about the effect of the tumor on tracts, whether they are displaced or infiltrated. Thus, diffusion tensor imaging with fiber tracking is a technique that has a potential in identifying vital pathways that may be at risk of injury or interruption by the surgical procedure. Once again, because most of these advanced MRI techniques are generally signal-to-noise starved, it is advantageous to use higher-field 3-T scanners for complete evaluation.

INFRATENTORIAL TUMORS Unlike in the adult population, where infratentorial tumors typically consist of extraaxial tumors like acoustic schwannomas and meningiomas and intraaxial tumors are mostly metastases, in the pediatric age group, infratentorial tumors represent primary neoplasms of the cerebellum and brainstem. It is only in the adolescent that extraaxial tumors, such as acoustic schwannomas and meningiomas, begin to be encountered, and then primarily in the situation of neurofibromatosis type II. Disseminated tumors of the CNS, originating from either infratentorial or supratentorial primary tumors, can seed the subarachnoid space and grow onto the surface of the cerebellum and brainstem. Cerebellar Tumors The three most common pediatric brain tumors of the cerebellum are, in decreasing order of frequency, the PNET (medulloblastoma), cerebellar astrocytoma, and ependymoma (8). Other cerebellar neoplasms include the hemangioblastoma, oligodendroglioma, and lymphoma. All of these are relatively infrequent, with the hemangioblastoma occurring in the adolescent in association with von Hippel– Lindau syndrome. Cerebellar tumors can be divided into those that arise primarily within the cerebellar hemispheres and vermian tissue, the astrocytoma, and PNET, and those that arise primarily within the 579

fourth ventricle, the ependymoma, and choroid plexus papilloma (CPP) or carcinoma. Cerebellar Astrocytomas Cerebellar astrocytoma is the most common cerebellar hemispheric tumor of glial origin, a tumor that is in the posterior fossa is second in frequency to the PNET. Cerebellar astrocytomas account for more than 10% of pediatric intracranial tumors and 25% of all posterior fossa tumors of children (9,10). There is no gender predilection. The most frequent astrocytoma is the pilocytic type. It should be noted that other glial-origin tumors arise in the cerebellar hemispheres, but less commonly. Patients with cerebellar astrocytomas usually present with symptoms of less than 2 months’ duration. Appendicular ataxia exceeds truncal and gait ataxia and precedes symptoms of increased intracranial pressure (8). Incidental astrocytomas may be found in the imaging studies of patients with predisposing conditions such as neurofibromatosis type 1 (NF1) or when imaging is done for conditions such as head injuries when the patient has no symptoms related to the posterior fossa. The pilocytic astrocytoma (PA) falls under the World Health Organization (WHO) classification as grade I, meaning extremely benign and generally curable if it can be completely resected. Fibrillary astrocytomas are the next most frequent glial tumors of the cerebellum. They represent approximately 15% of the glial tumors, compared to 85% for the pilocytic astrocytomas. These are more infiltrative and thus more difficult to totally resect and therefore to cure. Other less common glial neoplasms in the cerebellar hemispheres include ganglioglioma (GG) and oligodendroglioma. Glioblastomas of the cerebellum are very rare. They may be radiation induced and can be seen in patients who have been previously successfully treated for a brain tumor, such as PNET of the cerebellum. They tend to arise many years after the original therapy. The juvenile pilocytic astrocytomas (JPAs), most commonly present between 5 and 15 years of age, are characterized by a slow growth rate, and only occasionally metastasize within the cerebrospinal fluid (CSF) pathways (Table 9.1). Although unencapsulated, they remain remarkably circumscribed and do not undergo malignant differentiation with time. Grossly, the tumors are cystic, with mural nodules in 50%, and more solid with various cystic central cavities in 40% (Fig. 9.1) (11). Completely solid tumors comprise only 10% of the total. Calcification is uncommon, reported to be at most, in 20% of JPAs. The JPA lacks a blood–brain barrier (BBB), and therefore fluid leaks and accumulates, first as microcysts around the tumor nodule or within the nodule, and eventually coalesces into macroscopic cysts (Fig. 9.2) (11). This explains the frequent cystic nature of the tumor, as well as the associated edema. The disturbance in the BBB results in the high incidence of contrast enhancement on both CT and MRI. Twenty-five-year survival rate for patients with JPAs is on the order of 90% or better (12). Recurrence rates after gross total resection for cerebellar pilocytic astrocytomas vary from 0% to 12% (13). Based on their very slow growth rate, long-term progression-free survival may be seen even after subtotal resection. Second surgery for gross total resection is the method of choice for residual or recurrent low-grade cerebellar astrocytoma. TABLE 9.1 Posterior Fossa Tumors in Childhood

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FIGURE 9.1 Cystic cerebellar pilocytic astrocytoma on gross specimen. (Courtesy of Dr. N. K. Gonatas, Philadelphia, PA.)

FIGURE 9.2 Pilocytic astrocytoma, microscopic section. Note the biphasic appearance, with both loose and dense areas of bipolar fusiform cells with bland nuclei in a fibrillary matrix. Small and large cystic formations are typical in this lesion.

COMPUTED TOMOGRAPHY. CT findings of cerebellar astrocytoma are those of a mass arising in the vermis or the cerebellar hemispheres, the solid portion being less dense than the surrounding brain, with both the solid and cystic portions typically being slightly denser than CSF (9-3A). The density of the cystic portion is due to the proteinaceous nature of the fluid. These tumors on CT are less dense than PNET and less often calcified than ependymomas. In more than 75% of the tumors, the solid portion of the mass shows enhancement. The solid portion may represent a large component of the astrocytoma or only a mural nodule, or it may be just a part of the tumor cyst wall (Fig. 9.4A,B). A cyst that is not lined by tumor should not enhance. The majority of the symptomatically presenting cerebellar astrocytomas have associated hydrocephalus due to compression or due to direct involvement of the fourth ventricle by the tumor. Fibrillary astrocytomas of the cerebellum are often less well defined than the pilocytic astrocytomas, with more irregular margins, and are more likely to have calcifications. Oligodendrogliomas of the cerebellum tend to be ill defined and densely calcified. Glioblastomas of the cerebellum are rapidly growing, irregularly enhancing, partially necrotic, infiltrative masses.

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FIGURE 9.3 Cystic cerebellar pilocytic astrocytoma. A 10-month-old boy with enlarging head circumference. A: Axial noncontrast-enhanced computed tomography shows hydrocephalus with cerebrospinal fluid reabsorption around frontal and temporal horns (arrowheads). This is due to a large mass in the left cerebellar hemisphere (arrows). The mass has a lower-density cystic component and a higher-density, more solid component (arrow). The fourth ventricle is displaced, and there is low-density edema in the brainstem and vermis. B: Axial enhanced T1 magnetic resonance imaging (MRI), fat saturated. There is intense enhancement of the solid components of the cystic tumor. C: Coronal enhanced T1 MRI postgadolinium, nonfat-saturated, showing tumor enhancement.

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FIGURE 9.4 Solid cerebellar vermian astrocytoma. A: Axial noncontrast computed tomography (CT) shows a vermian mass projecting into the fourth ventricle. The mass is slightly less dense than the cerebellum. B: Axial contrastenhanced CT. There is enhancement throughout most of the tumor. C: Axial proton density magnetic resonance imaging (MRI) shows high-signal-intensity mass. D: Axial T2 MRI also shows high signal in the mass. E: Precontrast material injection T1 MRI. The mass is less intense than the cerebellum but higher than CSF. F: Contrast-enhanced T1 MRI. The enhancement of the tumor is analogous to that shown on CT in panel B.

MAGNETIC RESONANCE IMAGING. Cerebellar astrocytomas are hypointense on T1 and hyperintense on T2, proton density, and FLAIR (Figs. 9.4C–E and 9-5A). The solid portion of the tumor is typically more hyperintense than the solid component of otherwise similarly appearing cystic PNET. Analogous to CT findings, the vast majority of the astrocytomas show contrast enhancement at the site of the solid tumor (Figs. 9.3B,C, 9.4F, and 9-5B). Diffusion studies show increased motion of water within both the cystic and the solid portions of the tumor, with increased apparent diffusion coefficient (ADC) values (9-5C), another difference from the solid component of cystic PNET. Tumor dissemination remote to the site of the primary tumor is rare at the time of diagnosis or even in follow-up. Proton spectroscopy of low-grade cerebellar astrocytomas shows slight elevation of choline compared to Nacetyl aspartate (NAA), with a ratio of approximately 1.6:2.3:1 (14). This ratio is only from the solid portions of the tumor. The cystic portions of the tumor often show only elevated lactate and a lack of other metabolites. The presence of lactate in the cystic portion of the tumor has nothing to do with the tumor being aggressive, as in the case of malignant glioma, where it reflects anaerobic metabolism. Lactate in the cyst fluid of low-grade astrocytoma reflects the byproducts of metabolism that seep into the cysts. There is a low incidence of blood products in the wall of the cyst, and these manifest as marginal hypointensity on T2 and on susceptibility scans due to deposition of hemosiderin. Cerebellar astrocytomas do not present acutely as hemorrhagic masses, a finding that, when present, suggests a more aggressive tumor such as a PNET, atypical teratoid rhabdoid tumor (ATRT), or a tumor with a tendency to hemorrhage such as an ependymoma.

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FIGURE 9.5 Cystic pilocytic astrocytoma involving the vermis. A: Coronal fluid-attenuated inversion recovery magnetic resonance imaging (MRI). The solid component of the tumor has higher signal than the cystic component. B: Contrast-enhanced axial T1 MRI. There is enhancement of the solid component of the cystic tumor. C: Apparent diffusion coefficient (ADC) map MRI. The diffusion in the solid tumor is increased but not as much as within the tumor cyst.

Postoperative evaluation of a patient with a cerebellar astrocytoma is generally performed within 24 hours of surgery. The reason for this is to avoid postoperative contrast enhancement at the site of reactive granulation tissue, which could be misinterpreted for residual tumor. Several days after surgery, granulation tissue starts to form, with disturbance in the BBB, and enhancement occurs at the margins of the resection whether there is or there is no residual tumor. In general, the most sensitive postoperative technique to detect residual tumor is MRI. CT is used primarily in the postoperative period for evaluation of residual hydrocephalus and/or other complications following surgery, such as the presence of extraaxial collections or intracerebral hematomas. Whereas pilocytic astrocytomas of the cerebellum, most often cystic, are the most frequently encountered form of astrocytic tumor in the cerebellum, other forms do occur. Fibrillary astrocytomas are infiltrating and poorly defined tumors, and they may extend from the cerebellar peduncles into the brainstem; often they do not enhance. Their prognosis is less optimistic than that of the PA because over time the residual tumor can undergo malignant degeneration. GGs of the cerebellum do occur and are much less frequent than pilocytic astrocytomas. Like their counterpart in the supratentorial brain, GGs may be either cystic or solid, may contrast-enhance or not, and may be calcified. There is no easy way to differentiate these from other cerebellar astrocytic tumors except by pathology examination. Glioblastomas of the cerebellum are rare primary neoplasms. When they are found, they are more frequently the result of prior therapy, such as radiation therapy for a posterior fossa PNET that had been cured. Such a glioblastoma is detected during the long-term follow-up, often when the patient is a teenager or adult. More frequent than these glioblastomas of the cerebellum are radiation-induced dural-based meningiomas, which occur a decade or more after the completion of radiation therapy. When one meningioma is found postradiation and removed surgically, further follow-up imaging should be instituted because additional meningiomas are likely to develop with time. In postoperative follow-up of any cerebellar tumor, if there is a finding that suggests residual tumor, a closer follow-up is needed. Scar tissue will not grow but remains stable or shrinks, whereas tumor tissue will grow with time. When recurrence is detected, the feasibility of re-resection is contemplated. In the immediate postoperative period, comparison to preoperative imaging study will permit detection of residual tumor if there is significant amount. Under these circumstances, neurosurgeons are often willing to go back in at that time and resect the remaining tumor. As more and more MRI is used to study infants, children, and adolescents with symptoms such as developmental delay and headaches or posttrauma, a number of incidental lesions are being found. In such circumstances, a relatively frequent finding is an area of abnormal increased signal on T2 and FLAIR in the cerebellum. First, changes secondary to NF1 should be excluded by checking other sites within the brain. The stigmata of NF1 include bilateral and multiple sites of high T2 signal in cerebellar dentate nuclei and brainstem and in supratentorial brain, particularly globus pallidus. If these are present, then spongiform white matter dysplasia of NF1 is the likely etiology of the focus of high signal in the cerebellum. If spongiform changes of NF1 have been excluded, then the likelihood is that a tumor of the cerebellum has been found incidentally. Further evaluation with proton spectroscopy to look for elevated choline and depressed NAA levels can be useful if the lesion is large enough (greater than 1 cm × 1 cm × 1 cm). Such incidentally found lesions are followed with repeat contrast-enhanced imaging every 6 to 9 months. Some of these enhance initially, or with time begin to contrast-enhance. If the 584

lesion enlarges or begins to contrast-enhance, then it is surgically removed. The experience has been that the lesions that grow over time turn out to be neoplasms, most often low-grade astrocytomas. Without evidence of another disease process, such as NF1 or a demyelinating disease, such lesions should be suspected to represent neoplasm and should be systematically followed with imaging. Primitive Neuroectodermal Tumors of the Posterior Fossa (Medulloblastoma) PNETs can arise in different locations and have been known by different names depending on their location. The different sites of origin of the PNET include the posterior fossa, where the tumor has been called medulloblastoma; the pineal region, where it is called pineoblastoma; the supratentorial brain, where it is called central neuroblastoma (NB); and the eye, where it is referred to as retinoblastoma. These tumors are WHO grade IV (Fig. 9.6). Posterior fossa PNET is the most common malignant pediatric brain tumor, accounting for 15% to 30% of all pediatric CNS tumors and 30% to 55% of posterior fossa tumors (8). Between 250 and 500 pediatric brain tumors are newly diagnosed each year in the United States (8). PNETs of the cerebellum and vermis have an incidence of 0.5 to 0.7 per 100,000 (8). The posterior fossa PNETs are more frequent in Hawaiians and in Maori of New Zealand, where the incidence approaches 12 per million children. In non-Hawaiian children in the United States, the incidence of posterior fossa PNETs is 5 to 9 per million children. The peak age for presentation of these tumors is between 5 and 7 years, with 80% diagnosed between ages 1 and 10 years (15). The male-to-female ratio is from 1.3 to 2.7 to 1 (9,15). From 1% to 2% of PNETs occur in association with a genetic tumor syndrome (16). Four percent of patients with Gorlin syndrome develop PNETs (17,18), and in Turcot syndrome, 25% of all cerebral neoplasms are PNET.

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FIGURE 9.6 Primitive neuroectodermal tumor with subarachnoid space dissemination. A: Note the densely cellular proliferation of sheets of cells with small dark nuclei and scarce cytoplasm, along with a high mitotic rate. There are occasional rosette formations of nuclei around an amorphous anuclear center. (Courtesy of Dr. N. K. Gonatas, Philadelphia, PA.) B: Sagittal T1-weighted image shows midline posterior fossa mass extending inferiorly, mimicking inferior vermis and cerebellar tonsil. Note the trapped fourth ventricle with herniation of the fourth ventricle upward through the tentorial notch. Axial T2-weighted (C) and fluid-attenuated inversion recovery (D) images confirm the presence of a midline mass dorsal to the fourth ventricle and demonstrate hydrocephalus and characteristic lowintensity reflecting hypercellularity of the tumor. E: Scattered irregular enhancement, as opposed to diffuse intense enhancement, is noted, which is rather typical of such hypercellular tumors, as in the category of the primitive neuroectodermal tumors.

Eighty percent of the PNETs involve the vermian tissue to some extent (8). Twenty percent arise 586

laterally in the cerebellar hemisphere without involvement of the vermis. It is thought that in the younger children, the vermis, the inferior medullar velum, is the primary source of origin, and in the adolescent and older patient, the superior cerebellar hemisphere is the site of origin. Tumors arising laterally in the adolescent and young adult tend to be more desmoplastic than those that arise in the vermis of the younger patient. Brainstem involvement is seen in up to 38% of patients, and the incidence of hydrocephalus in more than 90% in some series (19–21). Although cysts can be seen within the tumor from 20% to 80% of cases, they are less a feature of PNET and more typical of the cerebellar astrocytoma; in addition, in the PNET the cysts tend to be small. PNETs characteristically present with a brief period of symptoms. In one series, symptoms were present for less than 6 weeks in half of patients and less than 12 weeks in three-fourths of patients (15). The symptoms are due to hydrocephalus and consist of headache, irritability, vomiting, blurred vision, and frequently ataxia. In 10% or less, the neurologic picture is that of acute decompensation brought on by hemorrhage into the tumor, causing acute hydrocephalus or brainstem compression (8). Recent advances in molecular subgrouping of medulloblastomas have revealed important implications (22). Tumor location and enhancement patterns prove to be important imaging markers of subtypes. Group 3 and 4 tumors are midline fourth ventricular. Group 4 tumors have minimal to no enhancement. Sonic hedgehog tumors arise in the cerebellar hemisphere. Wingless tumors (WNT) arise in the cerebellar peduncle/cerebellopontine angle. These WNT have a good prognosis, whereas Group 3 tumors have worse survival. Modern imaging, along with improved surgical radiation and chemotherapeutic techniques, has resulted in an improvement in 5-year survival rates for patients with this tumor, from 30% in the 1960s to current rates of 50% to 70% (23). Computed Tomography CT can be an important diagnostic aid in characterization and differential diagnosis of PNET. On CT, the precontrast enhancement density is either isodense or slightly increased at the site of the solid portion of the tumor (9-7A) (24). Cystic portions are hypodense. Contrast enhancement occurs in 95% of cases. Eighty percent arise in the midline, involving the vermis to some extent. Hydrocephalus is present in greater than 90% of patients presenting with this type of neoplasm. Rarely—approximately less than 5% of the time—the increased density in the tumor may reflect an acute bleed. The typical precontrast increased density seen in the PNET of the posterior fossa reflects the high cellularity—the greater amount of nuclear material compared to relatively low cytoplasmic and extracellular content. Although grossly disseminated tumor can be identified on CT before and/or after the injection of contrast, CT is a poor modality for the detection of disseminated tumor when compared to the high sensitivity of contrast-enhanced MRI (Figs. 9.8B and 9.9).

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FIGURE 9.7 Primitive neuroectodermal tumor (PNET) of the cerebellum in a 2-year-old boy. A: Axial nonenhanced computed tomography. The tumor mass (arrows) is of greater density than the brainstem. B: Axial T2 magnetic resonance imaging (MRI). The tumor contains numerous small cysts. The solid component is relatively hypointense to cerebellum. C: Axial fluid-attenuated inversion recovery MRI. The tumor is mostly isointense to cerebellum. D: Axial T1, contrast enhanced and fat saturated. The tumor enhances. E: Axial diffusion MRI. There is decreased diffusion within the tumor.

FIGURE 9.8 Primitive neuroectodermal tumor disseminated to the spinal subarachnoid space at diagnosis with subsequent diffuse intracranial spread. A: Sagittal enhanced, fat-saturated T1 magnetic resonance imaging shows tumor enhancement (arrowheads) along the dorsal aspect of the thoracic cord. B: Ten months later, axial unenhanced computed tomography shows diffuse subarachnoid tumor seeding, seen as areas of increase density (arrowheads).

Magnetic Resonance Imaging A review of MRI findings in 42 consecutive Children’s Hospital of Philadelphia patients with posterior fossa PNETs revealed the tumors to be hypointense on T1 in 100%, isointense to the cerebellar folia on T2 in 95%, and contrast enhancing in 95% (unpublished data). There was restricted diffusion in 95% 588

(Figs. 9.6A–D and 9.7B–D). Although these tumors most often enhance intensely, they can also show irregular enhancement or even none at all (9-6E). These two findings (low signal of the solid portion on T2 and restricted diffusion) are distinguishing features from JPA when evaluating a macrocystic posterior fossa mass. In those cases showing only mild or no enhancement (Fig. 9.10), this distinction becomes obvious because intense enhancement is a hallmark of JPA. PNET tumors may also be found incidentally (Fig. 9.11). Heterogeneity within the tumor on MRI prior to injection of contrast material can be due to hemorrhage, cysts, or necrosis (Figs. 9.11 and 9.12). The tumors that showed restricted diffusion and thus were hyperintense on diffusion sequence were dark and decreased in signal intensity on the ADC map (9-7E). Measurements of ADC values for solid components of PNETs (range 0.67 to 0.99, mean 0.83 × 10−3 mm2/s) are consistently lower than those for ependymomas (range 1.0 to 1.3, mean 1.23 × 10−3 mm2/s) and can be useful for differential diagnosis (26). Proton spectroscopy shows evidence of malignant neoplasm by demonstrating a significant increase of choline relative to NAA, often a ratio of 3 or 4 to 1 (14). Taurine, an amino sulfonic acid, is also elevated in PNETs and may be demonstrated with proton spectroscopy performed with a short echo time of 20 to 35 ms. Taurine concentration in 13 patients with PNETs ranged from 2.62 to 11.15 mmol/kg with a mean of 6.09 ± 2.24. The mean concentration in 16 non-PNET tumors was 0.76 ± 0.95 mmol/kg. Thus, taurine concentration is another marker for the differential diagnosis of PNET from other tumors (27).

FIGURE 9.9 PNET dissemination. PNET tumor in 9 year-old girl that is disseminated throughout the subarachnoid space intracranially and intraspinally. A: Coronal T1 post gadolinium shows tumor in fourth ventricle and subarachnoid spread. B: Diffusion-weighted images show restricted motion of water in primary tumor as well as disseminated tumor. C,D,E: T1-weighted images of spine show disseminated tumor coating the spinal cord.

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FIGURE 9.10 A 5-year-old girl with vomiting. A: Axial T2-weighted image demonstrates large, partially cystic posterior fossa mass. Note that the solid component is low signal, that is, isointense to gray matter. B: Less than striking enhancement is also seen after intravenous contrast. The signal on T2 and the enhancement are typical of primitive neuroectodermal tumor (PNET) and not consistent with juvenile pilocytic astrocytoma as the diagnosis (surgically proven PNET).

MRI is a very important technique in the preoperative evaluation of PNETs because it is the only technique that shows the full extent of the primary tumor in all three planes (axial, coronal, and sagittal planes) and demonstrates with high sensitivity whether there is tumor dissemination. Dissemination may be present at the time of diagnosis prior to surgical resection in the cranial subarachnoid space, in the spinal subarachnoid space, and not infrequently at both sites (9-8A). In our experience, dissemination to the spinal subarachnoid space was present in 11% of cases at the time of the initial diagnosis of the posterior fossa PNET. In follow-up with a mean time of 2 years after surgical removal of the tumor, 22% of patients showed evidence of spinal dissemination (28). When there is tumor disseminated to the spinal subarachnoid space, there is significant morbidity and mortality, with 81% of patients dying within a median time of 10 months (Figs. 9.6 and 9.8) (28). Aggressive chemotherapy and radiation therapy have affected the survival rate but have not ultimately cured patients with disseminated disease. This brings up the question and controversy concerning surveillance neuroimaging: How effective is it, and how often and for how long should it be performed? The recommended interval between imaging studies is every 3 to 4 months during the first year and every 6 to 8 months in subsequent years, for a maximum of 7 to 8 years (23). Most medulloblastomas recur in close proximity to the primary tumor site with a mean time to recurrence of 13 to 15 months. The Great Ormand Street Hospital, London Sick Kids, and Toronto Sick Kids Hospital experiences have been that no child presents with recurrence of spinal disease alone without intracranial disease, and therefore their recommendation is only to do follow-up studies of the brain in those patients that did not have preoperative tumor dissemination or residual postoperative tumor (29).

FIGURE 9.11 Incidental primitive neuroectodermal tumor of the cerebellum. A 6-month-old boy with large head examined for possible benign enlargement of subarachnoid spaces. A: Axial T2 magnetic resonance imaging (MRI) reveals a small isointense mass (arrow) along the left side of the fourth ventricle. B: Coronal enhanced T1 MRI shows enhancement of the mass (arrow).

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FIGURE 9.12 Hemorrhagic primitive neuroectodermal tumor of restiform body (inferior cerebellar peduncle) presenting as an acute bleed. T2 magnetic resonance imaging shows marked hypointensity of the acute bleed. Surgery revealed a primitive neuroectodermal tumor as the etiology of the hemorrhage.

PNETs of the posterior fossa are divided into low risk and high risk based on patient’s age, tumor size, and metastatic stage. Low-risk tumors occur in patients older than 3 years, are up to 3 cm in the greatest dimension, and are without subarachnoid dissemination. High-risk tumors occur in patients younger than 3 years of age when radiation therapy is not feasible because of potential damaging effects of radiation therapy on the still-developing brain. These tumors are greater than 4 cm in the greatest dimension and have evidence of remote intraventricular or subarachnoid tumor dissemination. In case of low-risk tumors that have been completely resected and treated with both chemotherapy and radiation therapy, the 5-year survival rate is 75% to 80%. As part of the initial workup of patients with PNETs, not only is the brain examined preoperatively, but so is the spinal canal. The imaging protocol that we use for the spinal canal includes sagittal T2, sagittal T1, and contrast-enhanced sagittal and axial T1 of the entire spinal canal. Obtaining just sagittal contrast-enhanced images is fraught with difficulty. The tumor adherent to the pial surface of the spinal cord or nerve roots is best seen in the axial projection, and there may only be a question of metastasis raised on the basis of the sagittal images. In addition, when the spinal canal is examined only postoperatively, there can be issues because of an extent of hemorrhage into the spinal canal from the surgery in the posterior fossa. The high T1 signal intensity of blood products may mimic disseminated tumor on an enhanced study. There can also be the postoperative development of subdural hygromas that extend from the posterior fossa down through the spinal canal and tend to accumulate contrast material within them, confusing the picture of whether there is spinal dissemination of tumor. Furthermore, in the region of the cauda equina, fatty lipomas of the filum terminale may mimic disseminated tumor on post-enhanced image, especially if no pre-enhanced study is available for comparison. In the follow-up of patients who have undergone surgery for posterior fossa PNET, the routine is to get immediate postoperative study to exclude any residual tumor. The subsequent followup is done as previously stated. A particularly difficult issue is the evaluation of the non–contrast-enhancing PNET either in the brain or spinal canal, not only preoperatively, but also postoperatively, where less than gross dissemination of tumor may be very difficult to recognize (30). Techniques other than enhanced MRI may aid in recognition, such as relatively high-resolution diffusion imaging, looking for areas of restricted diffusion involving the subarachnoid space or ventricular lining. It remains to be seen whether newer targeted contrast agents or emerging molecular imaging methods can play a role in characterizing these tumors. Patients who survive long term are at risk of radiation-related injury (Fig. 9.13) and secondary neoplasms, such as meningiomas and glioblastoma multiforme (GBM). Atypical Teratoid/Rhabdoid Tumor Atypical teratoid/rhabdoid tumor is a highly malignant tumor that arises not only in the CNS but also in the kidney and other organs. It occurs at a younger age than PNET and is categorized also as a WHO grade IV tumor, but it is more malignant, and if it originates in the CNS, it carries a very poor prognosis; survival is rare (30–33). The appearance on both CT and MRI is similar to that of PNET (Fig. 9.14) (34). In fact, histologically, there often are large areas of PNET within the ATRT tumor (31). However, in addition, there are areas of rhabdoid cells that appear quite different from the PNET component. ATRTs comprise 1.3% of pediatric CNS tumors (35). They comprise 6.7% of CNS tumors in 591

patients less than 2 years of age (34). By location, 35% to 65% are in the infratentorial region, 27% to 62% supratentorial, and 4% to 8% are both supra- and infratentorial in origin, that is, multifocal (30–32). Dissemination at diagnosis is present in between 15% and 34% of cases (31,32). One year after treatment, an additional 35% of tumors have disseminated (34). MRI studies positive for tumor dissemination have a concurrent incidence of positive cytology on CSF examination in just over half (56%) of cases (34). The survival rate at 1 year is 71% and at 5 years is 28% (34). Clues that the tumor is of ATRT type are clinical, with the age at the onset of the tumor being very young. These tumors also show a tendency to occur in the cerebellar pontine angle or medullary pontine angle, appearing like an extraaxial mass, not infrequently hemorrhaging and projecting into the foramen magnum.

FIGURE 9.13 Radiation injury/necrosis. A 12 year-old girl many years post radiation therapy for PNET. A,B: Axial FLAIR images show abnormal hyperintensity at sites of white matter injury. C: T1 axial image post contrast shows bilateral enhancement of middle cerebellar peduncles.

FIGURE 9.14 Posterior fossa atypical teratoid/rhabdoid tumor in a 10-month-old boy. A: Axial fluid-attenuated inversion recovery magnetic resonance imaging (MRI). Tumor mass is isointense to cerebellum, with higher signal surrounding edema. B: Axial enhanced T1 MRI. There is irregular enhancement of the tumor.

Ependymomas of the Posterior Fossa Posterior fossa ependymomas represent from 10% to 20% of pediatric posterior fossa tumors, or up to 8% of all pediatric brain tumors and 1.7% of all childhood cancers. The peak age incidence is between 3 and 6 years, with a second peak occurring in the middle years of adult life (36). The tumor arises within the fourth ventricle, extending into and through the outlets and the foramina of Luschka and the foramen Magendie, and giving impression of a plastic tumor mass (Fig. 9.15). Ependymomas are welldifferentiated, moderate cellular gliomas with perivascular pseudorosettes, rare mitoses, and occasional areas of necrosis, hemorrhage, and calcification (Fig. 9.16). They are classified as WHO grade II. The overall incidence of ependymomas is 2.2 per million per year (20,21,37). Younger than the age of 5 years the incidence is 3.9 per million, and older than the age of 5 years the incidence is 1.1 per million. Forty percent of the cases occur younger than the age of 4 years, and 80% occur younger than the age of 8 years (38,39). There is no gender bias. Two-thirds of the cases occur in the posterior fossa and one-third in the supratentorial brain. This is a tumor that is not usually disseminated at the time of diagnosis, the incidence being approximately 5% (38,40). In general, local recurrence occurs, in 90% or more of the cases, before the tumor disseminates (41). The median time between tumor diagnosis and 592

recurrence is 22 months (8). Dissemination occurring after initial diagnosis and before local recurrence is unusual, only 7% to 8% of cases (42). However, once the tumor has recurred locally and continues to grow, then dissemination becomes more likely, reaching 24% of cases. Dissemination often leads to death. In a series of 52 children with ependymoma, recurrences developed in 54%, with a median time from surgery to first recurrence of 14.5 months. Forty-three percent of recurrences were asymptomatic, having been picked up on surveillance imaging (43). Thus, surveillance imaging is recommended after the immediate postoperative study for residual disease every 3 to 6 months for the first year and every 6 months for the next 4 years (43). If tumor recurs, then spinal imaging should also be performed.

FIGURE 9.15 Ependymoma fourth ventricle. A 11 month-old girl. A: Axial T2-weighted image shows a mixed signal intensity mass in the lateral recess of the fourth ventricle on the left. B: Susceptibility-weighted image (SWI) shows evidence of bleeding within the tumor mass. C: Postcontrast T1-weighted axial image shows inhomogeneous contrast enhancement.

FIGURE 9.16 Ependymoma, microscopic features. A: Histologic specimen shows cells with small bland nuclei and fibrillary eosinophilic matrix. B: Nuclear free areas, especially in perivascular regions, and tapering of fibrillary processes around blood vessels are characteristic features of ependymomas.

Poor prognostic factors include patient age younger than 2 years, a short history of symptoms prior to presentation, presence of brainstem and cranial nerve deficits, lateral location of tumor, and high Ki-67 immunolabeling index (43). The 5-year progression-free survival for ependymomas is 36% to 64% (44). The 10-year progressionfree survival is only 47% to 48% (44). In the posterior fossa, the most favorable circumstance for an ependymoma is one that is still localized within the fourth ventricle, not extending through the outlets, and not involving the cranial nerves or blood vessels that lie lateral and anterior to the brainstem. A completely resected ependymoma of the fourth ventricle stands a good chance of cure on the basis of surgery alone. Radiation and chemotherapy, although commonly used, are not by themselves curative. The 10-year actuarial local control for gross total resection and radiotherapy was 100%, for just gross total resection it was 50%, and for subtotal resection and radiotherapy it was only 36%. Computed Tomography Ependymomas are known for the production of calcification and for a tendency to bleed. Thus, with both CT and MRI, there is often an inhomogeneity to the tumor before and after contrast material injection. On a pre-enhanced CT, the appearance of an ependymoma is that of a mass of mixed density (45–48). The mixed higher densities seen within the tumor can represent calcification or hemorrhage (Fig. 9.17). It is the localization within the fourth ventricle and the mixed densities that characterize the ependymoma. Contrast enhancement on CT is often inhomogeneous (Fig. 9.18) (45–48). Hydrocephalus 593

is frequently present and depends on obstruction of the fourth ventricle or aqueduct of Sylvius. Extension of tumor through the outlets of the fourth ventricle into the cerebellopontine angle, in front of the brainstem, or down along the dorsal aspect of the cervical spinal cord may be visible on CT but is better seen on MRI.

FIGURE 9.17 Ependymoma of the fourth ventricle. Axial noncontrast computed tomography (CT) shows a mass in the fourth ventricle containing calcifications producing hydrocephalus.

Magnetic Resonance Imaging The MRI appearance of the ependymoma is that of mixed T1 signal intensity, the high signal intensity not infrequently being the result of blood products or calcium within the tumor (48–50). On MR images the ependymoma is seen filling and distending the fourth ventricle (Fig. 9.15) and extending through the outlets (Figs. 9.18 and 9.19). On T2-weighted images, the intensities again are often quite variable, consisting of both increased and decreased signals (Figs. 9.15 and 9-20A). Again, it is the mixture of calcifications, blood products, and tumor that contributes to this inhomogeneity. Contrast enhancement is also typically inhomogeneous (Figs. 9.15 and 9-20B). Critical to the preoperative evaluation is the delineation of the extent of the tumor, determining how far the tumor goes outside the fourth ventricle, whether it extends lateral and/or ventral to the brainstem, and whether it projects inferiorly along the cervical spinal cord. Any tumor that remains postoperatively will regrow and potentially can lead to death.

FIGURE 9.18 Ependymoma of the fourth ventricle. Contrast-enhanced computed tomography shows intrafourth ventricular mass with irregular contrast enhancement.

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FIGURE 9.19 “Plastic” ependymomas in two patients. A: Sagittal T1-weighted magnetic resonance imaging (MRI) (600/20). B: Sagittal T1-weighted MRI (600/20) with contrast enhancement. Masses (arrows) extend downward through the foramen magnum and mimic tonsillar herniation. Note the extensive enhancement of the second patient’s tumor after gadolinium (B). C: Axial T2-weighted MRI (6,000/99) shows a fourth ventricular mass extending through the foramina of Luschka bilaterally (arrows).

As part of the preoperative MRI evaluation, both the brain and the spinal canal are examined, but the yield in the spinal canal is limited. In the postoperative follow-up of tumor, both CT and MRI play an important role in searching for residual tumor, which may be seen as calcification on CT (9-21A) or as enhancement on MRI (9-21B). Residual tumor, whether local or distant from the original site of surgery, may initially be difficult to detect. Small areas of tumor seeding from an ependymoma to the ependymal surface of the ventricular system, such as the lateral ventricles, often will not show contrast enhancement in the early stages of growth. Only when the tumor develops a larger blood supply will start to enhance (Fig. 9.22). A tumor that persists and grows over time eventually will seed to the subarachnoid space not only intracranially, but also in the spinal canal. As these tumors grow, they often become hemorrhagic. Proton spectroscopy is a useful adjunct to the imaging studies because ependymomas have a different spectrum than do astrocytomas and PNETs, with preservation of creatine, elevation of choline, and decrease in NAA (14). The creatine is not preserved in PNET and astrocytoma. Choroid Plexus Papilloma Choroid plexus tumors comprise 2% to 4% of pediatric brain tumors (35), and 10% to 20% of those that arise in the first year of life (35,51). For every six choroid plexus tumors, one is a carcinoma and five are papillomas. At the time of presentation, 80% occur in patients less than 2 years of age (52). Overall, there is equal distribution between males and females. Forty percent arise in the fourth ventricle, with a slight male predominance, 3:2. Our experience has been that in the fourth ventricle, the tumors have been CPPs and not carcinomas. Choroid plexus carcinomas (CPCs) are more common in the lateral ventricles. In the posterior fossa, the choroid plexus tumor produces obstruction leading to hydrocephalus. With both supra- and infratentorial tumors, excess production of CSF is possible, resulting in hydrocephalus as well (53). Bleeding from the tumor into the ventricle can also lead to hydrocephalus by causing adhesions and obstruction of the CSF pathways. CPP of the fourth ventricle is most often cured by surgical procedure. Any benign tumor, if disrupted during the surgical procedure, can disseminate into the spinal canal or into the cerebral subarachnoid space.

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FIGURE 9.20 Ependymoma of the fourth ventricle in a 4-year-old boy. A: Axial T2 magnetic resonance imaging shows a heterogeneous hyperintense mass extending into the left Luschka foramen (arrow). B: Axial T1 postgadolinium image shows irregular enhancement.

FIGURE 9.21 Residual ependymoma in two patients. A: A 2-year-old girl. Unenhanced computed tomography reveals calcification in the residual tumor. B: A 7-year-old boy. Enhanced T1 magnetic resonance imaging shows a contrast-enhancing tumor (arrow) in the left cerebellopontine angle.

Computed Tomography CPP of the fourth ventricle lies within the fourth ventricle and usually does not extend through the foramina into the adjacent subarachnoid space, as is the case with the ependymoma. The tumor is usually of uniform increased density on CT and enhances intensely and homogeneously (9-23A) (54). The size is variable, from quite small—not much larger than the choroid plexus itself—to one that completely fills and distends the fourth ventricle. Magnetic Resonance Imaging The CPP typically on T1 is a hypointense mass, and it is usually somewhat hyperintense on T2 with focal hypointensities within it reflecting some of the blood flow that is quite rich within this tumor (Fig. 9.23B,C) (55). The enhancement pattern is typically homogeneous and bright (9-23D). Often, the appearance of the tumor has a characteristic cluster-of-grapes morphology (Fig. 9.24) that resembles the overall appearance of native choroid plexus. After a negative postoperative study, there is usually no further need for significant follow-up and no need to examine the spinal canal. Brainstem Gliomas The exact incidence of tumors arising within the brainstem is not known because the sensitivity of MR in detection of small tumors, particularly in the midbrain, is unfolding. Overall incidence is 10% to 20% of all pediatric braintumors (56,61). Most of the literature has been devoted to the classic pontine glioma, a tumor that occurs most often between 5 and 6 years of age, is diffusely infiltrating, and tends to run a malignant course with a life expectancy not exceeding 14 months (57). Chemotherapy has not shown any role in increasing survival, and radiation therapy, the preferred method of treatment for diffuse pontine gliomas, extends life only by several months (57,58). The prognosis of a brainstem tumor depends on its site of origin, whether it arises in the midbrain, pons, and medulla, and to a lesser extent on how it appears (59,60).

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FIGURE 9.22 Ependymoma dissemination into the lateral ventricle, early and late changes. A: Axial enhanced T1 magnetic resonance imaging (MRI). A nonenhancing nodule (arrow) is noted adhering to the wall of the left lateral ventricle. B: One year later, coronal enhanced T1 MRI shows multiple enhancing nodules of disseminated tumor.

FIGURE 9.23 Choroid plexus papilloma of the fourth ventricle in two patients. A: Axial unenhanced computed tomography shows a small dense mass (arrow) in the inferior fourth ventricle. B: Sagittal T1 magnetic resonance imaging (MRI), hypointense fourth ventricular mass. C: On coronal T2 MRI, a hyperintense mass occupies the fourth ventricle. D: Sagittal enhanced T1 MRI reveals intense enhancement of the mass.

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FIGURE 9.24 A 4-year-old girl with headaches. Sagittal T1-weighted (A) and axial T2-weighted (B) images show characteristic lobulated morphology of an intraventricular choroid plexus papilloma within the third and lateral ventricles. Note the marked enhancement after intravenous contrast on axial postcontrast T1-weighted images (C).

FIGURE 9.25 Pilocytic astrocytoma of the pons in a 17-year-old girl. A: Axial T2 magnetic resonance imaging (MRI) shows a left-sided, well-demarcated, high-signal-intensity mass in the pons. B: Sagittal enhanced T1 MRI shows diffuse contrast enhancement of the mass. C: Apparent diffusion coefficient (ADC) map MRI shows increased diffusion within the tumor mass.

A recent multicenter clinicopathologic reappraisal of brainstem tumors divided the tumors into fibrillary astrocytomas, which involve the ventral pons and present with abducens palsy and have a grim prognosis, and focal brainstem gliomas, often pilocytic astrocytomas, which arise outside of the ventral pons and have a tendency to exophytic growth, long clinical prodrome, and good survival (Fig. 9.25). The prognosis is clearly influenced by any underlying predisposing disease state, for example, NF1, in which the pontine gliomas have a much more benign and prolonged course than in non-NF1 598

patients. In general, tumors arising in the midbrain have a tendency to be indolent and of low-grade astrocytic nature, for which the treatment is often just shunting of the hydrocephalus that is secondary to the aqueductal occlusion (Fig. 9.26) (59,60). The tumors are followed by imaging, and if the tumor shows enlargement over time, then therapy in the form of chemotherapy and/or radiation therapy may be undertaken. The main problem with the midbrain tumors is that they can be mistaken for aqueductal stenosis on CT, where they can be missed and not detected until an MRI is performed. In addition, there can be a problem in differentiating a tumor of the tectal plate from a pineal region tumor because both may occupy the same space. When in doubt, the appropriate markers need to be obtained to rule out a germinoma, or on occasion it may be necessary to obtain a biopsy to differentiate the two. For the most part, tumors of the midbrain can be diagnosed on the basis of their location and MRI appearance. A subset of these tumors can extend into the thalamus, and these tend to have a less benign course, mainly related to their thalamic component. Midbrain tumors may eventually grow to involve the pons or cerebellum through the superior cerebellar peduncles, findings that are less frequent. Most pontine gliomas are diffuse infiltrating tumors that have a tendency to extend through the middle cerebellar peduncle into the cerebellar hemisphere, superiorly into the midbrain, and then up into the internal capsule or inferiorly into the medulla (Fig. 9.27). Although biopsy may show that the histology is low grade, the vast majority of these pontine diffusely infiltrating neoplasms behave as malignant tumors over the course of time (62). They frequently progress from a diffusely infiltrating tumor showing no enhancement to one having focal enhancement and then with diffuse enhancement and necrosis. These tumors are treated aggressively with both chemotherapy and radiation therapy; the radiation therapy appears to have the greatest benefit, albeit temporary. A reduction in size following radiation therapy is often achieved, but in subsequent months, regrowth and further expansion of the tumor occurs. Focal well-defined benign tumors can arise within the pons. The one that carries the best prognosis is the PA of the pons. It typically appears either as a focal contrast-enhancing mass or as one associated with a cyst. For these tumors, surgical removal is appropriate if the tumor is accessible, and radiation therapy for residual tumor may achieve long-term results.

FIGURE 9.26 Tectal glioma in a 7-year-old girl. A: Sagittal T2 magnetic resonance imaging (MRI) shows obliteration of the aqueduct by a high-signal mass. B: Axial fluid-attenuated inversion recovery MRI shows abnormal high signal (arrow) in the dorsal midbrain. C: Sagittal T1 MRI after contrast material injection shows no evidence of contrast enhancement at the site of the mass.

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FIGURE 9.27 Malignant pontine brain stem glioma in a 6 1/2-year-old boy. A: Sagittal T2 magnetic resonance imaging (MRI). There is abnormal increased signal in the markedly expanded pons. B: Axial fluid-attenuated inversion recovery MRI shows that the abnormal increased signal in the pons extends into the left cerebellum. C: Axial enhanced T1 MRI shows irregular contrast enhancement within the pontine mass.

FIGURE 9.28 Exophytic medullary brain stem tumors in two patients. A: Axial enhanced T1 magnetic resonance imaging (MRI) shows a noncontrast-enhancing mass (arrow) with an exophytic component projecting into the left internal auditory canal. B: Axial enhanced T1 MRI shows an exophytic contrast-enhancing tumor (arrow) extending from the right side of the dorsal medulla.

Tumors arising in the medulla tend to be different from the pontine tumors, in that they have a much higher incidence of low-grade features and a much lower incidence of high-grade features (62). They may extend into the cervical cord, but when they extend into the pons, they tend to be more aggressive. Medullary tumors have a higher incidence of exophytic growth than do pontine tumors (Fig. 9.28). Contrast enhancement of a medullary tumor does not necessarily mean an aggressive tumor. Radiation and chemotherapy are used, with radiation probably providing the greatest benefit. Computed Tomography On a nonenhanced CT, one-third of the pontine tumors are hypodense, one-third are isodense, and onefourth are mixed density, both decreased and isodense. Only 5% of tumors are of increased density, with the increased density representing either calcification or blood, and the hemorrhagic focus usually indicating a malignant zone within the tumor (Fig. 9.29) (46,63). Masses that are predominately 600

hyperdense, with or without surrounding focal edema, should be considered as possible cavernomas and can be further characterized and confirmed to be cavernomas on the MRI. In pontine gliomas, contrast enhancement is quite infrequent at presentation and quite common at or prior to death. In one series of 119 patients, contrast enhancement was present at presentation in 25% (57). Hydrocephalus is relatively infrequent in pontine tumors and was present in 23% of the 119 patients (57). In this same series of patients, necrotic areas were found initially in only 16% (57). In contrast to pontine and medullary tumors, hydrocephalus is the common presenting finding in patients with midbrain tumors.

FIGURE 9.29 Anaplastic brainstem astrocytoma. Computed tomography (A) and T1-weighted magnetic resonance imaging performed before (B) and after (C) injection of contrast material demonstrate a grossly expanded brainstem that obliterates the ventral prepontine cistern, compresses the fourth ventricle, envelopes (“encases”) the basilar artery, and causes obstructive hydrocephalus. Images in panel C show an irregular, thick-walled ring enhancement within the pontine mass.

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FIGURE 9.30 Brainstem astrocytoma infiltrating into the cerebellar hemisphere. A: Axial T1-weighted magnetic resonance imaging (MRI) (600/30) with contrast enhancement. B: Axial T2-weighted MRI (3,000/90). Seen is an expansion of the pons and effacement of the left side of the fourth ventricle by a poorly defined nonenhancing infiltrative mass (A) that extends from the brainstem into the cerebellar hemisphere (arrows, B). C: Gross specimen from a similar case shows striking enlargement of the pons and lower brainstem with basilar artery “encasement.” (Courtesy of Dr. N. K. Gonatas, Philadelphia, PA.)

Magnetic Resonance Imaging Regardless of the location within the brainstem, most of these gliomas have similar signal intensities on T1, FLAIR, and T2 (Figs. 9.30 and 9.31) (50,63,64). That is, like most astrocytic tumors elsewhere in the brain, they are hypointense on T1, and hyperintense on T2 and FLAIR. High signal on both T1 and T2 raises the question of blood products within the tumor, as should hypointensity on T2 or gradientecho T2* images (Figs. 9.27 and 9.32). Bleeds within a pontine tumor seen on MRI often are at the same site where contrast enhancement occurs and usually are at the site of malignant degeneration in the diffusely infiltrating pontine gliomas (Fig. 9.29). The mass that shows a rim of hemosiderin hypointensity on T2 or T2* should be thought of as a cavernoma of the brainstem and followed with imaging. Infratentorial Tumors in Pediatric Patients: Basic Differential Considerations A thoughtful approach needs to be taken when evaluating a pediatric patient with a posterior fossa mass if the radiologist wants to go beyond simple identification of a lesion, a task that our referring clinical colleagues can perform on their own in most cases. First, there is always a differential diagnosis in terms of tumor versus other, nonneoplastic etiologies. Other etiologies are demyelinating disease, which is most often multifocal but can be manifest as a solitary masslike focus, and infection, such as an abscess or a cerebritis. These entities are most often differentiated on the basis of clinical findings and the acuteness of the illness, as well as the likelihood of certain diseases within a population, such as tuberculosis being more common in some developing nations versus primary tumors of the brainstem. Infarction is usually a straightforward clinical diagnosis, and in the posterior fossa in children it often involves a differential diagnosis of vertebral artery dissection or, less commonly, embolic disease from sources such as congenital heart disease. Inborn errors of metabolism, such as maple syrup urine disease, can produce swelling of the brainstem and/or cerebellum. Again, these usually can be differentiated on a clinical basis and tend to have a certain symmetry in distribution that tumors do not have. When a mass is present and a neoplasm is a likely possibility, localization is the first step. Does the mass involve the brainstem or the cerebellar hemispheres, or both? Can it be determined where the tumor has arisen and where it has extended? What is the age of the patient at presentation; is the patient an infant, a child, or an adolescent? How rapidly have the symptoms developed, or is it an incidental finding? These factors, combined with the imaging findings, help to narrow the differential diagnosis. Multiple questions should be answered on the basis of the images. If it is a CT, what is the pre-enhancement density of the mass? Does the mass appear cystic or solid? Is there hemorrhage or calcification, and does the mass enhance, and, if so, where? With both CT and MRI, one is constantly on the lookout for other lesions such as subarachnoid spread of tumor or clues that the mass identified is part of a more diffuse process, such as NF1 or NF2. With MRI the interpretation should focus on signal intensity changes with T1, FLAIR, and T2, diffusion characteristics, and enhancement pattern. Proton spectroscopy is a useful aid in further narrowing the differential diagnosis.

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FIGURE 9.31 Classic brainstem astrocytoma. A: A bulky homogeneous mass that expands the collicular plate and causes marked hydrocephalus is seen on a sagittal T1-weighted magnetic resonance image. B: No enhancement is seen. C,D: T2-weighted images confirm the intraaxial location of the mass and show homogeneous signal intensity, characteristic of an astrocytoma.

FIGURE 9.32 Hemorrhage within a brain stem glioma in a 7-year-old girl. A: Sagittal T1 magnetic resonance imaging (MRI) shows regions of hemorrhage (arrowheads) within the tumor as high signal intensities. B: Axial T2 MRI shows blood within the tumor as focal hypointensity (arrow).

SUPRATENTORIAL TUMORS Based on results from modern imaging techniques, supratentorial tumors are more common than infratentorial tumors in the pediatric population. This is inclusive of hemispheric tumors, intraventricular tumors, pineal tumors, and sellar/suprasellar tumors (2,66,67). Gliomas are the most frequently diagnosed tumor type, accounting for 60% of all supratentorial hemispheric tumors (2,65,66). Their clinical presentation is more diverse than that of the infratentorial tumors (8). Most often, seizures or symptoms of mass effect bring the patient to clinical attention. In approaching supratentorial tumors it is easiest to classify them according to their location. Cerebral Hemispheric Tumors in Children Gliomas Gliomas are classified according to their cell of origin as astrocytomas, oligodendrogliomas, and ependymomas. The WHO classification assigns grades based on histologic picture, which is believed to predict the growth potential and invasiveness. Pilocytic Astrocytomas The WHO classifies PA as a grade 1 tumor. There is virtually no evidence of malignant degeneration 603

within this type of tumor. It does not change its aggressiveness with time. A PA that can be surgically excised is considered cured. If residual tumor is left postoperatively, it will grow eventually with time. As with any tumor of the CNS, this tumor, if it gains access to the subarachnoid space or to the intraventricular space, can seed and eventually grow, but not aggressively (Fig. 9.33). Pilocytic astrocytomas that arise in the supratentorial space are the most common glial-origin tumors in the pediatric population. They commonly occur in the optic chiasm, hypothalamus, and optic nerves and most often are associated with the predisposing syndrome of NF1. By age 20 years, optic gliomas are found in between 5% and 15% of NF1 patients (67). Tumors arising within the diencephalon are most often pilocytic astrocytomas and comprise between 4% and 6% of all pediatric brain tumors. They can also arise within the cerebral hemispheres, with signal and density characteristics that are analogous to those occurring in the cerebellar hemispheres. Thus, they can be both cystic and solid, and they can grow as a mural nodule or form a rim around a cyst. They may or may not show contrast enhancement. A tumor that contrast-enhances on one examination may not do so on the next, and vice versa. The change in contrast enhancement from examination to examination does not necessarily indicate a change in aggressiveness or response to treatment, if such was given. Tumor response is measured by a change in tumor size—either a response to therapy with a reduction in tumor volume or a failure of therapy with an increase in the size of the tumor mass. These are tumors that exude proteinaceous fluid from their surface, often producing locules of fluid, giving rise to cysts on the surface of the tumor (Fig. 9.34). The cysts can be more problematic as a mass effect than the solid portion of the tumor (Fig. 9.35). The cysts can dissect into the surrounding brain tissue, displacing structures. The tumor can grow into the cyst, eventually filling it with tumor tissue.

FIGURE 9.33 Chiasmal/hypothalamic pilocytic astrocytoma with dissemination (pathologically proven). Enhanced T1weighted images show a suprasellar mass (A) with extensive intracranial leptomeningeal nodular enhancement (B– D). Spinal seeding is also noted along the entire spinal cord and cauda equina (E,F). Despite diffuse dissemination, the patient continues to do well clinically. (Courtesy of Dr. Linea Fredrikkson, Portland, OR.)

Tumor dissemination occurs with chiasmatic hypothalamic pilocytic astrocytomas in approximately 2% to 5% of cases at the time of diagnosis, and over the course of follow-up it may be seen in up to 12% of patients at some point. Five-year progression-free survival for patients with diencephalic gliomas exceeds 85% in some series (68). NF1 in association with the diencephalic glioma is a favorable 604

prognostic factor because the tumors tend to remain stable on imaging (67). Ten-year survival rates when resection or resection and radiotherapy are used are on the order of 82% at both the 10- and 20year follow-ups. After the total removal of the tumor, 10-year tumor-free survival periods reach 100% (67,68). COMPUTED TOMOGRAPHY. The solid portion of the tumor is hypodense relative to cortex, and the cystic portion of the tumor is even more hypodense. The solid portion shows contrast enhancement if it has a disturbed BBB. Pilocytic astrocytomas have a significant blood supply. MAGNETIC RESONANCE IMAGING. Typically, the solid portion of these tumors is hypointense on T1 and hyperintense on FLAIR and T2 (9-36A) (67). The contrast enhancement is usually brisk (9-33B). Diffusion imaging shows increased motion of water throughout the tumor with elevated ADC values. Proton spectroscopy shows a mild elevation of choline relative to NAA and relative preservation of creatine. Follow-up is based on whether the tumor has been totally resected. If there is a residual tumor, then follow-up is necessary. Follow-up for such a low-grade tumor can be done relatively infrequently at either 6-month or 1-year interval. Pilomyxoid astrocytoma (PMA) once considered a PA variant is now a distinct entity of its own. Predilection for the suprasellar region is 60% (hypothalamic), are large, well-delineated masses, occurring in infants and young children, that behave more aggressively (WHO2) with a tendency to disseminate into the CSF pathways. PA tends to occur in older children and in patients with NF1, disseminate infrequently and are less aggressive (WHO1). The imaging features of density, intensity, and enhancement on CT and MRI of the PMA are nonspecific relative to the PA. Young age, large size, more often solid, and tendency to disseminate are helpful in the differential diagnosis (Fig. 9.37) (69,70). With SWI there is a higher incidence of blood products in the PMA (20%) than in the PA.

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FIGURE 9.34 Pilocytic astrocytoma, chiasm–hypothalamus. A,B: Bulky suprasellar mass with enlargement of the pituitary fossa, subfrontal and prepontine extension, and dense enhancement (B) in a child suggests the diagnosis of juvenile pilocytic astrocytoma. C,D: Characteristic cystic and solid components are best seen on the axial images both before (C) and after (D) injection of contrast material. E: Coronal images demonstrate how difficult it is to distinguish chiasmal from hypothalamic origin.

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FIGURE 9.35 Cystic pilocytic astrocytoma. A: Axial T1-weighted magnetic resonance imaging (MRI) (600/20). B: Axial T2-weighted MRI (3000/90). C: Axial T1-weighted MRI (600/20) with contrast enhancement. D: Coronal necropsy specimen. (From Okazaki H, Scheithauer B. Atlas of Neuropathology. New York: Gower Medical, 1988, with permission.) The thalamic–hypothalamic mass is partially cystic and has a solid mural nodule (arrows, A–C), which densely enhances (C). Note the typical solid nodule within the partially cystic left temporal neoplasm (D) from a different patient with a similar lesion.

Ganglioglioma GG is classified by the WHO as type 1 tumor in the vast majority of cases, that is, extremely low grade (Fig. 9.38). It comprises 1.3% of pediatric brain tumors, and the mean age at presentation is around 9.5 years (71). The age range is from 6 months to 80 years (72). The tumor is characterized by slow growth, resulting in a long clinical history, with seizures being the most common symptom (73,74). GGs have been found to be the structural lesions underlying chronic temporal lobe epilepsy in up to 20% to 40% of patient cohorts undergoing neurosurgery (73,74). They are most frequently located in the temporal and frontal lobes, but they may be found almost anywhere else within the brain (73,74). In our experience, 50% are cystic and 50% are solid (Figs. 9.39 and 9.40). Fifty percent show contrast enhancement (9-39B) (Table 9.2). Thirty-three percent show calcifications (Fig. 9.41) (75). It is the combination of the long history of seizures and the benign appearance on imaging that enables the radiographic diagnosis. The temporal lobe was the most common site for both groups, with both a larger mean tumor volume and a higher incidence of cystic change in the younger patients (83% vs. 63%). Imaging features reported in the literature include cyst formation in 35% to 55% of cases, calcifications in 35%, and contrast enhancement in 50%. Differential diagnosis includes PA and the pleomorphic xanthoastrocytoma (PXA).

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FIGURE 9.36 Pilocytic astrocytoma in a 10-year-old boy. A: Axial fluid-attenuated inversion recovery magnetic resonance imaging (MRI) shows left thalamic high–signal-intensity mass with a peripheral cyst. The mass produces hydrocephalus. B: Coronal enhanced T1 MRI shows contrast enhancement of the mass.

FIGURE 9.37 Pilomyxoid Astrocytoma. A 13 month-old boy. A: Axial T2-weighted image shows a homogeneously T2 bright well-defined mass in the hypothalamus. B: Coronal T1-weighted postcontrast image shows homogeneous contrast enhancement.

Luyken et al. (76) reported a series of 184 GG patients with a median follow-up of 8 years, of which 97% presented with long-term seizures (greater than 2 years). Seventy-nine percent of tumors were located in the temporal lobe and 12% in the frontal lobe. Of the 184 tumors, all but 13 were WHO grade 1. Of those 13, 11 were WHO grade 2, and 2 were WHO grade 3. All were operated on, and residual tumor was present in 21%. Calculated 7.5-year recurrence-free survival rate was 97%. WHO grade 1 tumor patients and patients with completely resectable temporal lobe tumors do the best. Radiotherapy is reserved for recurrent or progressive disease. No responses to chemotherapy have been reported. WHO grade 3 GGs are rare and appear more aggressive (Fig. 9.42).

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FIGURE 9.38 Ganglioglioma, histopathologic features. A: Microscopic features of this slow-growing tumor include a well-circumscribed mass often with an extensive fibrocollagenous component. B: Gangliogliomas typically contain neuronal cells with abnormal morphology, often binucleated “ganglion” cells (center). C: Neurofilament stain is positive for cells of neuronal origin. D: Glial fibrillary acidic protein–positive astrocytes indicate the most actively proliferating component of the tumors.

FIGURE 9.39 Gangliogliomas, cystic and solid, in two patients. In an 8-year-old girl with seizures (A) sagittal T2 magnetic resonance imaging (MRI) shows a high–signal-intensity cystic cavity with surrounding tumor (arrows) (B) sagittal enhanced T1 MRI shows peripheral enhancement of the tumor (arrows). C: In an 18-year-old woman with seizures, axial fluid-attenuated inversion recovery MRI shows in the posterior left frontal region a small high–signalintensity solid mass that scallops the inner table of skull.

FIGURE 9.40 Gangliogliomas, one enhancing and one not, in two patients. A: A 5-year-old girl. Coronal enhanced

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T1 magnetic resonance imaging (MRI) shows a solid enhancing left-sided mass spanning the temporal lobe and the basal ganglia. B: A 12-year-old boy. Axial enhanced T1 MRI shows a right frontoparietal mass that does not enhance.

TABLE 9.2 Pediatric Supratentorial Hemispheric Neoplasms

FIGURE 9.41 Ganglioglioma with calcification in a 13-year-old girl with left hemiparesis since birth. Axial unenhanced computed tomography shows a large right temporal lobe mass with extensive calcification.

Desmoplastic Infantile Ganglioglioma Desmoplastic infantile ganglioglioma (DIG) is a WHO grade I variant of the GG that arises in infants with a median age between 5 and 6.5 months. The tumor originates superficially from pia and cortex, so that the solid portion of the tumor lies peripherally within the mass, with the mass effect being due to both the solid portion and the typically large cyst located deep to the solid tumor. DIGs are large frontoparietal superficial tumors that show avid contrast enhancement on both CT and MRI (Fig. 9.43) (76). They invade the leptomeninges. Surgical resection can usually be accomplished and results in a 5year survival and even longer, approaching 100% survival. On CT, the cyst is hypodense, approaching CSF in density, and the solid portion of the tumor is slightly denser than the CSF and cyst fluid; after contrast material injection, it shows prominent enhancement. The mass effect is proportional to both the solid and cystic portions of the tumor. On MRI, the solid portion of the tumor is isointense to hypointense on T1 and isointense to slightly hyperintense on T2, and again shows avid contrast enhancement (Fig. 9.44) (77). Although these tumors are more frequently cystic, solid ones have been described, and whereas they are usually large, small ones have also been found.

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FIGURE 9.42 Anaplastic ganglioglioma. A 3-year-old boy. A: Axial FLAIR image shows large left cerebral hyperintense mass obliterating left lateral ventricle. B: Axial T1 post contrast shows minimal irregular enhancement. C: Axial ADC shows restricted motion of water consistent with more aggressive tumor.

FIGURE 9.43 Desmoplastic infantile ganglioglioma. A: T1-weighted magnetic resonance imaging (MRI) (600/20). B: T2-weighted MRI (3000/80). C: Contrast-enhanced computed tomography. D: Histopathologic specimen from a different patient, fibrin stain. (From Okazaki H, Scheithauer B. Atlas of Neuropathology. New York: Gower Medical, 1988, with permission.) Marked heterogeneity in a right hemispheric mass reflects cystic areas, solid tumor, and extensive fibrocollagenous matrix (arrows, A,B). The fibrocollagenous region is hypointense on T2-weighted image (B). Note the marked enhancement of the solid and desmoplastic components of the tumor (arrows, C). The extensive fibrocollagenous material in these lesions (dark-staining areas, D) can masquerade as an extraaxial mass.

Pleomorphic Xanthoastrocytomas PXA is a tumor of mixed neuronal and glial origin that is most commonly seen in the second decade of life; it is classified by the WHO as grade II, rarely grade III (78). These tumors account for less than 1% of all astrocytic neoplasms. Two-thirds of patients are younger than age 18 years, and there is no gender predilection. PXAs typically are large superficial hemispheric masses that frequently are cystic. From the pathologic viewpoint, they present a more difficult differential diagnosis due to the presence of large multinucleated cells and bizarre chromatin patterns and the fact that the tumor, being superficial in location, frequently invades the pia and arachnoid (Fig. 9.45). The cytoplasm of the cells is often vacuolated, representing spaces occupied by fat globules. Prominent mesenchymal or desmoplastic 611

features are usually present (79). However, there is an absence of mitoses. Although these tumors have an unusual histologic picture, they should not be mistaken for malignant tumors. The tumors can recur and demonstrate aggressive behavior, with a mortality rate between 15% and 20%. Recurrence-free survival was 72% at 5 years and 61% at 10 years, with an overall survival of 81% at 5 years and 70% at 10 years. PXAs arise in the supratentorial space, involving the temporal and frontal lobes most frequently. They are peripheral in location, and cysts are present in approximately one half (80). The CT and MRI appearances are not unlike those of the DIG; however, the age at presentation is quite different, with PXA occurring in later childhood. The mass is often solid, with a deeper cystic component, without significant surrounding edema. The solid portion of the mass enhances both on MRI and CT (Figs. 9.45A,B and 9.46) (80,81). Dysembryoplastic Neuroepithelial Tumor Dysembryoplastic neuroepithelial tumor (DNET) is an uncommon, slow-growing, quasi-hamartomatous tumor that occurs in the older child. The average age at diagnosis and the onset of seizures, which is the most common clinical presentation, are 9 years of age. The neurologic examination is usually normal. The tumor most frequently arises in the supratentorial brain, the temporal lobe being the most common site, but it can occur at other sites involving the cortex and subcortical white matter. These tumors are thought to represent 1.2% of brain tumors in individuals young than age 20 years, and are more common in males than females (82). The only effective treatment for the DNET is surgical resection. It comprises 0.8% to 5% of masses removed when surgery is performed as treatment for epilepsy.

FIGURE 9.44 Desmoplastic infantile ganglioglioma. A: Coronal T2-weighted image shows large left hemispheric cystic mass with peripheral solid tumor tissue (arrow). B: Sagittal enhanced T1-weighted image shows enhancement of the solid component of the tumor (arrow).

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FIGURE 9.45 Pleomorphic xanthoastrocytoma. A: Contrast-enhanced computed tomography. B: Coronal T1weighted magnetic resonance imaging after intravenous contrast. C: Histopathologic specimen. An enhancing lesion (A,B) with a subjacent cyst (B) is the typical appearance of pleomorphic xanthoastrocytoma. On pathology (C), hematoxylin and eosin stain shows extreme nuclear and cytoplasmic pleomorphism, including large hyperchromatic nuclei and multinucleated cells and lymphocytic infiltrate. (From Lipper M, Eberhard D, Phillips C, et al. Pleomorphic xanthoastrocytoma, a distinctive astroglial tumor: neuroradiologic and pathologic features. AJNR Am J Neuroradiol 1993;14:1397–1404, with permission.)

FIGURE 9.46 Pleomorphic xanthoastrocytoma in two patients. A: In a 5-year-old girl, axial enhanced T1 magnetic resonance imaging (MRI) shows a solid contrast-enhancing parietooccipital mass. B: In an 11-year-old boy, sagittal enhanced T1 MRI shows a partially cystic contrast-enhancing frontal mass.

Nolan et al. (83) reported 26 children with DNETs treated at the Hospital for Sick Children in Toronto. Of these, 73% had complex partial seizures and the rest had simple partial seizures (23%) or generalized seizures. Characteristic features on imaging were present in 20 (77%), whereas 6 had an atypical, more diffuse mass. Contrast enhancement occurred in one half. Tumors were located in temporal lobes in 38%, frontal in 31%, parietal in 23%, and occipital in 8%. The strong association of DNET with dysplasia supports the hypothesis that these tumors arise from precursor cells during cortical development. Histochemical studies demonstrate varying stages and pathways of oligodendroglia-like cell differentiation in the DNET. In one series, 86% of operative specimens contained some element of cortical dysplasia. Postoperatively, despite surgical resection, a 613

large portion of patients continue to have seizures. Pathologically, these tumors are classified as WHO grade I and are composed of glioneuronal elements; the columns of tumor cells are perpendicular to the cortical surface (82). Bundles of axons lined by oligodendroglioma-like cells are present. Grossly, these tumors appear to be viscous tumors with glioneural nodules and cortical expansion. A classic DNET involves just the cortex and does not contrast-enhance (Figs. 9.47 and 9.48). A less typical tumor involves not only the cortex, but also the subadjacent white matter, and shows contrast enhancement. On CT, DNETs appear as hypodense masses. On MRI, on T1-weighted sequence they show focal punctate hypointensities within the substance of the mass, seen as cystlike areas on T2-weighted images (Fig. 9.47) (83,84). These tumors frequently have a gyriform configuration (Fig. 9.49). On FLAIR, these may be hyperintense lesions. On diffusion, they do not restrict, but rather show increased motion of water. When they are superficially located, remodeling of bone in the overlying calvarium may be present. The differential diagnosis includes GG, low-grade cortical astrocytoma, and oligodendroglioma. Fibrillary Astrocytomas Fibrillary astrocytomas are tumors that are more frequently seen in the adult population. In the pediatric patient, these most commonly arise in the supratentorial brain and involve the white matter to a greater extent than the gray matter, but they may be seen in the basal ganglia and thalamic regions as well. They are diffusely infiltrating tumors without clear-cut margins. Pathologically, firmness of the white matter is noted, with a relatively white appearance to the brain tissue, and there is increased number of astrocytes without evident mitoses and with little vascular proliferation. Cystic change can occur and calcification can be present, but this is less frequent than just the finding of a diffusely infiltrating mass. In most tumors with little vascular proliferation, there is usually no contrast enhancement. However, in tumors that have a greater degree of vascular proliferation, contrast enhancement can occur. Pathologically, fibrillary astrocytomas can vary from WHO grade 1 to an anaplastic category when malignant degeneration occurs within the tumor. Treatment by surgery is successful if the entire tumor can be removed. However, often tumor extends beyond the obvious origins seen on imaging. When residual tumor is present, progression usually occurs within a 4- to 5year interval from the time of the initial treatment. Recurrence is almost always local.

FIGURE 9.47 Dysembryoplastic neuroepithelial tumor in a 15-year-old boy with seizures. A: Sagittal T1 magnetic

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resonance imaging (MRI) shows a left temporal lobe mass arising from the cortex and projecting into the adjacent white matter. The mass (arrows) contains a micronodular pattern of hypointensities. B: Axial fluid-attenuated inversion recovery MRI shows nodular hypointensities with mass. C: Axial T2 MRI. The mass (arrows) is of high signal with focally brighter areas. D: Axial enhanced T1 MRI. The mass shows no enhancement.

FIGURE 9.48 Residual dysembryoplastic neuroepithelial tumor in a 13-year-old boy at 3 years postresection. A: Sagittal T1 magnetic resonance imaging (MRI) shows three residual tumor nodules lining the operative cavity. B: Axial fluid-attenuated inversion recovery MRI. The tumor nodule is isointense (arrow). C: Coronal T2 MRI shows the tumor nodule (arrow). D: Coronal enhanced T1 MRI. There is no enhancement of the residual tumor (arrow).

FIGURE 9.49 Dysembroplastic neuroepithelial tumor (DNET). 11 year-old boy with seizures. A: Axial T2 shows welldemarcated T2 hyperintense mass in the left posterior temporal lobe without mass effect. B: Axial T1 post contrast, there is no enhancement.

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FIGURE 9.50 Fibrillary astrocytoma in a 13-year-old girl. A: Axial unenhanced T1 magnetic resonance imaging (MRI) shows a slightly hypointense left thalamic mass, which causes hydrocephalus. B: Enhanced axial T1 MRI shows a focal area of enhancement within the tumor.

COMPUTED TOMOGRAPHY. Fibrillary astrocytoma appears on CT as a mass of decreased density arising typically within the white matter or central gray matter, usually without contrast enhancement, although some tumors may enhance. Calcification is more frequently seen when the tumor involves the central gray matter (Fig. 9.50). With time, as malignant degeneration occurs, contrast enhancement becomes more marked, the surrounding vasogenic edema becomes more pronounced, and the mass effect increases. The follow-up enhanced MRI is probably the best modality for demonstrating tumor degeneration into a malignant neoplasm. MAGNETIC RESONANCE IMAGING. The MRI appearance of the fibrillary astrocytoma is that of a poorly defined increased signal intensity mass on T2 and FLAIR arising in the supratentorial white matter or central gray matter (Fig. 9.51). When the tumor involves the cortical gray matter, differentiation from cortical dysplasia may be difficult. Vuori et al. (85), in a series of 18 patients with seizures and cortical brain lesions on MRI, found on proton magnetic resonance spectroscopy that decrease in NAA and an increase in choline were more pronounced in low-grade gliomas (LGGs) than in focal cortical dysplasias. Contrast enhancement is variable and often not prominent, and when present, it should raise a suspicion of a more aggressive neoplasm, one that is anaplastic. Tumor margins are generally better defined on MRI than on CT, but tumor may be located in regions where there is no signal intensity change (Fig. 9.51). MRI is the most sensitive tool for follow-up to demonstrate residual and recurrent tumors. Once malignant degeneration has occurred, intraventricular and subarachnoid spread of tumor can occur. Gliomatosis Cerebri Gliomatosis cerebri (GC) is a neoplasm that can occur in the first two decades but is more common in adults. This is a diagnosis made by the radiologist because the small sample examined for histopathology is not the basis of the diagnosis; rather, it is based on the extent of the lesion on imaging or necropsy. Clinical symptoms are typically discordant with the size of the lesion because the MR often demonstrates a much more impressive mass within the brain than the symptoms would indicate. Seizure is the most common presenting symptom (38%), followed by hemiparesis (23%). These tumors are diffusely infiltrating tumors found predominately in the white matter, but they also may extend into the central gray matter and up to the cortex (Fig. 9.52). The WHO further defines GC as involving at least two cortical lobes with preservation of anatomic architecture and sparing of neurons (85). GC may be unihemispheric, but not infrequently with time it becomes bihemispheric. The WHO classifies these tumors into two types. Type 1 exhibits the diffuse infiltrating enlargement of affected structures with no focal mass effect. In type 2, there is a diffuse lesion with a focal mass effect, which is a malignant glioma (9-52E) (86). Our experience with these tumors indicates that they begin as a type 1 and eventually become type 2, with the tumor undergoing malignant degeneration (Fig. 9.52). Histologically, these tumors are composed of elongated glial cells that resemble astrocytes that infiltrate the myelin tracts. There is variable mitotic activity. Microvascular proliferation is typically absent, so that neurons and axons survive. In the early stages of the tumor, contrast enhancement is not seen (952B). Early, there is no mass effect as such but an overall increase in the volume of infiltrated tissue. In Armstrong et al.’s (86) series of 13 children with GC, 47% progressed within the first year, and none 616

survived beyond 6 years.

FIGURE 9.51 Fibrillary astrocytoma in a 13-year-old girl. A: Axial T2 magnetic resonance imaging (MRI) shows a mixed-signal-intensity mass involving the frontal lobe, which causes pressure deformity of the adjacent calvarium. B: Axial enhanced T1 MRI. There are multiple areas of enhancement within the tumor mass.

FIGURE 9.52 Gliomatosis cerebri in an 11-year-old boy who presented with seizure. A: Axial T2 magnetic resonance imaging (MRI) shows an extensive high–signal-intensity mass throughout the right hemisphere. B: Axial enhanced T1 MRI. The tumor does not enhance at this time. C: Five years after diagnosis, axial unenhanced computed tomography shows a hypodense mass. D: Ten months later, axial fluid-attenuated inversion recovery MRI shows the tumor to be much more extensive than at the time of diagnosis. E: Axial enhanced T1 MRI. There are focal areas of enhancement in the posterior temporal and occipital lobes on the right.

COMPUTED TOMOGRAPHY. Initially it may not be possible to detect GC on CT. The hypodensity within the white matter (9-52C) may be difficult to appreciate. The mass effect on the ventricles and sulci and cisterns may be subtle. Therefore, MRI is the method of choice for identifying this neoplasm. MAGNETIC RESONANCE IMAGING. On MRI, GC is visualized as increased signal intensity within the affected structures and is best seen on FLAIR and T2 (Fig. 9.52A,D) (87). At presentation, type 1 does not contrast-enhance (9-52B). Surgical biopsy by needle is often unsuccessful with this tumor. It is easy to miss the tumor and obtain only normal white matter. A removal of a portion of tissue, such as a partial temporal lobectomy when the temporal lobe is involved, will yield the pathologic diagnosis. We 617

have used proton spectroscopy quite successfully in this tumor. The elevation of choline relative to NAA with preserved creatine indicates that there is indeed a diffusely infiltrating tumor of the brain tissue. Galanaud et al. (89) used proton spectroscopy to differentiate GC from LGGs. Their findings were that GC had higher levels of creatine and NAA and a lower level of choline than LGGs. This tumor may be mistaken in its early stages for cortical dysplasia, demyelinating disease, and viral encephalitis, among others. In the later stages, with type 2 GC, the diffuse tumor contains a focal mass, a malignant glioma, and the appearance is that of the GBM commonly seen in the adult (Fig. 9.52D,E). Glioblastoma Multiforme Glioblastomas comprise 8.8% of tumors in children (1). Their appearance is identical to that seen in the adult. They are highly aggressive tumors, with poor patient survival, especially for tumors arising in the first 3 years of life when radiation therapy is not used and therapy consists of chemotherapy and surgery. Because these tumors are highly vascular and the new tumor blood vessels are abnormal, intratumoral hemorrhage is not uncommon. Indeed, when a child presents with a hemorrhagic mass, glioblastoma should be considered as a possibility, as well as PNET and atypical teratoid rhabdoid tumor. Of course, the differential diagnosis of a hemorrhagic mass includes nonneoplastic processes such as arteriovenous malformations (AVMs), coagulopathies, and cortical vein and venous sinus thromboses. The incidence of high-grade gliomas in the pediatric population is 0.13 per 100,000 children (88). There is a slight male predominance. Five-year event-free survival is 18% with radiotherapy, and with radiotherapy and chemotherapy, it is 26% to 46%. For children younger than the age of 3 years the response rate when treated with chemotherapy is 6%. Without treatment, median progression-free survival is 6 months, and with radiation it is 12 months (89–91).

FIGURE 9.53 Subependymal giant cell astrocytoma, microscopic sections. A: Features of these lesions associated with tuberous sclerosis consist of diffuse proliferation of astrocytes within a fibrillary, partially vacuolated background. B: At higher magnification, note the heterogeneity of cells with small and very large astrocytic nuclei and abundant cytoplasm.

Subependymal Giant Cell Tumors Subependymal giant cell tumors (SGCTs) are relatively rare tumors that occur most often in association with tuberous sclerosis (TS), with an incidence between 6% and 18% in children with this syndrome, but they also can be seen in patients without TS (92–94). These tumors arise from subependymal nodules, which are present in 88% to 95% of individuals with TS (6). The incidence of TS is 1 in 5,800 live births. Although SGCTs may be diagnosed in utero with fetal MRI or by ultrasound, the usual age at presentation with TS is between 2 and 20 years. Although these tumors possess histologic features seen in high-grade astrocytomas, such as endothelial proliferation, mitoses, and necrosis, their behavior is indolent (Fig. 9.53) (8). They are of mixed glioneuronal lineage (93). Gross total resection is the treatment of choice (95). Growth of a subependymal nodule noted from study to study indicates the development of SGCT. This occurs typically near the foramen of Monro, and therefore eventually hydrocephalus develops. Contrast enhancement of the mass is the rule, but enhancement alone does not prove the presence of SGCT (Figs. 9.54 and 9.55). Hypointensity on T2 is also nonspecific because calcification and iron deposition are present in both subependymal nodules and tumors. Primitive Neuroectodermal Tumors of the Supratentorial Brain Supratentorial PNETs are highly malignant tumors that have a mean age at presentation of 5.5 years, occur in a male-to-female ratio of 2:1, and represent 5.6% of PNETs of the CNS (96,97). Over the years these tumors have been designated by a variety of names, including pineoblastoma, ependymoblastoma, 618

neuroblastoma, and retinoblastoma. In many instances, the different names reflected different locations of the tumors. These WHO grade 4 tumors are composed of undifferentiated neuroepithelial cells, with large nuclei and scant cytoplasm (Fig. 9.56). These PNETs that arise within the cerebral hemisphere involve the white matter and cortex and basal ganglia to varying extents. Survival is approximately onethird with surgical resection and aggressive treatment with radiation and chemotherapy (96). Pineoblastoma is discussed later under pineal tumors.

FIGURE 9.54 Subependymal giant cell tumor in an 8-year-old girl. A: Axial unenhanced computed tomography (CT) shows a partially calcified subependymal mass at the foramen of Monro. B: Axial CT postcontrast shows intense enhancement of the mass.

FIGURE 9.55 Subependymal giant cell tumor in a 16-year-old boy. A: Axial fluid-attenuated inversion recovery magnetic resonance imaging (MRI) shows a large, high-intensity subependymal mass at the right foramen of Monro, causing hydrocephalus. B: Sagittal enhanced T1 MRI. The tumor enhances intensely.

Computed Tomography The appearance of supratentorial PNET on CT is similar to that seen with the PNET (medulloblastoma) of the posterior fossa, with the exception of a higher incidence of calcification, which approaches 50% to 70% (98), and also a higher frequency of large cysts and necrosis. The tumors are isodense to hyperdense prior to contrast material injection (Figs. 9.57A and 9.58). Calcification may be present (Fig. 9.59). They typically contrast-enhance and exert a mass effect on the ventricles and sulci. When dissemination occurs, it may or may not be visible with CT, but it is better evaluated by enhanced MRI. Magnetic Resonance Imaging Similar to the posterior fossa PNET, the solid nonhemorrhagic portion of the supratentorial PNET is isointense to cortex on FLAIR, and on T2 it shows decreased diffusion with decrease in ADC values; it contrast-enhances in 95% of cases (Figs. 9.57B–E and 9.60) (25). MRI is the method of choice for localization and delineation of the extent of the PNET, as well as for demonstration of subarachnoid and intraventricular spread of tumor. Proton spectroscopy is a useful adjunct to imaging, by demonstrating markedly elevated choline and depressed NAA. MRI is the preferred method of follow-up for evidence of residual tumor, recurrent tumor, and subarachnoid dissemination. The greatest difficulty in the evaluation of these tumors occurs when the original tumor is not a contrast-enhancing form of tumor. In such a case, tumor dissemination typically also does not enhance. Diffusion imaging may be extremely 619

useful in such circumstances, by demonstrating high signal at sites of disseminated nonenhancing tumor. With supratentorial PNETs, evaluation of the spine for dissemination is important both before and after surgery.

FIGURE 9.56 Pineoblastoma. The histologic specimen shows marked hypercellularity throughout the tumor with infiltration by poorly differentiated cells with scant cytoplasm. (Courtesy of Dr. Alexander Mark, Washington, DC.)

Supratentorial Atypical Teratoid Rhabdoid Tumor Atypical teratoid and rhabdoid tumors are highly malignant and occur both infratentorially and supratentorially, being relatively evenly divided between the two compartments. Ninety-four percent of them are intraaxial. The signal intensity and diffusion characteristics of supratentorial ATRT are similar to those of the supratentorial PNET (Fig. 9.61). Calcification demonstrated by CT is seen in approximately 50% of cases, and spectroscopy is similar to that of the PNET. Their CT appearance also is not dissimilar from that of PNET (34). Supratentorial Ependymomas Supratentorial ependymoma has an appearance that is similar to that seen in the posterior fossa with one important exception, that is, it most frequently arises in the white matter and not in the ventricle. In the posterior fossa, it is always an intraventricular and/or cerebellar pontine angle mass. In the supratentorial brain, it is most frequently a hemispheric, cerebral white matter tumor, and rarely an intraventricular tumor. Shuangshoti et al. (101) reported 32 cases of supratentorial extraventricular ependymal neoplasms. Age at diagnosis ranged from 9 months to 75 years, with 47% in the second or third decade of life. No gender predilection was present. Left cerebral hemisphere involvement was more prevalent than right (3:2), with frontal lobe location being 38%, parietal 22%, and parietooccipital 13%. A cystic lesion with or without a mural nodule was the most frequent finding (42%). Histology was subependymoma in 2 cases, ependymoma in 19, and anaplastic ependymoma in 11. No correlation was found between clinical outcome and histologic or biological parameters (99). Median survival time for this series of patients was 8.6 years.

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FIGURE 9.57 Supratentorial primitive neuroectodermal tumor. A: Axial unenhanced computed tomography. The mass in the left hemisphere (arrows) is variably hyperdense. B: Axial T2 magnetic resonance imaging (MRI). The solid portion of the mass (arrows) is isointense to the cortex. C: Coronal fluid-attenuated inversion recovery MRI. The mass (arrows) is predominately isointense to cortex. D: Axial enhanced T1 MRI. Only the medial portion of the tumor enhances. E: Axial diffusion MRI. The mass shows decreased diffusion.

FIGURE 9.58 PNET supratentorial CT hyperdense tumor, noncontrast-enhanced.

Computed Tomography Fifty percent or more of the ependymomas have evidence of calcification in the tumor (Figs. 9.62A and 9.63) (98). The supratentorial ependymomas tend to be large at presentation and are often necrotic, with solid tumor surrounding the necrotic area. Contrast enhancement is frequent (9-54B). These tumors can present as an intracerebral hemorrhage and thus can mimic an AVM. Follow-up is important to demonstrate that there is a neoplasm at the site of the hemorrhage. Magnetic Resonance Imaging The MR appearance of the supratentorial ependymomas is again similar to that of the posterior fossa 621

ependymoma, with the exception of their location, which typically is within white matter. They tend to hemorrhage and frequently calcify (Fig. 9.64). They are inhomogeneous on T1, T2, and FLAIR, and they contrast-enhance (Fig. 9.65). Follow-up of these tumors is critical because any residual tumor after surgery can lead to death if it is not removed. Tumors do not respond to radiation or chemotherapy in a satisfactory way. Any residual tumor will eventually grow, and once it gains access to the ventricle or subarachnoid space, it will disseminate.

FIGURE 9.59 Supratentorial primitive neuroectodermal tumor. Serial computed tomography images show a huge mass in the right hemisphere with internal calcifications, hyperdense regions suggesting hypercellularity, and a possible invasion of the posterior portion of the superior sagittal sinus. It is difficult to determine whether this lesion is intraaxial or extraaxial.

Supratentorial Hemispheric Tumors As in the posterior fossa, there is a broad differential diagnosis for supratentorial masses arising within the cerebral hemisphere. Whenever blood products are present, vascular causes of bleeding need to be considered. Both hemorrhagic tumors and ruptured AVMs can present acutely and may be difficult to differentiate on CT or on routine MRI, especially if the nidus of the AVM is compressed by the hematoma. Large cavernomas, with multiple different ages of blood products, produce significant mass effect and may be mistaken by the uninitiated for an aggressive neoplasm. Inflammatory disease in children is often associated with much more edema than that seen in adults, and a giant multiple sclerosis plaque or more focal area of encephalitis can easily mimic a neoplasm. Excision of inflammatory disease is not often indicated when treatment with appropriate drugs would contain the disease process. Under such circumstances, where uncertainty exists, tincture of time, with close monitoring with imaging, may be very important.

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FIGURE 9.60 PNET supratentorial. A 2-year-old boy. A: Axial CT, noncontrast-enhanced, shows a hyperdense right hemispheric mass. B: Axial T2 image shows the solid portion of the mass to be isointense to the cortex. C: Coronal T1, postcontrast, shows enhancement. D: Axial DWI shows restricted motion of water.

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FIGURE 9.61 Pineal rhabdoid tumor. T1-weighted (A) and T2-weighted (B) images demonstrate a bulky, complex, hemorrhagic mass in the pineal region that invades the thalamus. Diffuse but somewhat heterogeneous enhancement (C) is identified on coronal images.

FIGURE 9.62 Supratentorial ependymoma. A: Axial unenhanced computed tomography (CT). There is a necrotic tumor mass with calcification in the solid rim. B: Axial enhanced CT. The solid portion of tumor, the rim, enhances.

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FIGURE 9.63 Ependymoma supratentorial. A 6-year-old boy. Axial CT, noncontrast, shows large right cerebral mass with foci of calcification and extensive surrounding vasogenic edema.

FIGURE 9.64 Ependymoma supratentorial. A 15-year-old girl. Axial T2 shows a hypointense mass in the left cerebrum due to intratumoral bleeding, with surrounding vasogenic edema.

Extraaxial Tumors Tumors that arise outside of the cerebral hemispheres, diencephalon, cerebellum, and brainstem are considered in a separate category. Anatomically, a tumor may be in the posterior fossa, supratentorial space, or both when it involves a large portion of skull base. Specific anatomic sites are recognized, including tumors that are intraventricular, pineal, sellar/suprasellar, and skull base in origin. Of these, the sellar/suprasellar tumors are the most frequent in the pediatric population, and this is primarily because of inclusion of intraaxial low-grade astrocytomas that arise in the hypothalamus–visual pathway, most often in association with NF1. Choroid Plexus Papilloma and Carcinoma The CPPs have already been discussed in connection with the posterior fossa tumors. These tumors represent only 2% to 4% of pediatric brain tumors (35). They occur most frequently during the first years of life (35,51) and are more common in the lateral ventricles. In the lateral ventricles, there are five papillomas for every carcinoma. The mean age for presentation of CPC is 2.2 years (100,101). CPCs are aggressive tumors, 80% of which occur in the lateral ventricle, with an incidence of 82% of hydrocephalus (101). Subependymal invasion is present in 73% of CPCs, and dissemination is present at diagnosis in 45% (101). Gross total resection is the only effective cure. Five-year survival rates of between 26% and 43% have been reported. Differential diagnosis includes CPP, central neurocytoma, ependymoma, PNET, and ATRT (102,103).

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FIGURE 9.65 Supratentorial ependymoma. A: Axial T2 magnetic resonance imaging (MRI). There is a large left hemispheric hyperintense tumor with surrounding edema. B: Coronal enhanced T1 MRI. There is enhancement of the wall of the necrotic tumor. C: Axial T2 MRI from a different patient than shown in panels A and B reveals a hypointense bleed along the posterior portion of the necrotic left parietal tumor.

FIGURE 9.66 Choroid plexus papilloma in three patients. A: Axial computed tomography. There is a hyperdense right lateral ventricular mass. The lateral and third ventricles are dilated from excess cerebrospinal fluid production. B: Axial T2 magnetic resonance imaging (MRI) shows a huge intraventricular papillary mass with focal hypointensities that traps the right occipital and temporal horns of the right lateral ventricle. C: Coronal enhanced T1 MRI. There is intense enhancement of the left atrial intraventricular mass.

Computed Tomography On CT, both CPCs and CPPs appear as high-density intraventricular masses that contrast-enhance. These tumors are often associated with hydrocephalus, whether due to obstruction of CSF pathways or overproduction of CSF (9-66A) (53). Extension of CPC through the wall of the ventricle and subarachnoid spread is better appreciated on MRI than on CT (9-67A). The CPPs remain within the confines of the ventricle and have a multilobulated appearance (54).

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FIGURE 9.67 Choroid plexus carcinoma. A: Axial contrast-enhanced computed tomography. There is a large enhancing mass with surrounding edema within the left hemisphere. B: Axial T2 magnetic resonance imaging (MRI). The mass is hypointense and surrounded by edema. C: Axial enhanced T1 MRI. There is intense enhancement of the mass. D: Sagittal enhanced T1 MRI shows subarachnoid spread of the tumor.

FIGURE 9.68 Third ventricular CPP. A 6-month-old girl. Sagittal T1 post contrast shows contrast enhanced third ventricular mass.

Magnetic Resonance Imaging Both CPPs and CPCs have a heterogeneous appearance on T1 and T2 images (Figs. 9.66B and 9-67B). This is due to their high vascularity, with vascular flow voids identified in 55% of CPCs, and with blood products of various ages seen in 45% to 55% of CPCs (101). Contrast enhancement is intense in both CPPs and CPCs (Figs. 9.66C, 9.67C, and 9.68). MRI best shows extension of tumor through the ventricular wall in CPCs (73%) and the lack of such in CPPs (101). Subarachnoid and intraventricular tumor disseminations are best demonstrated on contrast-enhanced T1-weighted sequence (9-57D). Pineal Tumors 627

Tumors of the pineal region comprise between 3% and 8% of all pediatric brain tumors (Table 9.3) (8). A cyst in the pineal gland is a frequent normal finding (Fig. 9.69A–D), and typical pineal cysts do not require follow-up imaging. A large cystic pineal tumor that is 1.5 cm or more in diameter should be viewed with suspicion, but if there is no solid component that extends beyond the margins of the normal pineal shape, the “lesion” is still highly likely to represent a cyst, even with significant mass effect. It may be reasonable to follow up a very large pineal cyst at least once with imaging. Because there is no BBB in capillaries of the pineal, the pineal gland normally enhances. Calcification within the pineal, seen on CT, is not normal before age 6 years. After age 6 years, and especially as a child approaches puberty, calcification becomes quite common and more prominent. TABLE 9.3 Pineal Region Tumors

In the pediatric age group, the most common pineal tumor is the PNET, which usually occurs in younger children in the first decade of life and with an equal gender predilection. In the second decade of life, the most common tumor of the pineal gland is the germinoma. Most of these represent a typical germinoma, a tumor that is easily treatable with radiation and chemotherapy. Less frequently, more malignant variations of the germinoma occur—nongerminomatous germ cell tumors, embryonal cell carcinoma, yolk sac tumor, choriocarcinoma, or malignant teratoma (104). Except when totally excised, generally these are not curable tumors (104). These pineal tumors tend to occur almost exclusively in males. The germinoma, teratoma, and choriocarcinoma have a suprasellar variant. Whereas in the pineal region the germinoma occurs predominately in males, in the suprasellar region the germinoma may be more frequent in females (8). Most children with pineal tumors have a rapid clinical course, with diagnosis within 1 month of onset of symptoms (105). Mass lesions of the pineal present most often with headaches and nausea due to hydrocephalus caused by an obstruction of the aqueduct of Sylvius. They may also present with Parinaud syndrome, consisting of vertical gaze paralysis and pupillary dilation if the mass exerts pressure on the tectum of the midbrain (8). Computed Tomography The demonstration on CT of abnormally early calcification of the pineal, that is, before the age of 6 years, especially if there is any soft tissue component surrounding it, should raise the concern that a pineal tumor is present (9-70A). The bilaterality of congenital retinoblastoma raises the possibility of trilateral retinoblastoma with a pineoblastoma of the pineal gland, which is histologically identical to retinoblastoma in the eye (106). During the first decade of life, this same type of pineal tumor—the pineoblastoma—occurs more frequently not in association with retinoblastoma, but as a solitary tumor within the pineal gland. Calcification in the pineal region again can be present, and the mass is often of increased density relative to the surrounding brain (107). Contrast enhancement is common. As the tumor enlarges and produces a mass effect, obstruction of the CSF pathways at the site of the posterior third ventricle or aqueduct of Sylvius is common, producing hydrocephalus. The resultant increased intracranial pressure with nausea and vomiting may be the mode of presentation. Because of the pressure by the tumor on the collicular plate, downbeat nystagmus may also occur.

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FIGURE 9.69 Pineal cyst. A: Sagittal T1-weighted magnetic resonance imaging (MRI) (600/20). B: Axial T1-weighted MRI (800/30) with contrast enhancement. Note the minimal dorsal enhancement (arrows), representing residual normal pineal parenchyma, choroid, or veins. C,D: Histologic specimens of a small pineal glial cyst demonstrate the nature of this common finding, which is derived from cystic degeneration within the glial element of the pineal gland.

Magnetic Resonance Imaging Pineoblastoma is similar on MRI to the medulloblastoma in the posterior fossa and the supratentorial cerebral PNET. It is hypointense on T1, isointense on FLAIR, and relatively isointense on T2 (Figs. 9.70B and 9.71) (108,109). The tumor shows some tendency for hemorrhage. Contrast enhancement is usual (Fig. 9.70C,D). Hydrocephalus is frequent. Diffusion is restricted with bright signal on diffusion sequence and dark signal on ADC. Choline is markedly elevated on proton spectroscopy, indicating malignancy. Germinoma Intracranial germinomas constitute 1% to 2.5% of primary intracranial neoplasms. They are most frequent in the pineal and suprasellar areas and much less frequent in the basal ganglia (Figs. 9.72 and 9.73) (110,111). The germinoma of the pineal gland tends to occur in teenage boys, has CT and MR appearances that are almost identical to those of PNET, and, for the most part, is not distinguishable from it by imaging (Figs. 9.74 and 9.75A–D). Age and gender of the patient help in the differential diagnosis, as do the markers obtained from the cerebrospinal fluid, once hydrocephalus has been controlled by intraventricular cannula. Germinoma consists of uniform undifferentiated cells with large nuclear lined clear cytoplasm and with mitoses and lymphocytes (9-75E). Unlike the teratoma, the germinoma is a homogeneous-appearing tumor (Table 9.3). The pineal teratoma, whether it is benign or malignant, has a greater tendency toward heterogeneity due to the presence of various types of tissue within the tumor, which include ectoderm, mesoderm, and endoderm. Consequently, the teratoma may have fat, calcification, and a variety of other substances (Fig. 9.76). The benign teratomas of the pineal tend to present later in adolescence, whereas the malignant ones are rapidly growing tumors that tend to present in the first year of life. In the series of Moon et al., pineal and suprasellar germinomas ranged in size between 1.2 and 4.5 cm, and the basal ganglionic ones were larger (112). Within 2 weeks of completion of radiation therapy, tumor size was decreased in all patients by 85% to 100% (112). In this same series, 52% of the tumors had some cystic component, and the cystic component showed slower response to therapy than did the solid portion of the tumor. 629

Pineal Region Tumors The most frequent issue that arises concerning the pineal gland is the presence of a pineal cyst, a common benign finding. Only occasionally is such a cyst large, and only rarely may it cause a minimal mass effect. Referring physicians become concerned when the radiologist emphasizes the need for follow-up, which in most cases is not needed. Spontaneous bleeding into the pineal cyst can occur and can alter the signal intensity on T1 and T2, so that it does not follow the signal of CSF.

FIGURE 9.70 Pineoblastoma, pineal primitive neuroectodermal tumor. A: Unenhanced computed tomography. Abnormal, partially calcified pineal mass produces hydrocephalus. B: Axial T2 magnetic resonance imaging (MRI) shows a relatively hypointense pineal mass eccentric to the left and producing hydrocephalus. C: Axial enhanced T1 MRI shows intense enhancement of the mass. D: Sagittal enhanced T1 MRI demonstrates the enhanced pineal mass.

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FIGURE 9.71 Pineoblastoma. A 14-month-old boy. A: Sagittal T2 image shows a isointense to cortex large pineal mass. B: Proton MRS shows marked elevation of choline and decrease in Naa. C: T1 axial image post contrast shows no contrast enhancement.

FIGURE 9.72 Pineal and suprasellar germinoma. Suprasellar nodularity and pineal mass on unenhanced T1weighted images (A,B) show enhancement with nodular solid features after administration of contrast material (C,D).

FIGURE 9.73 Suprasellar hemorrhagic germinoma. A: Sagittal T1-weighted magnetic resonance imaging (MRI) (600/20). B: Axial T2-weighted MRI (2500/80). the intra- and suprasellar mass (arrows, A) elevates the chiasm and hypothalamus. Note the intratumoral hemorrhage on T2-weighted image, with intracellular deoxyhemoglobin (open arrows, B) layering posteriorly, in the periphery of an otherwise homogeneously low intensity mass (closed arrows, B).

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FIGURE 9.74 Pineal germinoma. Pineal mass with brainstem edema on fluid-attenuated inversion recovery (A,B) and with central low intensity (B) enhances diffusely after administration of contrast material (C). The localization to the pineal region is best made on sagittal image (C).

FIGURE 9.75 Pineal germinoma. A: Sagittal T1-weighted magnetic resonance imaging (MRI) (600/20). B: Axial T2weighted MRI (3000/90). C: Axial T2-weighted MRI (3000/90). D: Sagittal T1-weighted MRI (600/17) with contrast enhancement. Intrinsic pineal mass (closed arrows, A–C) displaces superior colliculi (open arrow, A). Note the homogeneous low intensity on T2-weighted images (B,C) and the high intensity in thalami (C) and midbrain (B)

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indicating parenchymal invasion. Mass enhances diffusely (arrows, D) after contrast administration. E: Histologic specimen of germinoma exhibits large polygonal cells with distinct boundaries and large spherical nuclei containing nucleoli admixed with small mature lymphocytes.

FIGURE 9.76 Pineal teratoma. A: Sagittal T1-weighted magnetic resonance imaging (MRI) (600/20). B: Axial T1weighted MRI (600/20). C: Axial T2-weighted MRI (2800/80). Inhomogeneous, partially high-intensity pineal mass (arrows, A,B) represents fat-containing teratoma. The fatty portion of the mass parallels the intensity of subcutaneous fat (A–C).

Tumor masses in the pineal region do not always arise in the pineal. They may grow into the region from adjacent structures, such as the tectum of the midbrain, the superior vermis, or the thalamus. The differential diagnosis is quite different, and the therapy may be different depending on the site of origin. For example, a tectal tumor is usually indolent and does not need biopsy or treatment beyond shunting, whereas PNETs or ATRTs needs resection, chemotherapy, and radiation therapy (if the child is 3 years or older). A germinoma of the pineal, although biopsied by some, can be diagnosed on the basis of chemical CSF markers and response to treatment (radiation and/or chemotherapy). Sellar, Suprasellar Tumors Sellar and suprasellar masses can be either extraaxial (e.g., craniopharyngioma, pituitary adenoma, Rathke cleft cyst) or intraaxial (e.g., hypothalamic astrocytoma–visual pathway glioma and hamartoma). The most frequently encountered intraaxial masses are those of the hypothalamus–visual pathway that arise in association with NF1 and are usually pilocytic astrocytomas. The most frequent extraaxial masses are craniopharyngiomas. Masses arising in this location tend to present because of disturbance in vision and/or hormonal function and, if large enough, due to increased intracranial pressure secondary to hydrocephalus. In the older child and in the adolescent, the differential diagnosis is expanded for both intraaxial and extraaxial masses. Tumors of germinal origin, germinomas, and choriocarcinomas may arise in either space, schwannomas and meningiomas start to be encountered most often in association with NF2, and plexiform neurofibromas are encountered with NF1. Craniopharyngioma Craniopharyngiomas have a frequency of 0.5 to 2 per 100,000 per year, accounting for 6% to 9% of all brain tumors in children (112). In pediatric population, 80% to 90% of neoplasms arising in the 633

pituitary region are craniopharyngiomas (113). Mean age at presentation for children is late first decade. There is no gender predilection. Craniopharyngiomas arise from squamous rests located at any point along the invagination of the primitive stomadeum, Rathke’s pouch, from nasopharynx to hypothalamus. Three-fourths of tumors are suprasellar; the remaining are either supra- and intrasellar (20%) or just intrasellar (5%) (116,118). Headaches, visual deficits, and endocrine dysfunction are common forms of presentation. In the series of 66 patients with craniopharyngioma intracranial hypertension was present in 68%, visual symptoms in 44%, motor deficits in 12%, and seizures in 4.5%. Whereas endocrinologic signs were evident in 36%, 80% of the 66 patients had biochemical evidence of endocrine dysfunction. In another series, hydrocephalus was present in 53% and giant tumors (greater than 5 cm) in 20% (113). Most craniopharyngiomas are both solid and cystic, with 10% being purely cystic (Fig. 9.77) (113). When a gross total resection is possible, it is the preferred method of treatment (114). When it is not, the management becomes vexing (8). In Puget et al.’s series of 66 patients, 53% of the tumors recurred with a mean time to tumor recurrence of 6.4 years. Five-year progression-free survival exceeds 80% to 90% (116). In Puget’s series, 76% were well integrated into society, but 24% suffered from memory disturbance and/or behavioral dysfunction due to hypothalamic disturbance.

FIGURE 9.77 Craniopharyngioma in an 11-year-old girl. A: Axial unenhanced computed tomography shows partially calcified (arrow) cystic suprasellar mass (arrowheads). B: Sagittal T1 magnetic resonance imaging (MRI) shows the mass to have both an intrasellar and a suprasellar component and to produce hydrocephalus. C: Axial T2 MRI. The more solid component is calcified and is hypointense (arrow); the more cystic component is higher in signal intensity (arrowhead). D: Axial enhanced T1 MRI. The more solid component enhances peripherally and somewhat centrally, whereas the purely cystic component has only marginal enhancement.

Computed Tomography The CT appearance of the craniopharyngioma is variable depending on its composition and the amount of solid and cystic components. Calcification in either the cyst wall or the solid component is highly indicative of this tumor (9-77A) (116). The cyst fluid is of higher density than that of CSF. The cyst content does not enhance initially after contrast material injection, whereas the solid component and the wall do enhance promptly (116). The 90% rule implies that 90% are partially cystic, 90% are suprasellar, and 90% enhance (117). Magnetic Resonance Imaging 634

The most common MR picture of a craniopharyngioma is that of a cystic mass that is hypointense on T1, hyperintense on T2, and enhances in the cyst wall or the mural tissue (Fig. 9.77). Calcifications, if large enough, appear focally hypointense on T2 and T2* images (Fig. 9.77) (116,117), but MR has low sensitivity for calcification. Heterogeneity of signal with hyperintensity and mixed hypo-, iso-, and hyperintensity is seen both on T1 and T2 images. Occasionally, craniopharyngiomas can be “giant” and can extend quite far from their usual suprasellar location (Fig. 9.78). Rathke Cleft Cyst Rathke cleft cyst is a nonneoplastic cyst derived from glandular rests in the Rathke cleft region of the intermediate lobe of the pituitary gland. Eighty percent lie at the interface of the anterior and posterior lobes of the pituitary (Fig. 9.79). Histologically, they consist of a single- or pseudo-stratified layer of epithelium with an underlying connective tissue (119). Aho et al. (119) reported a series of 160 patients with Rathke cleft cysts, of which 118 were either initially symptomatic with endocrine dysfunction or visual impairment or became symptomatic during follow-up (or were found to have cyst enlargement on follow-up imaging). Sixty-one of the 160 patients were discovered incidentally to have Rathke cleft cysts. Of these 61 cysts, 19 progressed on follow-up, and the remaining 42 (69%) showed no progression by imaging or clinically for up to 9 years of follow-up. Aho et al. (119) found that preoperative hypopituitarism improved after surgical removal of the Rathke cleft cyst. This improvement was most impressive in patients with growth hormone deficiency or hypogonadism, which represented 53% of the patients. Recurrence after surgery is between 5% and 11%. The recurrence rate is higher (37%) in those patients in whom squamous metaplasia is present. Rathke cleft cysts on CT are low-density masses, usually intrasellar in location but occasionally both intra- and suprasellar, and do not contain calcifications and or show contrast enhancement (116). On MRI, they are more often slightly hyperintense on T1 and hyperintense on T2. Just as on CT, they do not show contrast enhancement on MRI (116).

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FIGURE 9.78 A young man with headaches and diplopia. A: Sagittal T1. B: Axial T2. C: Axial T1. D: Coronal T2 fluid-attenuated inversion recovery (FLAIR). E: Axial T1 postcontrast. A cystic-appearing mass with an irregular solid component destroys the clivus and bulges into the nasopharynx on T1- and T2-weighted images (A–C). Note that the fluid component is not isointense to cerebrospinal fluid on FLAIR (D). Thin peripheral enhancement with irregular enhancement of the solid component (E) is present. On close inspection, the lesion is seen to involve the posteriorinferior part of the sella (A–C). A differential diagnosis included unusual-appearing chordoma, but pathology showed craniopharyngioma.

The differential diagnosis of Rathke cleft cyst includes epithelial cyst, epidermoid cyst, dermoid cyst, and craniopharyngioma. Hypothalamic Hamartoma Hypothalamic hamartomas (HHs) are nonneoplastic masses resulting from abnormal migration of neurons within the hypothalamus. They typically present with precocious puberty and/or gelastic seizures. They arise as a pedunculated mass from the floor of the third ventricle (“parahypothalamic type”) (120). In the series of 11 patients, the size of the hamartomas averaged 15.8 mm + 4.7 mm, and there was no increase in size in a follow-up of 36.8 ± 16.2 months. In a series of 67 girls with central precocious puberty manifesting with onset of secondary sexual characteristics before age 8 years, 10 had MRI abnormalities, of which 6 were due to HH (121). The pathomechanism is thought to be 637

luteinizing hormone–releasing and hormone–secreting cells in the HH (122).

FIGURE 9.79 Rathke cleft cyst in two patients. A,B: Sagittal and coronal T1 magnetic resonance imaging (MRI) shows a high–signal-intensity intra- and suprasellar mass. C: Coronal T1 MRI. The intrasellar mass has a central cystic component.

HHs are uniformly isointense to gray matter on T1-weighted imaging, and in two-thirds of cases they are slightly hyperintense or isointense to gray matter on T2-weighted imaging (Fig. 9.80) (123,124). They do not show enhancement (116,125). On CT, they are isodense to gray matter and also do not contrast-enhance. Pituitary Adenomas Pituitary adenomas comprise 2.7% of supratentorial tumors of childhood, or approximately 3.5% to 6% of all surgically treated primary pediatric pituitary tumors. The most frequently seen adenoma in children is prolactinoma (53%), followed by corticotropinoma and then somatotropinoma. Nonfunctioning pituitary adenomas are rare in children, accounting for only 3% to 6% of pediatric adenomas (126). Only one-fourth of pediatric patients with pituitary adenomas present before the age of 12 years. Corticotropinoma is the most common tumor seen prepubertally, and 93% of prolactinomas present after the age of 12 years (126). The CT and MRI appearances of pituitary adenomas in children do not differ significantly from those seen in adults. However, they usually are not hemorrhagic or cystic and in most cases do not invade the cavernous sinuses, findings sometimes seen in adult pituitary adenomas. They usually do not reach sufficient size to grossly expand the sella, but present either as microadenomas within the substance of gland or expand the gland superiorly into the suprasellar region. The differential diagnosis includes the Rathke cleft cyst, craniopharyngioma, pituitary hyperplasia, and pars intermedia cysts. Sellar, Suprasellar Tumors It should be emphasized that not every contrast-enhancing mass in the suprasellar region is a neoplasm. Inflammatory processes can and will involve the optic chiasm, hypothalamus, and infundibular stalk region, mimicking the symptoms and appearance of a neoplasm. These include histiocytosis, sarcoidosis, 638

acute demyelinating diseases, and infectious diseases. Clinical and laboratory correlation (including evaluation of CSF) become important. The pituitary gland enlarges at puberty, particularly in females, and this, on occasion, causes concern in referring physicians or in less experienced radiologists, as do generous pars intermedia cysts, both normal findings.

FIGURE 9.80 Hypothalamic hamartoma. A: Sagittal T1 magnetic resonance imaging (MRI) shows a pedunculated mass arising from the region of the tuber cinereum. B: Axial fluid-attenuated inversion recovery. The mass is minimally hyperintense. C: Coronal enhanced T1 MRI. The mass does not enhance.

FIGURE 9.81 Disseminated neuroblastoma. A 2-year-old boy. Axial T1 image post contrst shows subarachnoid spread in posterior fossa.

Skull Base Tumors Metastases 639

Metastases in infants and children are rarely hematogenous to the brain. They are not so rare to the skull base and leptomeninges in hematologic neoplasms (leukemia and lymphoma) and neuroblastoma (NB). The initial clinical manifestation of these tumors may be related to skull base metastases. For example, an infant may present with a black eye due to hemorrhagic metastatic neuroblastoma prior to discovery of the primary neuroblastoma. With aggressive treatment and prolongation of life, there is an incidence of NB spread intracranially (Fig. 9.81) and hemorrhage into the metastasis. CT and MRI are both effective ways of looking at the marrow space for infiltration by tumor, and CT is clearly better for demonstrating bone destruction and periosteal reaction (Fig. 9.82). Plexiform Neurofibromas These cordlike masses that infiltrate widely and are of sufficient size to produce a mass effect are a manifestation of NF1. They are most commonly found in the region of the orbit and sella but may be found anywhere in and around the skull base. They are best demonstrated on MRI using T2 and FLAIR sequences. They contrast-enhance, but not necessarily intensely, so that fat-suppressed T1 images are best for separating them from adjacent normal soft tissues (e.g., fat) (Fig. 9.83). There is no effective chemotherapy or radiation therapy for these tumors. Surgical excision can be used for cosmetic purposes.

FIGURE 9.82 Metastatic neuroblastoma of the skull base in an 11-month-old girl who presented with proptosis and black eyes. A: Axial T2 magnetic resonance imaging (MRI) shows marked bone expansion of the greater wings of the sphenoid bone. B: Coronal enhanced T1 MRI. There is diffuse enhancement of the expanded bones. C: Diffusion MRI. The tumor shows restricted diffusion.

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FIGURE 9.83 Plexiform neurofibroma. Neurofibromatosis type 1 patient with prior removal of the left globe. Axial, fatsaturated, enhanced T1 magnetic resonance imaging shows a prominently enhancing mass that extends along the course of the fifth cranial nerve through the Meckel’s cave into the orbit.

Schwannomas and Meningiomas NF2 usually presents during adolescence or young adulthood, but when patients are examined earlier because of family history or when there is earlier occurrence of symptoms (e.g., third-nerve palsy), the presence of lesions characteristic of or suspicious for NF2 can be found on imaging. Schwannoma in an infant or child, even if a solitary one, should raise the suspicion of NF2. An acoustic schwannoma in a child, even if unilateral, indicates NF2, until proven otherwise. When meningiomas are detected in a pediatric patient they also raise the possibility of NF2 (127). Tumors Occurring in Children Younger Than 2 Years of Age In children younger than 2 years of age, most tumors arise supratentorially (128–132). Astrocytic tumors comprise 30% to 40%, PNETs 20% to 40%, and ependymomas 5% to 15%, whereas CPPs account for 5% to 12%. PNETs of infants are more frequently supratentorial than infratentorial (128–132). Teratomas are rare, often congenital neoplasms, frequently malignant (Fig. 9.84).

FIGURE 9.84 Benign teratoma. A 4-day-old boy. A: Axial noncontrast CT shows poorly defined large left hemispheric mass with some low and high densities. B: Axial T2 image better defines extent of mass. C: Susceptibility weighted image, axial shows extensive, malformed vascularity within the mass.

Second Pediatric Brain Tumors and Neoplasms Broniscer et al. (133) reported 1,283 patients with primary CNS tumors, of which 24 subsequently developed one or more secondary tumors. The 10-year estimated cumulative incidence of second malignant neoplasms was 1.4%. The incidence for development of second tumor was 4.4% for medulloblastoma, 0.4% for LGG, and 20.2% for choroid plexus tumors. The median age at diagnosis of the primary tumor was 4.6 years, and the median age at diagnosis of the second tumor was 15.9 years. Median interval between the occurrence of the first and the second tumor was 7.9 years. Gliomas were the most frequent second tumor (42%), followed by meningiomas (21%) and then desmoid tumors (8%). Eight of 10 patients with glioma succumbed in the first year after diagnosis and treatment, whereas meningioma patients were alive at a median follow-up of 6 years. Underlying genetic abnormalities were found in 29% of patients who developed a second tumor. 641

CONCLUSION Pediatric brain tumors are not simply earlier versions of adult tumors; rather, they encompass both benign and extremely malignant tumors that are rarely seen in the adult in addition to those encountered in adults. Location, age of patient, and rapidity of onset of symptoms are all helpful in interpretation of studies, but ultimately the density and pattern of enhancement on CT and signal intensity, enhancement, and diffusion pattern on MRI become keys to differential diagnosis of neoplasms arising in the pediatric brain. Proton spectroscopy and perfusion imaging can provide important additional information in certain cases. Ultimately, results of pathologic evaluation, where appropriate, in combination with imaging information lead to the best choices in therapy. Despite all of the advances in therapy during recent decades, certain tumors continue to pose major therapeutic challenges; these include disseminated PNET, ATRT, residual ependymoma, and intrinsic diffuse brainstem gliomas, to name only a few. However, great strides have been made in curing tumors that previously had a grave prognosis, such as localized PNET, ependymomas of the fourth ventricle, and glial neoplasms that lend themselves to total resection.

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10 Intracranial Hemorrhage Scott W. Atlas and Keith R. Thulborn

The initial recognition of intracranial hemorrhage has crucial and immediate implications for further diagnostic workup, clinical management, and ultimately patient outcome. Although the basic signal intensity of evolving intracranial hemorrhage has become widely known, new pulse sequences and higher scanner field strengths continue to emerge, and these have added even more importance to understanding the biological variables (Table 10.1) and technical operator-dependent imaging parameters (Table 10.2) that alter the magnetic resonance imaging (MRI) patterns when hemorrhage is present. Although these complex patterns make MR interpretation challenging, they also make hemorrhage an excellent vehicle for demonstrating the principles underlying MR contrast. As in past editions, this chapter goes beyond the simple pattern recognition style of radiologic diagnosis to a more detailed description of the physics and biochemistry underlying the various MR phenomena illustrated during the evolution of cerebral hematomas. Once understood, these principles can be used to understand the signal characteristics of many other entities. This allows the radiologist to put forth more specific diagnoses, instead of long lists of possibilities that often add little value to the referring clinical team. Beyond the initial diagnosis, the radiologist needs to be cognizant of several specific goals when interpreting brain MR studies in the search for hemorrhage (Table 10.3). These goals center on recognizing key neuroanatomic findings that influence patient management and direct further workup. Fundamental principles of neuroradiologic diagnosis, separate from the consideration of MR signal intensities, must be used to assist the clinician in providing optimal patient care. Localization of the hemorrhage to the intraaxial or extraaxial space is central to assessing etiology and to the initiation of treatment. If blood is extraaxial, it is important to specify whether it is subdural or epidural. If hemorrhage is intraaxial, it must be determined whether it originated in the subarachnoid space rather than the parenchyma. In certain instances, intracranial hemorrhage can be multi-compartmental, so familiarity with etiologies for these cases is essential for appropriate tailoring of further workup (see later sections in this chapter). TABLE 10.1 Physiologic Factors Influencing Magnetic Resonance Appearance of Hematomas

Once the basic neuroanatomic features are assessed, more sophisticated diagnoses that are crucial to patient management often can be gleaned from MR on detailed analysis of signal intensity. In clinical settings, it should be common for MR to be recommended after an acute intracerebral hemorrhage is 647

diagnosed on computed tomography (CT) because the etiology of the hemorrhage can be discerned by using the information that is uniquely available from MR studies. This third level of image interpretation—the analysis of the subtle secondary findings on MR associated with hemorrhage—can be extremely important to the ultimate diagnosis of etiology and workup. The conceptual framework for understanding the MR appearance of intracerebral hematomas has been summarized in multiple reviews (1–5) based on in vitro studies, animal models, and clinical observations (2,6–19). As put forth in the original descriptive model (12), the two most important biophysical properties in the generation of MR signal intensity patterns seen in evolving intracranial hematomas are the paramagnetic effects of iron associated with the changing oxygenation states of hemoglobin and the integrity of red blood cell (RBC) membranes that, when intact, compartmentalize the paramagnetic iron. Iron clearly plays a dominant role, even more so now that higher-field scanners are in practice (20,21), because its magnetic properties vary as its biochemical form, oxidation state, and spatial distribution change. Investigations have also supported the role of RBC membrane integrity in MR features of hematomas (22). Other pathophysiologic processes, including findings relating to the presence of an underlying neoplasm (i.e., persistent hypoxia, lack of integrity of the blood–brain barrier, alteration of the degree of edema, recurrent bleeding, bleeding into cystic or necrotic regions), coagulopathy, and nonparamagnetic protein concentration contribute to signal intensity patterns on these images. RBC volume (23), thrombus formation, and clot retraction (24) may be of some importance. Structural alterations, such as cavitation and hemoglobin resorption or degradation, become significant as the more acute processes of iron metabolism and edema decrease in importance during hematoma evolution. TABLE 10.2 Operator-Dependent Factors Influencing Magnetic Resonance Appearance of Hematomas

TABLE 10.3 Goals of Imaging Hemorrhage

This chapter reviews the physicochemical principles of the magnetic properties of matter and their applications to biological systems, discusses the biochemical pathways of iron metabolism and water balance in resolving intracerebral hematomas, and presents a qualitative scheme for relating these biochemical processes to the relaxation phenomena underlying signal contrast observed in MR images of hemorrhage. Factors most important to the intensity patterns in evolving intracranial hematomas are stressed. More recent concepts concerning the use of MR in the diagnosis and characterization of intraand extraaxial hemorrhages, including subarachnoid hemorrhage (SAH), are included. When important, the effect of field strength is emphasized. MR features suggestive of specific clinical etiologies of intracranial hemorrhage are also discussed. MR mimics of hemorrhage, based on signal intensity patterns, will be illustrated. Origin of Magnetism A magnetic field is generated by a moving electric charge (25). The strength of the magnetic field is determined by the size of the electric charge and by its momentum. The magnetic field generated by the unit charge is termed a magnetic dipole. An electron confined to an atomic orbital represents a moving 648

charge with both orbital angular momentum and spin angular momentum. Each angular momentum of the electron (i.e., orbital and spin) generates a magnetic field. Because the nucleus also possesses an electric charge and may have nonzero spin angular momentum (spin quantum number 0, 1/2, 3/2, …), it may also generate a magnetic field. However, because the magnetic moment of any charged particle is inversely proportional to its mass, and the mass of the nucleus is three orders of magnitude greater than that of the electron, the contribution of the nucleus to the magnetic properties of the atom is much less than that of the electrons. Hence, although nuclear magnetic interactions occur and nuclear magnetization is the origin of the signal used to construct the MR image, the magnetic properties of tissue are determined chiefly by the electronic configuration of the atoms and molecules. The two major types of magnetic properties of matter most relevant to a discussion of human biological systems are diamagnetism and paramagnetism. These concepts are first reviewed in terms of the different electronic configurations of the atoms and molecules that make up the constitutive material. Other magnetic properties of matter are discussed in detail elsewhere (5) and are reviewed here briefly. Diamagnetism Most biological materials consist of elements such as carbon, oxygen, and hydrogen, in which the electrons are paired in atomic and molecular orbitals. The pairing of electrons with opposite spin angular momentum minimizes the energy state of the electrostatic and magnetic interactions of closely placed identical charges (i.e., the electrons). In the paired condition, the net spin angular momentum of electrons is zero (i.e., there is no net magnetic moment). However, the paired electrons still have orbital angular momentum, constituting charges circulating in a confined orbital. If such a current loop is placed in an applied magnetic field, Lenz’ law states that this current loop (i.e., the electrons) generates a magnetic field opposing the applied magnetic field in vector direction (10-1A). This reduces the magnitude of the local magnetic field within the material below that of the original applied magnetic field. Materials that reduce the magnitude of an applied magnetic field are termed diamagnetic; greater than 99% of human tissue is diamagnetic.

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FIGURE 10.1 A: Diamagnetism. B: Paramagnetism. C: Antiferromagnetism. D: Ferromagnetism.

Paramagnetism Biological substances containing atomic or molecular structures with unpaired electrons have magnetic properties dominated by those unpaired electrons, due to the resultant magnetic dipole arising from the electronic spin angular momentum. Iron, in its ferrous and ferric oxidation states, is an important example of a naturally occurring substance in which the number of unpaired electrons varies with the biochemical state of the metal ion. If the magnetic dipoles of a collection of atoms or molecules are widely separated and randomly oriented in space, such that the unpaired orbital electrons on different atoms cannot interact, then the total magnetic field from that collection is zero. However, individual electronic magnetic dipoles can respond to an applied magnetic field by aligning in a parallel or antiparallel manner to that field, according to quantum mechanical requirements of the two–energystate system for spin particles. The distribution of electrons between the two energy states is governed by the Boltzmann distribution. At physiologic temperatures, more electrons align parallel to the applied field, resulting in an enhancement (i.e., an increase in magnitude) of that applied field (10-1B). This phenomenon is analogous to the alignment of nuclear spins in the nuclear magnetic resonance (NMR) experiment. Materials that have no intrinsic magnetic field in the absence of an applied magnetic field but augment an applied magnetic field on exposure to it are termed paramagnetic. Naturally occurring paramagnetic substances include copper, iron, and manganese. Antiferromagnetism, Ferromagnetism, and Superparamagnetism Some biologically important materials, such as the ferric oxyhydroxide crystalline structure of ferritin 650

and hemosiderin (two forms of iron storage substances), consist of closely packed ensembles of atoms with unpaired electrons and demonstrate yet another type of magnetic behavior that is relevant to MR. In such substances, unpaired electrons of neighboring atoms interact to minimize net magnetic forces. Resultant magnetic forces that produce “preferred” patterns of spin alignments are termed exchange forces. If unpaired electrons of pairs of adjacent atoms align with opposing spins, magnetic forces are minimized. In an applied magnetic field, spin pairing must be actively disrupted if individual electronic spins are to realign with the applied magnetic field. Because this disruption requires energy, the overall response of the material to the applied field (i.e., the degree of augmentation of the applied field) is less than that of a paramagnetic substance. Note that the net (effective) magnetic field is still increased in comparison with the magnitude of the original applied field (10-1C). Materials exhibiting this behavior are termed antiferromagnetic. The alignment pattern in antiferromagnetic substances can be disrupted if the thermal energy is increased, and initially the response to an applied field is enhanced as the temperature is increased. Above a critical temperature, known as the Néel temperature, adjacent spin pairing is disrupted, and the antiferromagnetic substance becomes paramagnetic. If the unpaired electrons of a group of atoms in a crystal interact to align in domains (termed Weiss domains), each domain has its own net magnetic field. Adjacent Weiss domains can then interact via these magnetic fields to minimize the resultant magnetic field outside of the material. If that material is immersed in a high magnetic field, domains respond to both the applied field and neighboring domain fields to enhance markedly the overall field (10-1D). Such materials possess a magnetic field even in the absence of an applied magnetic field and are termed ferromagnetic. As the ferromagnetic crystal is reduced in size to that of a single domain, this single-domain equivalent particle has a net magnetic dipole equivalent to that of a single domain. If a collection of such single-domain particles is free to rotate in an applied magnetic field on a time scale that is shorter than the observation time, the magnetic dipoles behave as expected for paramagnetism (discussed earlier). However, the larger magnetic moment of the particle (because it is a domain or group of atoms acting as one) produces a greater enhancement of the applied magnetic field compared with paramagnetic substances. Such particles are termed superparamagnetic (26–28). Superparamagnetic materials do not retain their magnetic field when removed from an applied field. If the size of the particles (which normally contain many domains) is reduced below the size of a single domain, the aligning exchange forces and disaligning thermal forces become comparable. Assuming that the time scale of the observation is longer than the switching rate of the equilibrium between the aligned and disordered states, then the magnetic properties of the particles depend on the temperature–volume relationships, which determine the switching frequency. An aggregate of such particles behaves paramagnetically but with a greater magnetic dipole than if no domain formed at all and thus is termed supermagnetic (25). Antiferrimagnetism and Ferrimagnetism When a crystal lattice is composed of two different substances, the lattice symmetry can be such that the resultant structure allows exchange forces between atoms of the two substances to operate separately. This behavior resembles two separate crystals occupying the same space. The exchange forces may allow individual opposition (antiferrimagnetism) or group opposition (ferrimagnetism). Magnetic Susceptibility Any material, when placed into a constant magnetic field, responds by generating its own magnetic field. The magnetic susceptibility of a substance (or tissue) describes this magnetic response. The induced magnetic field has two important characteristics: a magnitude and a vector direction. Materials can be categorized based on their induced fields (i.e., based on their magnetic susceptibilities) (Table 10.4). Diamagnetic materials respond to an applied field with a very weak induced field (approximately 10−6 × the magnitude of the applied field) and in a vector direction that opposes that of the applied field. Paramagnetic materials have a larger induced field (approximately 10−2 to 10−4 × the magnitude of the applied field), which is in the same vector direction as the applied field. Superparamagnetic and ferromagnetic materials generate a very large induced field, equal to or even greater than the applied field, and, as with paramagnetic substances, the induced field is in the same vector direction as the applied field. The tissue interaction with the static magnetic field B0 to produce magnetization m, which either reduces (diamagnetism) or enhances (paramagnetism, antiferromagnetism, ferromagnetism, 651

superparamagnetism) the effective magnetic field Beff within the material (note that the magnetization m refers to the effects of electronic configurations, not to the nuclear magnetization M measured in the NMR experiment), can be quantified in terms of the magnetic susceptibility χ of the material, where TABLE 10.4 Magnetic Susceptibility Based on Characteristics of the Induced Magnetic Field

FIGURE 10.2 The effective magnetic field Beff is modified from the applied magnetic field B0 by the presence of tissue, depending on whether it is diamagnetic (χ < 0) or paramagnetic (χ < 0). The boundary between these regions has a gradient in Beff that functions as an apparent fluctuating magnetic field bz when spins diffuse across the boundary. Thus diffusion causes Mxy relaxation characterized by T2*. Because no fluctuating fields occur along bx or by, Mz and, therefore, T1 are unaltered.

where Thus, χ < 0 for diamagnetic materials, χ < 0 for paramagnetic materials, and χ = 0 for a vacuum. When placed into the static magnetic field of the imaging magnet, therefore, tissues of different magnetic susceptibilities establish different effective local magnetic fields (Fig. 10.2). Consequently, when there are two adjacent regions of differing magnetic susceptibilities in the imaging volume, there are actually two adjacent regions of differing magnetic fields (Fig. 10.2). Gradients, or differences, in magnetic susceptibility χ could be thought of as equivalent to magnetic field inhomogeneities. The response of the nuclear magnetization measured in the MR image is altered dramatically by the different stages of iron metabolism found within an evolving hematoma due to their differences in magnetic susceptibility.

MR CONTRAST Most clinical MR images are based on the nuclear spin system of hydrogen (I = 1/2), referred to simply as protons. The proton is intrinsically the most sensitive nucleus for MR and occurs in the highest concentration in the human body, given the abundance of water in human tissue. The protons have charge and spin and therefore behave as a magnetic dipole, as discussed for electrons earlier. As such, they respond to other magnetic fields, such as applied external magnetic fields, and to other local dipole fields produced by adjacent nuclei with nonzero spin and unpaired electrons. Image contrast is the difference in signal intensity arising from different regions of the object. If two regions have different magnetic environments, signal intensities from each region will be different and contrast will be observed. The nature of interactions between the magnetic environment and the proton spin system is 652

discussed in terms of the MR process. Relaxation Mechanisms in Hemorrhage For diamagnetic tissues, the most important relaxation mechanism accounting for both longitudinal and transverse relaxations is attributed to proton–proton dipole–dipole interactions (27,29). Other mechanisms, scalar spin coupling, chemical shift anisotropy, quadrupolar, and spin–rotational effects, are usually less important in proton MR and are described elsewhere (30,29,31). The image contrast in hemorrhage requires discussion of two effects of nondiamagnetic substances. These are considered under relaxivity and susceptibility effects. A third process of exchange is discussed separately. Relaxivity Effects The rotational and translational diffusion of water molecules in biological systems occur on a time scale that produces an isotropically fluctuating magnetic field in the range of the Larmor frequencies for protons at current imaging field strengths. If the water molecules are able to approach a paramagnetic center, then magnetic interactions between the nuclear magnetic dipoles of the water (protons) and the magnetic dipoles of the paramagnetic centers (unpaired electrons) allow efficient energy exchange to occur. This interaction results in relaxation of the water proton to its magnetic equilibrium state (32). The phenomenologic equation for such intermolecular proton–electron dipole–dipole interactions with a paramagnetic agent, P, in bulk solution is given as where and i = 1, 2; R is the relaxivity constant (s−1 mM−1); and [P] is the concentration (mM) of the paramagnetic substance P. Here, 1/Ti(dia) is the relaxation rate due to diamagnetic relaxation processes and 1/Ti(para) is the relaxation rate in the presence of the paramagnetic species. In the presence of a suitable paramagnetic substance, the paramagnetic term dominates over the diamagnetic term in Equation 3. The same equation applies for both longitudinal and transverse relaxation. Because T1 is generally longer than T2 in biological systems, 1/T1 is smaller than 1/T2 and so the constant term R[P] contributes a greater proportion to the longitudinal relaxation rate (1/T1) than to the transverse relaxation rate (1/T2). The implication for MR is that the relaxivity effects attributed to dipole–dipole interactions with paramagnetic substances are detected with greater sensitivity on T1-weighted (short repetition time/echo time [TR/TE]) images than on T2-weighted (long TR/TE) images. The contributions of “inner-sphere” (ligand exchange in which water molecules are in the first coordination sphere of P) and “outer-sphere” (diffusion with close approach of water near but without coordination to P) effects to paramagnetic relaxation rates can be further analyzed by the more mechanistic Solomon–Bloembergen equations, which are presented in detail elsewhere (34). It should be noted that application of Equation 3 to biological systems as complex as cerebral hematomas can only be approximate because of the heterogeneity in type and distribution of the various paramagnetic substances involved. The strength of the dipole–dipole interaction between water and paramagnetic substances depends on several factors (Table 10.5): the number of unpaired electrons in the paramagnetic material (which, in turn, determines the magnetic moment), the concentration of the paramagnetic substance, the electron spin relaxation rate, and, perhaps most relevant to the clinical images, the distance between the (potentially) interacting dipoles (interdipole distance). TABLE 10.5 Factors Affecting Strength of Proton–Electron Dipole–Dipole (PEDD) Interaction

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FIGURE 10.3 Proton–electron dipole–dipole interaction schematic. The magnetic movement μ of the unpaired electron (e−) in the paramagnetic center is much larger (approximately 700 times) than that of the water protons (p+), as denoted by the larger arrow of the e−. The distance between the dipoles strongly influences the strength of the interaction (see text). The longer spirals imply stronger interactions at shorter distances between dipoles.

In fact, the strength of the dipolar interaction is proportional to the inverse sixth power of the interdipole distance (Fig. 10.3). The implication of this geographic restriction on the strength of relaxation enhancement is profound when one considers the MR intensity pattern in acute hematomas. When the water proton is unable to approximate close enough to the paramagnetic center (i.e., the unpaired electrons of deoxyhemoglobin), no dipole–dipole magnetic interaction, and therefore no relaxation enhancement, occurs by relaxivity mechanisms. This failure of interaction can be ascribed to the quaternary structure of deoxyhemoglobin (Fig. 10.4) (33). Therefore, even though deoxyhemoglobin is clearly paramagnetic, the acute hematoma is not hyperintense on T1-weighted images. After the acute event, when deoxyhemoglobin undergoes conversion to methemoglobin, conformational changes in the hemoglobin molecule–iron complex result in accessibility of the water proton to the unpaired electrons of iron in methemoglobin (Fig. 10.4) (33) and dipolar relaxation enhancement follows, resulting in the typical high intensity of methemoglobin in subacute and chronic hematomas. Susceptibility Effects As can be seen from Equation 3, dipole–dipole relaxation mechanisms affect both T1 and T2 (although not necessarily equally). This is because the fluctuating magnetic field of a randomly tumbling paramagnetic center is isotropic, operating along the x, y, and z axes. Magnetic susceptibility–induced relaxation, in contrast, does not affect both T1 and T2. This selective T2 relaxation enhancement can be understood by considering the precise mechanisms involved in generating magnetic susceptibility effects. There are two types of static magnetic fields that are highly anisotropic, operating only in the direction of the main field B0: inhomogeneities in B0 due to magnet imperfections and magnetic susceptibility–induced field variations Beff. If the inhomogeneities in Beff are large over the dimensions of the voxel, the field variations produce dispersion in frequencies within the voxel, leading to rapid loss of transverse magnetization (this has also been described as loss of phase coherence of spins within that voxel). The combination of this loss of transverse magnetization from B0 inhomogeneities with dipole–dipole relaxation mechanisms is characterized by a combined relaxation time termed T2*. (Note that T2* refers to total transverse relaxation and can be described by the following equation:

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FIGURE 10.4 Structure of hemoglobin complex in various stages of evolving hemorrhage. A: Oxyhemoglobin. B: Deoxyhemoglobin. C: Methemoglobin. Note that iron (Fe) is nearly within the same plane as the atoms comprising the porphyrin ring (dark color) in the oxyhemoglobin (A) molecule. On deoxygenation, there is a subtle alteration in the position of Fe to become positioned outside of the porphyrin plane (B), which prevents access to water. In the methemoglobin state (C), note that the Fe is now positioned again nearly within the plane of the porphyrin ring, allowing close approximation by water (W). (Courtesy of Dr. Peter Janick, Philadelphia, PA, as modified from Dickerson RE, Geis I. Hemoglobin: Structure, Function, Evolution, and Pathology. Menlo Park, CA: Benjamin Cummings; 1983, with permission.)

where T2 equals the transverse relaxation induced by spin–spin interactions, T2″ equals the transverse relaxation from B0 inhomogeneities, and T2′ equals the transverse relaxation related to susceptibility gradient–induced field inhomogeneities.) Spin-echo imaging minimizes the effects of static magnetic field variations (field inhomogeneities) with the use of the 180-degree refocusing RF pulse. In fact, this recovery of signal loss from field inhomogeneity is probably the major reason for the success of the spin-echo technique in imaging. Conversely, reversal of the readout gradient in the absence of a 180degree RF pulse, which is used in gradient-echo imaging for generation of the echo, does not compensate for signal loss due to field inhomogeneities. As a consequence of the gradient-echo technique, gradient-echo imaging is extremely sensitive to field inhomogeneities, a feature that assumes greater importance at lower field strengths (33). An additional cause of phase dispersion–induced signal loss distinct from that due to static field variations (as described earlier) relates to what can be considered time-varying magnetic field changes. The molecular diffusion of water that occurs through regions of variable Beff during TE (time between the 90-degree RF pulse and echo) produces frequency variations (Equation 2) and concomitant loss of phase coherence in the transverse plane resulting in signal loss in Mxy. The local fields experienced by the moving spins over the time of diffusion, although the fields are static, are analogous to a situation in which spins are stationary and change over that same period of time. In effect, then, the field can be considered to be varying over the time of spin diffusion. Note that this loss of signal is not recovered by the 180-degree RF pulse of the spin-echo sequence, so, in fact, both conventional spin-echo imaging and gradient-echo techniques are sensitive to this cause of hypointensity. This effect becomes more apparent as the TE exceeds the diffusional correlation time (time for a proton to move from one position to another position). Spins diffusing in the x–y plane experience these variations in Beff as a fluctuating magnetic field along bz, with resultant enhancement of transverse, but not longitudinal, relaxation (Fig. 10.2) (hence the term selective T2 shortening). This effect is well known in NMR spectroscopy (29), where a known magnetic field gradient G can be applied to a sample to measure the diffusion coefficient D of protons through a solvent. The signal intensity S for a Hahn spin echo at TE is given as Magnetic susceptibility differences due to compartmentalization of paramagnetic species (e.g., iron) have a great effect on the signal intensity of evolving hematomas on T2 images. This compartmentalization is due to the presence of intact RBC membranes in early hematomas. Recent analysis of apparent diffusion coefficients from diffusion MR in clinical hematomas (22) supported this concept by documenting that water diffusion is significantly and equally restricted in intracranial 655

hematomas with signal patterns consistent with intracellular oxyhemoglobin, intracellular deoxyhemoglobin, and intracellular methemoglobin as compared with hematomas containing extracellular methemoglobin (Fig. 10.5). Differences in susceptibilities between, for example, compartmentalized paramagnetic deoxyhemoglobin within an RBC and diamagnetic water can result in significant T2 relaxation if sufficient diffusion is permitted to occur during the imaging sequence (Fig. 10.6). Such effects cause marked signal loss in acute hematomas on long-TR/TE (T2-weighted) MR images without similar degrees of signal loss on either long-TR/short-TE (proton density–weighted) or short-TR/short-TE (T1-weighted) MR images. It has also been shown (35) that the use of prolonged interecho intervals (τcpmg) results in shortening of the effective T2, again by allowing more diffusion of water protons through areas of differing magnetic fields. The clinical importance of understanding this diffusion-related mechanism of T2 shortening is clear when one considers the clinical situation of attempting to depict acute (or chronic) hemorrhage on low–field-strength systems. To maximize the hypointensity on low–field-strength scanners, the long-TR protocol should include long TE with very long τcpmg. Indeed, the strength of this T2-shortening mechanism is related to several factors (Table 10.6). Exchange Processes Changes in the (nonparamagnetic) protein content within the hematoma also evolve as clot formation, clot contraction, and necrosis occur. From in vitro studies (36–38), increasing protein concentration would be expected to promote T1 and T2 relaxation rates. It is possible that the exchange of water between bulk and protein-bound (hydration layer) phases may be a significant contributor to proton relaxation in some situations of hemorrhage, especially on low-field scanners, where paramagnetic susceptibility mechanisms are not nearly as prominent as on high-field imagers. In fact, the lack of susceptibility-induced relaxation effects accounts for the lack of marked hypointensity (and therefore the lack of ability to detect with certainty) in most acute hematomas at low field. Investigators demonstrated that changes in RBC volumes may be responsible for some of the changes in T2 relaxation rates in hematomas (23). With shrinkage of RBCs due to decreases in intracellular water, it has been shown that T2 can decrease significantly in in vitro studies of blood clots. This relaxation rate increase is probably related to protein concentration–dependent changes in the correlation time (a viscosity effect) (39), but further work needs to be done to clarify the significance of this mechanism in the in vivo hematoma. Clark et al. (24) attempted to quantify the effects of deoxygenation, protein (hematocrit), clot formation, and clot retraction in generating signal intensity changes of acute hematomas. In their study, it was apparent that the contributions of fibrin clot formation and clot retraction to T2 shortening were minimal (less than 2% combined). Furthermore, most T2 shortening was related to deoxygenation, with the remainder of change in T2 associated with hemoconcentration. Increasing edema has also been suggested to allow increased diffusion rates by removing diffusional barriers, such as macromolecules and cell membranes, thereby promoting T2 relaxation. In areas of necrosis, diffusional barriers may not be removed to the same degree as in vasogenic edema in relatively intact tissue. The relative influences of protein exchange and aggregation on in vivo relaxation processes cannot be predicted as yet. Field Strength Effects Nuclear magnetic relaxation dispersion describes the variation of 1/T1 and 1/T2 with magnetic field strength. A formal mathematical treatment of nuclear magnetic relaxation dispersion is presented elsewhere (40). The observations relevant to hemorrhage are summarized as follows. At zero magnetic field, 1/T1 = 1/T2. As field strength increases, the Larmor frequency changes according to Equation 2. The efficiency of relaxation requires matching correlation times of local fluctuating magnetic fields generated by rotational and translational diffusion to the Larmor frequency. This occurs over a wide range (10−10 to 10−11 seconds) corresponding to low-imaging field strengths where the effects on T1 and T2 relaxation rates are comparable. At higher fields, 1/T1 tends toward zero, but 1/T2 tends to a nonzero value termed the “secular” contribution to relaxation. This contribution to the T2, but not to the T1, relaxation rate arises from the local fluctuating fields parallel to B0 as described for susceptibility-induced relaxation. Hence, higher magnetic field strengths enhance susceptibility effects and the related signal loss; this changes the appearance of hematomas on 3 T because more profound hypointensity will be shown in the presence of deoxyhemoglobin, hemosiderin, or other 656

compartmentalized paramagnetic material (20,21). In vitro studies of deoxygenated erythrocytes show a quadratic dependence of 1/T2 on magnetic field strength over a range of 2 to 5 T (16). The importance of the imaging parameters in determining sensitivity to the susceptibility effects has been emphasized by in vitro studies of blood clots (8). Clinical experience has also indicated that higher-imaging magnetic field strengths increase sensitivity of spin-echo images to susceptibility-induced relaxation mechanisms, irrespective of the source of the susceptibility variation (12,40). Note that the contrast in acute hemorrhage, for example, which is mainly based on T2 shortening from deoxyhemoglobin (24,41), may not be detected on low–field-strength systems using spin-echo techniques because the effect is approximately proportional to the square of the magnetic field (16). Therefore, the signal intensity in these lesions on low–field-strength magnets may be similar to nonparamagnetic lesions, where contrast is determined mainly by such factors as water content and the presence of macromolecules (e.g., hemoglobin and other plasma proteins in the case of blood). In this circumstance, at lower field strengths, gradient-echo imaging should probably play a larger role. Similarly, the change of clinical protocols discarding conventional spin-echo imaging and instead using sequences that use multiple refocusing pulses like fast spin-echo imaging also necessitate a more liberal use of gradient-echo scans. More recently, the introduction of 3 T MR systems into the clinical setting has reintroduced the topic of field strength and sensitivity to iron-containing lesions, especially intracranial hemorrhage, to clinical radiologists. Today, after decades of clinical MR, there is no debate that higher-field 3-T MRI is more sensitive than 1.5 T to all stages of hemorrhage (and components of hematomas) that are detected by virtue of their short T2 (Fig. 10.7).

FIGURE 10.5 A: Average apparent diffusion coefficient (ADC) versus putative biophysical state in intracranial hematomas. Note that hematomas containing intracellular oxyhemoglobin (OxyHbIntra), intracellular deoxyhemoglobin (DeoxyHbIntra), and intracellular methemoglobin (MetHbIntra) all have restricted diffusion (reduced ADC), whereas

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hematomas with extracellular (“free”) methemoglobin (MetHbFree) have elevated ADC. B: Hyperacute hematoma in left basal ganglia. T1-weighted (a) and T2-weighted (b) images show characteristic features of hyperacute hematoma, including a peripheral rim of marked hypointensity more prominent on gradient-recalled echo image (c). Although the diffusion-weighted image (d) demonstrates high intensity, the calculated ADC map (e) shows markedly reduced ADC within hyperacute hematoma.

FIGURE 10.6 Compartmentalized paramagnetic deoxyhemoglobin within regions of an intact RBC results in areas of different magnetic susceptibility, both within the confines of the cell and compared with the diamagnetic extracellular water. Therefore, as water diffuses through these regions, it experiences different magnetic fields.

TABLE 10.6 Factors Affecting Strength of Magnetic Susceptibility–Induced Relaxation Enhancement

MR Techniques and Hemorrhage MR contrast in the presence of hemorrhage is highly dependent on the mode of image acquisition (Table 10.2). Image acquisition protocols generally use four basic pulse sequences (Fig. 10.8). The spin-echo sequence uses a 90-degree RF pulse to convert the equilibrium longitudinal magnetization Mz into transverse magnetization Mxy and then a 180-degree RF pulse to refocus the dephasing in Mxy (due to B0 inhomogeneities) to generate an echo. This approach provides the time necessary for gradient switching required to perform spatial encoding. This sequence was designed to correct the otherwise deleterious effects of magnet imperfections (B0 inhomogeneities) that cause rapid signal loss. However, if the B0 inhomogeneities arise from the lesion itself, as in hematomas, the MR contrast that would have reflected this phenomenon would also be diminished. The effects of diffusion of water through the localized magnetic field gradients are not corrected unless the TE is made very short relative to the correlation time of water diffusion. Magnet and gradient technologies have improved dramatically since the introduction of spin-echo imaging. Hence, magnet imperfections are seldom a dominant effect and values of TE are becoming much shorter without loss of image quality from artifacts generated by rapid gradient switching. These improvements have led to faster alternative and adjunctive sequences. The gradient-recalled echo (GRE) sequence uses an RF pulse (usually less than 90 degrees) to convert 658

only part of the equilibrium longitudinal magnetization Mz into Mxy and replaces the 180-degree RF pulse with a gradient reversal to rephase the spins to produce the echo. Although sensitivity to paramagnetic constituents of hematomas is increased, the penalty is that normally occurring border zones of differing susceptibility (e.g., air–tissue interfaces) also produce signal loss, decreasing visualization of large regions of the brain. Care must be taken to avoid mistaking artifacts for pathology in these regions, particularly around the petrous bones and paranasal sinuses. Because these intravoxel dephasing effects depend on voxel size, various maneuvers may be used to obviate problematic artifacts; paradoxically, the fundamental reasons for these susceptibility-related artifactual causes of signal loss are identical to those that form the basis of the desired increased sensitivity for hemorrhage detection. Susceptibility-weighted imaging (SWI) is another clinical MR technique that is extremely sensitive to differences in magnetic susceptibility from the presence of iron (42). Signals from substances with different magnetic susceptibilities compared to their neighboring tissue will become out of phase with these tissues at sufficiently long TEs. In SWI, phase images are high-pass filtered and then transformed to a phase mask. This mask is multiplied into the original magnitude image to create enhanced contrast between tissues with different susceptibilities. Regardless of field strength, SWI is even more sensitive than GRE imaging to susceptibility-related signal loss (Fig. 10.9). One problem with SWI is its depiction of ends of normal intracerebral medullary veins (containing deoxyhemoglobin) as marked hypointensity, which can mimic very small acute (or old) hematomas, thereby confounding the clinical issues.

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FIGURE 10.7 Multiple hemorrhagic cavernomas, 1.5 T GRE versus 3 T GRE versus 3 T FSE. Even though some lesions are visible on the 1.5 T GRE image (A), the hypointensity of those lesions is more pronounced on the 3 T GRE (B) and more lesions are demonstrated at 3 T (B). The lesions are either less well seen or invisible on 3 T FSE image (C).

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FIGURE 10.8 Timing diagrams for spin-echo (A), gradient–recalled echo (B), and echo planar (C) pulse sequences showing the radiofrequency pulses (90, 180, and α degrees) and two in-plane spatial-encoding gradients. (The sliceselection gradient is not shown because it is the same in all sequences.)

Over the recent years, it has become routine that screening brain MR protocols use faster scanning methods, including sequences like fast spin echo (FSE) rather than conventional spin-echo techniques. This time-saving method has been incorporated into most clinical protocols because of improvements in gradient switching technology, which has permitted shortening of the interecho time τcpmg and an increase in the number of echoes per TR. This sequence differs from the conventional spin-echo sequence by using a train of 180-degree RF pulses to generate a set of echoes that are individually spatially encoded during a single TR. This significantly shortens the total acquisition time because several spatial encoding steps are performed in a single pulse train. The implications in the setting of cerebral hematoma are that dephasing effects in the presence of heterogeneous magnetic susceptibilities are virtually eliminated by the generation of spin echoes. Moreover, the short τcpmg minimizes the signal loss effects of diffusion (Fig. 10.10). Hence, “T2-weighted” FSE has lower sensitivity for the hypointensity of both acute and remote hemorrhages than conventional spin-echo images. If the clinical history suggests that hemorrhage may be present, supplemental GRE or SWI scanning should be used (Figs. 10.7, 10.11, and 10.12). Echo planar imaging (EPI) and other very fast acquisition sequences are now available on virtually all mid- and high-field MR scanners. The main impetus for these “ultrafast” sequences is recent advances in the therapy of acute stroke, the high value of diffusion-weighted imaging, the use of 3D techniques, and a small but increasing demand for the real-time exploration of brain function. These applications require very fast scanning, and many of them are performed with special EPI-capable hardware and software. The EPI sequence uses a single RF pulse train of either spin-echo or GRE format with a complete twodimensional spatial-encoding scheme of gradient switching (“single-shot EPI”). Various ways of implementing the readout gradients are available and are outside the scope of this chapter (43). The advantage of the EPI method is the very high temporal resolution: images of the brain can be obtained on the order of tens of milliseconds. EPI methods are being used for diffusion-weighted MR, perfusionweighted MR, and task-activation MR. Generally, EPI methods are very sensitive to magnetic susceptibility effects in both the spin-echo and GRE modes due to the nature of the variable readout gradients (note that in spin-echo EPI, only a single 180-degree RF pulse is used to generate an echo at the selected TE, whereas many gradient reversals are used without 180-degree pulses; i.e., even spin661

echo EPI uses gradient refocusing) (Fig. 10.13). It is not only the difference of appearance of hemorrhage on EPI-based sequences that is important. Perhaps most important is the understanding of when to use EPI-type sequences to assist in either hemorrhage detection or delineation of the etiology of already recognized hemorrhage (see MR Patterns Specific for Clinical Etiologies of Intraparenchymal Hemorrhage).

FIGURE 10.9 Sensitivity of GRE versus SWI to T2-shortening. 3 T GRE images (A) is normal except for a possible tiny dot of low signal in the right parietal white matter, a lesion clearly demonstrated along with others on 3 T SWI (arrows, B). It is uncertain how many of these low signal “foci” represent tiny hemorrhages or simply ends of veins. Note markedly low signal in normal intramedullary veins traversing brain parenchyma on SWI (B).

FIGURE 10.10 Effect of interecho time τ cpmg: spin echo versus fast spin echo (FSE). Axial images were obtained with the same repetition time (TR) and echo time (TE) (or effective TE), using conventional spin-echo (A) and FSE (B) sequences in a patient with multiple cavernous hemangiomas. Note that with the use of a long τ cpmg in conventional spin echo (A), the acute pineal region hemorrhage is markedly hypointense, whereas with the use of a short τ cpmg in FSE (B) the lesion is less hypointense. These differences are seen despite the fact that the same TR and TE are used in these two images.

FIGURE 10.11 Acute infarction with hemorrhage. Computed tomography (A) and conventional T2-weighted magnetic resonance (B) clearly demonstrate acute right middle cerebral artery infarction, but only gradient-recalled echo (C) shows markedly hypointense hemorrhage scattered throughout the lesion.

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FIGURE 10.12 Multiple acute hemorrhages in diffuse axonal injury, fast spin echo (FSE) versus gradient-recalled echo (GRE). T2-weighted FSE images (A) do not reveal any of the numerous hemorrhages clearly seen on the GRE images (B) in the brainstem, corpus callosum, and white matter.

FIGURE 10.13 Comparison of fast spin echo (FSE), echo planar imaging (EPI), and gradient-recalled echo (GRE) for acute hemorrhage. Acute hemorrhage within cerebral infarction as marked hypointensity is increasingly more visible and more extensive going from the FSE (left) to the spin echo EPI (middle) to the GRE (right) image.

EVOLUTION OF INTRAPARENCHYMAL HEMATOMAS Using the concepts of relaxation discussed in the preceding sections, it is possible to understand the appearance of the various stages in the biochemical evolution of intracranial hemorrhage. The fundamental reason why hemorrhage is unique on MR is that most blood breakdown products are paramagnetic, and they are paramagnetic because of unpaired electrons of their associated iron moiety (Table 10.7). Although some variations can certainly occur, most intracranial hematomas behave in a predictable fashion as they change over time (Table 10.8). The exact time course of biochemical changes (44) may vary, depending on the pathophysiologic state and on specific imaging technical factors (Tables 10.1 and 10.2). In truth, the clinical dating of the actual hemorrhagic event is notoriously inaccurate, so the nomenclature of the temporal stages of hematomas (i.e., acute, subacute, and chronic) is somewhat arbitrary. Of those factors that are intrinsic to the anatomy and pathophysiology of the lesion, those known to be most important to image interpretation include the age of the hemorrhage, the location of the hematoma (i.e., intraaxial vs. extraaxial, subarachnoid vs. subdural/epidural) (45), and the presence of an underlying lesion (46,47) that affects the blood–brain barrier (47) and the repair response mounted by the patient. Wellvascularized regions, for instance, are expected to show a faster repair response than poorly vascularized regions. Such variability has been reported from biochemical studies of hemorrhage outside of the central nervous system (48). As stated earlier, the radiologist must also be cognizant of the 663

operator-dependent factors that potentially change the MR appearance of hemorrhage (Table 10.2), including the main magnetic field strength, the exact pulse sequence parameters used (37,49), and the method of echo formation (i.e., spin echo, GRE, FSE, or EPI) (6,49). For instance, the signal loss related to the presence of intracellular paramagnetic deoxyhemoglobin and intracellular methemoglobin will be far more evident on 3-T images and seen earlier than on 1.5-T scans. Note that in the following discussion, all T1-weighted images are spin echo unless otherwise stated, and T2-weighted images are generated from conventional spin-echo or FSE techniques. T1-weighted images used TR of 500 to 800 ms and TE of 10 to 25 ms. T2-weighted images used TR of 2,500 to 4,000 ms, and TEs (or effective TEs) were long (greater than 70 ms). TABLE 10.7 Unpaired Electrons Associated with Blood-Breakdown Products

TABLE 10.8 General Guidelines for Temporal Evolution of Intracranial Hematomas at 1.5 T

FIGURE 10.14 Evolution of intraparenchymal hemorrhage on magnetic resonance. In the earliest stage of acute hematomas, blood is still oxygenated within intact RBCs. Separate plasma water with clot retraction and a small amount of edema may be seen at this early time point. Rapid deoxygenation, first at the periphery and then

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throughout the hematoma, occurs, whereas RBCs remain intact. Note the slight increase in edema. As the lesion undergoes oxidation, the peripheral hemoglobin within intact RBCs forms methemoglobin. Although this oxidation process and conversion to methemoglobin occur throughout the hematoma, RBCs lyse. As free methemoglobin is formed, hemosiderin and other iron storage forms are deposited within macrophages in the adjacent brain. Eventually, the lesion contains no intact RBCs, and methemoglobin is resorbed or metabolized, leaving only a collapsed cleft lined by hemosiderin and ferritin without any notable central constituents.

TABLE 10.9 Iron Metabolic States in Cerebral Hemorrhage and Magnetic Resonance Relaxation Effect

It has become generally accepted that evolving intracranial hematomas typically change over time mainly, but not exclusively, in two important ways that alter MR signal intensity patterns: the oxygenation state of hemoglobin changes, and initially intact RBC membranes eventually lyse (Fig. 10.14). As the oxygenation state of the hemoglobin molecule changes with hematoma evolution, it is the iron moiety associated with hemoglobin that most directly influences changes in MR signal intensity. The magnetic properties of iron, determined by its electronic configuration, vary with its biochemical form, spatial distribution, and oxidation state. The changing electronic configuration is summarized in Table 10.9 to demonstrate how the magnetic properties of hemorrhage and hence the nuclear relaxation processes that underlie the signal contrast in the MR image depend on the biochemical pathways of iron metabolism. Although iron is the most abundant transition metal in the human body, being vital for oxygen transport by hemoglobin in the erythrocyte of blood and many catalytic processes involving enzymes, free iron is toxic, as is demonstrated by toxic ingestions and iron overload states (50–52). The toxicity, believed to be due to enhanced free radical production by unchelated iron (53), requires that all iron be tightly bound in well-controlled metabolic pathways of absorption, transport, storage, and conversion into functional end products. The repair of hemorrhage requires a tightly controlled iron salvage pathway in which iron from the extravasated erythrocytes is mobilized from hemoglobin, detoxified by chelation to short-term iron transport proteins for transfer back to the reticuloendothelial system, or converted to long-term storage proteins for local deposition (51,54,55). “Hyperacute” Hematoma The advent of early aggressive therapy for ischemic cerebral infarction has fostered a new motivation for emergency brain imaging (56). Before the introduction of emergent treatment of acute ischemic stroke, imaging was mainly performed to exclude other pathologies masquerading as infarction and to exclude hemorrhage. Recent advances in therapy of these patients (57) have dramatically changed the overall importance of imaging in this emergency setting, particularly when diffusion and perfusion MR are available, because these techniques are beginning to play an important role in assessing tissue viability and consequently patient management (58–62). Moreover, the recognition of early intracranial hemorrhage specifically on MR has also become more important because the primary assessment of early stroke patients is moving toward MR and away from CT (56,63). Therefore, it is now more relevant to clinical practice, and in fact essential, to understand the appearance of very early, or “hyperacute,” hematomas because the presence of such hemorrhage is typically a contraindication to thrombolytic therapies. Freshly extravasated erythrocytes of arterial blood mostly contain, for the purposes of practical discussion, fully oxygenated hemoglobin. Hemoglobin is a tetramer of polypeptide chains, with each 665

polypeptide chain having a prosthetic heme group bound within a hydrophobic cleft (33,64). Each heme group is a protoporphyrin IX, chelating a single iron in the ferrous oxidation state (six d electrons). Initially, the iron is bound in octahedral geometry with six ligands. The tetrapyrrole nitrogen of the protoporphyrin constitutes four ligands in a plane around the iron. The imidazole group of a histidine from the polypeptide chain is the ligand below the protoporphyrin plane, whereas molecular oxygen is the exchangeable ligand above the plane. The interaction of the six ligands with the metal center in oxyhemoglobin causes the six outer electrons in the five d orbitals of the ferrous ion to pair in the electronic orbitals of the lowest energy (Fig. 10.15). Because there are no unpaired electrons in the iron (or other atoms in hemoglobin), oxygenated blood is diamagnetic (χ < 0). In addition to intact RBCs containing oxygenated hemoglobin, other components of blood are also present in the hyperacute hematoma, including serum proteins and platelets, but they probably contribute little to the MR image (24,65). Because there is no paramagnetic component of blood at this time, there can be no proton–electron dipole–dipole interaction and no paramagnetic relaxation enhancement. Therefore, the bulk of a hyperacute hematoma would appear nearly identical to most brain lesions on MR, essentially as a high–spin-density region, with slightly shortened relaxation times (compared with water) due mainly to the macromolecular content of blood (i.e., protein content) (66). On clinical images, hyperacute hematomas appear slightly hypointense or isointense to brain on Tweighted images and slightly hyperintense to brain on T2-weighted images (Figs. 10.16 and 10.17). Although in theory the bulk of a hyperacute hematoma may not be distinguishable from other intracranial mass lesions (11,67), particularly at lower field, important clues to the presence of a hyperacute hematoma must be recognized (19). Specifically, a thin, irregular rim of marked hypointensity at the periphery of the lesion on T2-weighted images (Figs. 10.16–10.18) is paramount to recognize. This has been attributed to very rapid deoxygenation of blood within the hematoma at the blood–tissue interface. There is evidence from animal models that no iron storage products such as ferritin or hemosiderin are present in the surrounding brain at this early time point (19). The peripheral hypointensity is more evident on 3 T than on lower-field scanners and may only be identifiable on GRE images regardless of field strength (Fig. 10.19). This is one of many reasons why T2*-weighted GRE or some other highly sensitive scanning method, like SWI should be part of all routine stroke MR protocols. There may also be serum extravasation just beyond the hematoma (Fig. 10.17). If simple hyperacute hematomas are imaged using intravenous contrast administration, there should be no intralesional enhancement (Fig. 10.19). Note that on diffusion MR, intracellular blood shows relatively restricted diffusion compared with normal brain parenchyma (Fig. 10.5). Therefore, when interpreting calculated apparent diffusion coefficient images alone, an early hematoma would show restricted diffusion, even in the absence of acute infarction (22), underscoring the well-understood caveat that conventional images need to be interpreted alongside apparent diffusion coefficient images if accurate diagnoses are to be made. Acute Hematoma Notwithstanding the increasing demand for emergency MR in the setting of acute stroke, it is still accurate to state that, in most clinical settings, the earliest stage of intracranial hematoma likely to be commonly encountered by the clinical radiologist is the acute hematoma. The basis of the unique appearance of acute hematomas on MR can be traced to the biochemical state of the hemoglobin molecule. The role of hemoglobin is to bind oxygen in the lungs, where the partial pressure of oxygen is high enough to saturate the binding sites on the heme groups, and to transport it to the tissues, where the partial pressure of oxygen is low enough to allow dissociation. The partial pressure of oxygen in tissues undergoing aerobic respiration is lower than that required to saturate fully the oxygen-binding sites of hemoglobin, thus releasing molecular oxygen to the tissues. Within hours after bleeding, several important changes occur that dramatically affect the image of the acute hematoma. A cerebral hematoma causes compression of surrounding tissue, reducing perfusion and, therefore, oxygen delivery from fresh blood to these regions. Deoxygenation of the extravasated blood occurs due to several factors. The underperfused surrounding tissue lowers the tissue partial pressure of oxygen, thereby promoting oxygen dissociation. The erythrocytes are not aerobic but convert glucose to lactate anaerobically. The resultant lower pH also promotes oxygen dissociation through the Bohr effect. The accumulation of CO2 similarly promotes this effect.

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FIGURE 10.15 Schematic representation of the electronic configuration of the five d suborbitals of iron in its various biochemical forms based on the relative energies of the orbitals arising from interactions with the ligands coordinated to the iron center. The number of unpaired electrons determines χ, but the aggregation state of the iron determines the magnitude of χ.

FIGURE 10.16 Hyperacute hematoma. The preacute hematoma in the right subinsular lateral ganglionic region is hyperdense on computed tomography (A) and has dissected into the right lateral ventricle. Hematoma is isointense to gray matter and is surrounded by low intensity from clot retraction on T1-weighted image (B). Note the characteristic thin rim of marked hypointensity on the periphery of the hematoma on the T2-weighted image (C) due to early deoxygenation. Edema surrounding the lesion is high intensity on the T2-weighted image (C).

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FIGURE 10.17 Hyperacute hematoma. The bulk of the lesion is isointense on the T1-weighted image (A) and slightly hyperintense on the proton density–weighted (B) and T2-weighted (C) images. Note the peripheral rim of marked hypointensity, best seen on gradient-recalled echo (D). In addition, serum from clot retraction (open arrow) is identifiable adjacent to the hematoma and external to the rim of hypointensity, indicating that the hypointense rim is part of the clot and not the brain.

FIGURE 10.18 Hyperacute hematoma. Isointense right parietal mass with an intraventricular component on T1weighted image (left) has a thin, irregular rim of hypointensity on T2-weighted image (center). This rim of hypointensity is more apparent on GRE (right).

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FIGURE 10.19 Hyperacute hematoma, 3-T MR. The left parietal intraparenchymal hematoma is isointense to brain on T1 (A) and slightly hyperintense on T2 with only a trace of peripheral low signal at its periphery (B), even though this is a 3-T study. The GRE image clearly shows the peripheral and internal hypointensity (C). Note the absence of any enhancement after gadolinium (D) in this simple hematoma.

The loss of molecular oxygen changes the coordinate geometry of the heme ferrous ion to a fiveligand system of deoxyhemoglobin that decreases the energy separation between the groups of higherand lower-energy d orbitals. The six d electrons redistribute among the five d suborbitals, leaving four unpaired electrons of parallel spin (Fig. 10.15). Deoxyhemoglobin is thus paramagnetic (χ < 0). Because the paramagnetic ferrous ion is shielded from the close approach of water molecules by the hydrophobic cleft of the globin protein (Fig. 10.4), dipole–dipole interactions required for a relaxivity effect cannot occur. However, when deoxyhemoglobin is packaged within erythrocytes, the magnetic susceptibility of the interior of the RBC is different from the suspending diamagnetic environment (extracellular plasma), resulting in susceptibility variations within the hematoma. These susceptibility inhomogeneities result in T2* relaxation enhancement that is not mirrored in changes in T1 relaxation. Regardless of the precise site of the field gradients, it is the packaging of the paramagnetic deoxyhemoglobin within the erythrocytes that produces susceptibility gradients. The importance of the integrity of the RBC membrane has been demonstrated in vitro (7,27,64,68) and confirmed by in vivo diffusion MR (22). Although the actual site of the magnetic field gradient within or around the erythrocyte has not been clearly delineated, the most convincing evidence based on measurement of line widths of NMR signals for different nuclei with different intra- and extracellular distributions suggests that both intra- and extracellular magnetic field gradients are responsible for the susceptibility effect (7). Acute hematomas contain intracellular (compartmentalized) deoxyhemoglobin and consequently appear as markedly hypointense on T2-weighted images (12) (Figs. 10.20 and 10.21). Note that the longer the TE, the more signal decay occurs (Fig. 10.20). Furthermore, in theory, the longer the interecho interval (the time between the 180-degree RF pulses, or τcpmg), the longer is the time for the diffusing protons to experience differing magnetic fields, so the shorter is the apparent T2 (35). It, therefore, follows that for the diagnosis of acute hematomas on lower–field-strength scanners, one should use a long TR, but also a very long TE and long τcpmg, to exploit as much as practically possible the diffusion-related signal decay. We reiterate that GRE imaging is also very useful, particularly on low-field systems, and we routinely use GRE sequences in all clinical scenarios in which hemorrhage is a 669

reasonable likelihood (Fig. 10.22). Because these effects are proportional to the square of the applied magnetic field strength, very little effect is present in low-field systems (unless parameters are used to optimize visualization of T2 effects, i.e., long TR and extremely long TE with a long interecho time), so that under low-field conditions using conventional spin-echo techniques, the acute hematoma is usually isointense with brain on T2-weighted images. At high field strength, marked hypointensity is seen on T2-weighted and even more so on GRE images. The degree of hypointensity (the amount of T2 shortening) due to intracellular deoxyhemoglobin depends on the magnetic moment (which is proportional to the concentration of intracellular deoxyhemoglobin), the relative magnetic susceptibilities of the intracellular and extracellular spaces, the heterogeneity of distribution of the paramagnetic material (i.e., the deoxyhemoglobin) (69), the applied field strength, and pulse sequence parameters used in the imaging sequence. During the acute hematoma stage, the retraction of clot that occurs with deoxygenation effectively raises the hematocrit. The result of increasing protein content is well known (66) and causes parallel increases in the rates of T1 and T2 relaxation (1/T1 and 1/T2). This effect is not field dependent, would not change with oxygenation or TE, and would not be affected by the implementation of gradient refocusing (instead of RF refocusing, as in spin-echo imaging). The signal intensity of acute hematomas is influenced only to a minor extent by the protein content (24). At this relatively early stage of hematoma development, the surrounding edema gives a high-intensity perimeter around the hemorrhage on the T2-weighted images (Figs. 10.20 and 10.21). Fibrin clot formation and retraction have not been shown to affect significantly the in vitro appearance of the acute hematoma at 1.5 T (24).

FIGURE 10.20 Acute hematoma. The lesion near the fourth ventricle is isointense on T1-weighted image (A) and becomes hypointense on proton density–weighted (B) and T2-weighted (C) images. Minimal hyperintensity is already present on the periphery of the hematoma on T1-weighted image, indicating conversion to intracellular methemoglobin.

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FIGURE 10.21 Acute and subacute-to-chronic hematomas in hypertension, computed tomography (CT) versus magnetic resonance (MR). Acute left ganglionic hematoma is hyperdense on CT (A), isointense on T1-weighted image (B), and markedly hypointense on T2-weighted image (C) and gradient-recalled echo (D). Subacute-to-chronic hematoma in the right subinsular region is hypodense on CT and not definable as hemorrhage without MR, which shows a characteristic signal intensity pattern of free methemoglobin.

In acute hematomas, there is no evidence of high intensity on T1-weighted images within the bulk of the hematomas. In fact, the acute hematoma is isointense or minimally hypointense to brain on T1weighted images. The lack of hyperintensity of intracellular deoxyhemoglobin is attributed to the quaternary structure of the deoxyhemoglobin molecule, which precludes water protons from attaining the requisite proximity to the unpaired electrons of the paramagnetic deoxyhemoglobin molecule (Fig. 10.4). The result of the relatively large distance between water protons and the unpaired electrons of deoxyhemoglobin results in a lack of the dipole–dipole interaction between these substances. Therefore, no T1 shortening is observed on T1-weighted images. In practice, it is common to see a very thin peripheral conversion to methemoglobin at the initial time point of imaging on T1-weighted images, even though most of the lesion is isointense (Figs. 10.20 and 10.21). Note that the hypointensity of acute hematomas on T1-weighted images is mainly a reflection of T2 shortening, in that the signal has already decayed, due to the extremely short T2 of deoxyhemoglobin, even at the relatively short TE used on T1weighted images. Therefore, the hypointensity on what is called a T1-weighted image is actually a T2 effect. Subacute Hematoma The inflammatory repair response within the surrounding tissue of phagocytes, such as macrophages, infiltrates the boundaries of the hematoma to clear extravasated materials and damaged tissues. Glial cells also show phagocytic activity. RBCs are phagocytosed or lysed by enzymes released into the region by the inflammatory cells (44,70). As the energy status of the erythrocytes declines, the reductase enzyme systems of the RBC (NADH-cytochrome b5 reductase, NADPH-flavin reductase) (71) used to maintain the heme iron in the ferrous oxidation state become nonfunctional. Hemoglobin is oxidized to methemoglobin, in which the iron, still bound to the heme moiety within the globin protein, is in the ferric state with five d electrons. As such, the iron is paramagnetic (χ < 0). Note that if the O2 tension is too high or too low, conversion to methemoglobin is retarded (72,73); this retardation has an effect on hematoma appearance and has been theorized as the cause of the prolonged stage of hypointensity 671

on T2-weighted images in intratumoral bleeds (47). The globin also undergoes structural changes, ultimately irreversible, in which the ferric iron is no longer protected from the surrounding solvent (74) (Fig. 10.4). The electronic configuration of the iron changes from initially five unpaired electrons, one in each of the five d suborbitals, to one unpaired electron as the weak sixth ligand of water is exchanged for a hydroxide and then another imidazole nitrogen of a histidyl residue of the protein. These states of iron, termed the hemichromes, have been defined by electron paramagnetic resonance spectroscopy (75). As the paramagnetic center is now exposed to water, dipole–dipole interactions can occur to enhance relaxivity effects on T1 and T2 relaxation.

FIGURE 10.22 Evolving pontine hematoma. A: Axial computed tomography, 48 hours after ictus. B: Sagittal T1weighted magnetic resonance (MR), 48 hours after ictus. C: Axial T1-weighted MR, 48 hours after ictus. D: Axial T2weighted MR, 48 hours after ictus. E: Axial T1-weighted MR, 4 weeks after ictus. F: Axial T2-weighted MR, 4 weeks after ictus. The high-attenuation pontine hematoma on computed tomography (A) distorts the ventral aspect of the fourth ventricle on initial examination. Note that as early as 48 hours after the ictus, there is already peripheral hyperintensity on sagittal (B) and axial (C) T1-weighted images, indicating the presence of methemoglobin (1). The

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central portion of the lesion is hypointense and becomes black on long-repetition time/echo time image (D), consistent with intracellular deoxyhemoglobin (2), whereas the peripheral part is also markedly hypointense (panel D, 1), consistent with intracellular methemoglobin. Approximately 4 weeks later, most of the hematoma has filled in with hyperintensity on both T1-weighted (E) and T2-weighted (F) images, as a manifestation of extracellular methemoglobin (3). Simultaneous with the appearance of free methemoglobin, we see the peripheral rim of marked hypointensity (4) in the adjacent brain, especially prominent on the T2-weighted image (F), due to ferritin and hemosiderin.

FIGURE 10.23 Early subacute hematoma with intracellular methemoglobin. Hyperdense hematoma in the left frontal lobe on computed tomography (A) is high intensity on T1-weighted image (B) and markedly hypointense on T2weighted (C) and fluid-attenuated inversion recovery (FLAIR) (D) images, consistent with intracellular methemoglobin. Hyperintense edema surrounding the lesion is especially well seen on FLAIR (D).

For all practical purposes, high intensity is present on T1-weighted images whenever methemoglobin exists. Thus, a hematoma at this stage shows hyperintensity on T1-weighted MR images. This high signal intensity of early subacute hematomas typically begins at the periphery of the hematoma and converges radially inward (Fig. 10.22) (41). Theoretically, this occurs initially at the peripheral aspect of the hematoma (Figs. 10.20 and 10.21) because the outer rim is the region with optimal conditions for the autoxidation of the oxyhemoglobin (41). At this early subacute stage, marked hypointensity is still present in the periphery of the hematoma on the T2-weighted spin-echo image (Fig. 10.22). This is the sole instance in hematomas in which both mechanisms of relaxation enhancement (i.e., proton–electron dipole–dipole interaction and further T2 shortening from compartmentalized gradients of magnetic susceptibility) occur simultaneously (Figs. 10.22 and 10.23). With the initial appearance of peripheral intracellular methemoglobin, the center of the hematoma is unchanged (compartmentalized intracellular deoxyhemoglobin remains). Occasionally, an entire hematoma is imaged that has signal intensities consistent with total conversion to intracellular methemoglobin (Fig. 10.23). Intracellular methemoglobin has been proposed to be the basis for the appearance of the MR image at this transient stage of hemorrhage (41), that is, methemoglobin is believed to be compartmentalized within still-intact RBCs. This hypothesis has been substantiated by diffusion MR data (22). The approximate time range in which to identify the signal characteristics of intracellular methemoglobin in hematomas is usually 2 to 7 days after the hemorrhage. It should be noted that in clinical practice it is distinctly unusual to identify hematomas containing the signal intensity pattern ascribed to intracellular methemoglobin. The decline in energy status of the RBC causes loss of membrane integrity. Because the loss of RBC integrity removes the paramagnetic aggregation responsible for the susceptibility-induced T2 relaxation 673

process, the effective T2 shortening now disappears. This phenomenon has been documented to occur on lysis of red cells containing deoxyhemoglobin in in vitro experiments (35). These changes occur along with the further formation of methemoglobin from deoxyhemoglobin. Hemolysis results in the accumulation of extracellular methemoglobin within the hematoma cavity. The extracellular methemoglobin further enhances T1 relaxation (35) and is manifested as high intensity on the T1weighted images (Figs. 10.21 and 10.23). Concurrent with these changes, high signal intensity also appears on the T2-weighted images. As already stated, most subacute hematomas in clinical practice are already seen as high intensity on both T1- and T2-weighted images. A number of factors probably contribute to this seemingly contradictory appearance because we have already stated that methemoglobin, in the absence of RBC integrity, allows dipolar relaxation mechanisms to ensue, which theoretically shorten both T1 and T2. At this stage of evolution, the hemorrhage is essentially a complex lesion (analogous to a solution) of paramagnetic methemoglobin and nonparamagnetic proteins, but to a great extent it is a very high proton density collection. The presence of methemoglobin shortens the T1 (compared with either a solution of nonparamagnetic protein at clinically relevant concentrations or simple water) of this relatively high– spin-density (compared with brain parenchyma) lesion and causes high intensity on virtually all conventionally used spin-echo images (14). In fact, measured T1 values of subacute-to-chronic hematomas are similar to those of lower-intensity white matter (14). Note that if one used a very long TR (e.g., greater than 10 seconds), the subacute-to-chronic hematoma would appear of lower intensity because the extremely long TR would eliminate any contribution of T1 shortening to the intensity, so T2 effects would dominate the contrast (Fig. 10.24). After cell lysis, therefore, the late subacute-to-chronic hematoma has high intensity on T2-weighted images, which is due to T1 shortening of a high–spindensity solution, as described by Hackney et al. (14). Results obtained by direct measurement by Gomori et al. (35) and those indirectly obtained from the experiments of Bradley and Schmidt (76) and Di Chiro et al. (11) showed that extracellular methemoglobin causes significantly more T1 relaxation enhancement than intracellular methemoglobin. The explanation for this phenomenon, which is probably not evident on clinical images, is obscure but clinically unimportant. Eventually, as the methemoglobin is resorbed and degraded, the amount of relaxation time enhancement declines and the signal intensity decreases from its marked hyperintensity on T1-weighted images. Of significance, the high water content in the subacute-to-chronic hematoma cavity contributes significantly to the signal intensity of the chronic hematoma on both T1- and T2-weighted images.

FIGURE 10.24 Effect of very long repetition time (TR) on the appearance of free methemoglobin in late subacute hematoma. A: Routine long-TR/short–echo time (TE) magnetic resonance (MR) image (3,000/30). B: Very long TR/short-TE MR image (6,000(30). Although this left temporal extraaxial hematoma (arrows) is high intensity on routine long-TR image (A), it becomes low intensity using very long TR (B) because the T1 effects are minimized.

Extracellular protein degradation releases iron that is detoxified by chelation to extracellular ironbinding proteins such as lactoferrin and transferrin. These binding proteins serve as detoxification and transport proteins, recycling free iron back to the reticuloendothelial system via the circulation. The chelated iron remains paramagnetic (χ < 0). The iron remains accessible to water, so that relaxivity effects may be expected. The specific relaxivity and susceptibility effects of ferric ions chelated to these proteins are described in vitro (37,77–79) but are unknown for resolving in vivo hemorrhage. The concentration of these substances may be too low to have a significant role in determining signal intensity within an MR image. Remote Hematoma and Residual Iron 674

The effects of iron storage substances on the MR characteristics of normal brain tissue have been summarized elsewhere (28,80,81). Iron from hemorrhage clearly enters and must be processed in a different manner, although the final products may be similar. Much of the intrinsic iron, and probably iron arising from hemorrhage, is not yet biochemically characterized (28,82). After hemorrhage, heme proteins phagocytosed by macrophages and glial cells are degraded in lysosomes, with the iron being stored in the hydrophobic center of the major iron storage protein called ferritin (54,83). Ferritin is a water-soluble protein of molecular weight about 450,000 formed from 24 polypeptide subunits surrounding a crystalline core of ferric oxyhydroxide containing up to 4,500 ferric ions. If the quantity of available iron exceeds the capacity of the cell to synthesize apoferritin, excess iron is stored as hemosiderin (54). Hemosiderin is a poorly biochemically characterized insoluble aggregation of ferric oxyhydroxide with less protein than ferritin. These storage forms with large aggregates of iron behave paramagnetically at biological temperatures (χ < 0) (28,40,78,79,84), but at very low temperatures they behave antiferromagnetically and probably superparamagnetically (28). The iron in these storage forms is inaccessible to water, so relaxivity effects are not observed. Magnetic susceptibility variations are present in tissues containing such materials, with effects observed on T2*. On MR, along with the appearance of the extracellular methemoglobin constituting subacute-tochronic hematomas, a thin regular rim of low signal intensity begins to appear around the hematoma in the adjacent brain parenchyma that is most marked on the T2-weighted images (12) (Figs. 10.20 and 10.21). This rim grows in thickness as the hematoma resolves. The source of this circumferential region of T2 shortening is the iron in the aforementioned storage forms that has been scavenged from methemoglobin breakdown products and accumulates within the lysosomes of macrophages and glial cells. An area of marked hypointensity on T2-weighted images and particularly on GRE images can remain at the site of an old hemorrhage indefinitely (Figs. 10.25 and 10.26). This appearance is analogous to the yellow–orange staining of the brain by hemosiderin deposits seen in pathology specimens at sites of old intraparenchymal hemorrhage (Fig. 10.26). The presence of the low signal intensity on T2-weighted images from old hemorrhage, when seen in association with a separate acute hemorrhage, can be used to infer the presence of certain underlying etiologies (e.g., bleeding diathesis, multiple occult cerebrovascular malformations, etc.) and is especially useful in the evaluation of suspected cases of child abuse (implying that there were multiple different episodes of bleeding). Furthermore, the absence of prominent hypointensity at the periphery of an old hematoma suggests deviation from the normal evolution of hemorrhage and can indicate an underlying disruption of the blood–brain barrier (47), such as seen in intratumoral hemorrhage.

FIGURE 10.25 Chronic hematoma with persistence of a small amount of methemoglobin. A: Sagittal T1-weighted magnetic resonance (MR). B: Axial T2-weighted MR. Three years after this patient's hematoma, a small amount of hyperintense methemoglobin (A, arrows) persists amid the dense hypointensity of ferritin/hemosiderin deposition seen on the T2-weighted image (B).

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FIGURE 10.26 Chronic hematoma with residua of slitlike cavity lined by ferritin/hemosiderin. A: Computed tomography (CT). B: T1-weighted magnetic resonance (MR). C: T2-weighted MR. D: Necropsy specimen, gross. E: Perl stain for hemosiderin. F: Immunohistochemical stain for ferritin. Chronic right subinsular hematoma (arrows) is seen as a subtle region of slight hyperdensity on CT (A), low intensity on T1-weighted MR (B), and profound hypointensity on T2-weighted MR (C). No evidence of central fluid or central methemoglobin is present in this collapsed cleft, the only residua of prior hemorrhage. Necropsy section shows collapsed cleft as residua of prior subinsular hematoma (D). Histopathology stains are positive for hemosiderin (E, dark blue) and ferritin (F, dark brown).

As the methemoglobin in the cavity is slowly broken down into smaller degradation products, its T1 676

shortening effect is lost (75). This process can result in a slowly decreasing intensity in the cavity on T1weighted images. These signal changes of decreasing intensity from methemoglobin degradation and resorption usually are not evident in intraparenchymal hematomas until several months after the bleed. Occasionally, methemoglobin can even persist for years (Fig. 10.25), although its presence after several years probably indicates either recurrent bleeding or an abnormal evolution of blood breakdown products, one of several features of underlying tumor as the etiology of the bleed (47). Remote hemorrhage may actually have any of the following three appearances on spin-echo images: central hyperintense methemoglobin with peripheral hypointense hemosiderin and ferritin (Fig. 10.22), central cerebrospinal fluid (CSF)–like intensity with peripheral hypointensity (Fig. 10.27), and a linear residual cleft of hypointensity (Fig. 10.26), whereby central methemoglobin and central fluid have been completely resorbed. Thus, by the time several months or years pass after the hemorrhagic episode, the only clue that a cavity was once hemorrhagic may be the collapsed cleft of hemosiderin and ferritin in the adjacent brain. As is the case for acute hematomas, if the T2 is significantly shortened below the TE used for T1-weighted images, then the susceptibility effect will be observed on T1-weighted images and hypointensity will be seen from short T2 even on the T1-weighted image. TABLE 10.10 Etiologies of Intraparenchymal Hematomas

MR PATTERNS SPECIFIC FOR CLINICAL ETIOLOGIES OF INTRAPARENCHYMAL HEMORRHAGE There is a long list of clinical etiologies of intracerebral hematomas (Table 10.10), and a detailed discussion of those entities and their imaging findings are beyond the scope of this chapter (the reader is referred to the appropriate chapters in this text for a detailed discussion of those entities). Based on a thorough familiarity with the previously described signal intensity patterns in evolving intracranial hematomas, important clues can be recognized and quite often specific diagnoses can be deduced by a purely pattern recognition consideration of the MR findings of intracerebral hemorrhage. The accurate diagnoses of many of these entities are often based on traditional neuroanatomic features (e.g., location, multiplicity, symmetry, mass effect) (Figs. 10.28–10.32). Some of these entities are recognized only after the supplemental use of iron-sensitive sequences because their hemorrhagic components may only be detected by GRE or SWI. Therefore, as stated elsewhere in this text, we routinely add GRE sequences to those protocols for those cases in which a lesion that is often associated with hemorrhage is suspected. These diagnoses can often be prompted by the MR alone, even in the absence of clinical history (Table 10.11).

FIGURE 10.27 Chronic hematoma. Left ganglionic hyperintense lesion with surrounding rim of markedly hypointense

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hemosiderin indicates residua of chronic hematoma on T2 (A). Note some of the signal of the fluid-filled residual cavity is suppressed on fluid-attenuated inversion recovery (B).

FIGURE 10.28 Right parietal lobe cavernous angioma. Hyperintensity centrally on T1-weighted image (A) indicating methemoglobin, surrounded by marked hypointensity of storage iron on T2-weighted image (B) without edema and more prominent hypointensity on gradient-recalled echo (C) (in this case, obscuring the central signal) represent a pattern that is nearly specific for cavernous angioma.

FIGURE 10.29 Acute hemorrhage in acute infarction. Acute left occipital lobe hematoma on T2-weighted (A) and gradient-recalled echo (B) images is clearly defined as hemorrhagic infarction when one notes diffusion-weighted images (C–F) showing restricted diffusion within left posterior cerebral artery territory.

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FIGURE 10.30 Acute hemorrhage in acute infarction, only seen on gradient-recalled echo. Right posterior cerebral artery territory infarction on T2-weighted (A) and fluid-attenuated inversion recovery (B) is shown to contain acute hemorrhage only visible on gradient-recalled echo (C).

Hemorrhagic Intracranial Neoplasm One entity that illustrates the concept of using MR to further characterize a CT-documented hematoma and will serve as the prototype of lesions with important secondary MR findings in intracranial hemorrhage is intratumoral hemorrhage. Hemorrhage into malignant neoplasms accounts for approximately 10% of all spontaneous intracranial hematomas (85). It occurs in up to 14% of brain metastases (86) and less than 5% of primary gliomas (87). Of all intracerebral metastases, those most prone to hemorrhage include melanoma, choriocarcinoma, renal cell carcinoma, bronchogenic carcinoma, and thyroid carcinoma (85,86,88). Of primary gliomas, glioblastoma multiforme, oligodendroglioma, and ependymoma are most likely to demonstrate significant hemorrhage on pathology, although all malignant gliomas commonly show microscopic evidence of hemorrhage. The pathogenesis of hemorrhage into intracerebral neoplasms is probably multifactorial. Factors such as high grade of malignancy, abnormal tumor vascularity, rapid tumor growth with subsequent necrosis, and vascular invasion have all been proposed as mechanisms of intratumoral bleeding (89–91). The preoperative diagnosis of tumor as the underlying etiology of intracranial hemorrhage is often extremely difficult. CT patterns of intratumoral hemorrhage are extremely variable (90). Atypical location, multiplicity of hemorrhagic lesions, and early intravenous contrast enhancement may suggest malignancy as the etiology of intracranial bleeding on CT. Cerebral angiography has also occasionally played a role in revealing underlying tumor as the cause of intracerebral hematoma. Clearly, these modalities are often of limited use in elucidating the underlying malignant lesions because the hematoma often obliterates any evidence thereof (87).

FIGURE 10.31 Patterns of hemorrhage in the elderly, and importance of gradient-recalled echo. A: Hypertensionassociated remote hemorrhages are characteristically located in the deep gray matter and often associated with lacunar infarctions. Note that these hemorrhages are not identifiable on T2-weighted images (top) but are obvious on

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gradient-recalled echo (bottom). B: Remote hemorrhages due to amyloid angiopathy are situated peripherally and spare the basal ganglia, as seen on gradient-recalled echo (bottom). Often these patients have normal T2-weighted images.

FIGURE 10.32 Thrombosed giant aneurysm. Large hemorrhagic mass on T1-weighted (top), T2-weighted (middle), and fluid-attenuated inversion recovery (bottom) images shows the characteristic multilamellated pattern of a clot having various ages and central hyperintensity on T1-weighted images around the most recently clotted lumen.

TABLE 10.11 General Pattern Recognition Clues to Etiologies of Intracranial Hematomas

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MR signal intensity patterns of hemorrhagic intracranial malignancies differ from those of nonneoplastic intracranial hematomas (Table 10.12) and can generally be used to distinguish tumor from lesions such as cavernomas (47). In general, signal intensity patterns are more heterogeneous and markedly complex when compared with those seen from nonneoplastic hematomas (Figs. 10.33 and 10.34). In malignant lesions, multiple 681

concomitant stages of hematoma appear, often in an atypical pattern. The complex appearance of hemorrhagic tumors is further complicated by the frequent finding of areas of nonhemorrhagic tumor tissue (Fig. 10.34). Cystic or necrotic regions containing hemorrhage debris or hemorrhagic fluid levels also add to this complex appearance (Figs. 10.33–10.35). TABLE 10.12 Intratumoral Hemorrhage versus Benign Intracranial Hematomas

The temporal evolution of MR intensity patterns in hemorrhagic malignancies is often delayed or different from those seen in benign intracranial hemorrhage (47). Intracellular deoxyhemoglobin is found only in acute nonneoplastic hematomas but can persist for weeks in intratumoral hemorrhage (Fig. 10.33). Subacute methemoglobin (high intensity on T1-weighted images), which forms initially at the periphery of nontumoral intracranial hematomas and subsequently converges over days, can remain at the periphery of hemorrhagic tumors for months. Furthermore, the lack of evolution into peripheral hemosiderin is common in intratumoral hemorrhages (Fig. 10.36). This overall delay in hemorrhage evolution in malignant lesions, as compared with the evolution seen in nonneoplastic hematomas, has been postulated to be caused by profound intratumoral hypoxia (47), which has been documented in human neoplasms (92). Because it is well known that methemoglobin formation is intimately related to local oxygen tension (72,73), it follows that the persistence of marked intratumoral hypoxia could delay methemoglobin formation and alter the expected MR signal intensity patterns in hemorrhagic neoplasms (Fig. 10.37). Recurrent bleeding has also been postulated as an etiology for these findings in neoplastic hemorrhages (93).

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FIGURE 10.33 Hemorrhagic neoplasm with debris–fluid levels and persistent deoxyhemoglobin. Hemorrhagic glioblastoma in the left hemisphere shows multiple debris–fluid levels on the first postoperative scan (top set of T1and T2-weighted images). Follow-up magnetic resonance (bottom set of T1- and T2-weighted images) 2 months after partial resection of the posterior part of the lesion shows the persistence of deoxyhemoglobin within the ventral hemorrhagic portion of the mass. Also, note the lack of any evolution of the ventral hemorrhagic part of the mass, persistent hyperintensity on T2-weighted images around the hemorrhage, and marked mass effect, even though most of the lesion is chronic.

FIGURE 10.34 Hemorrhagic neoplasm with enhancing nonhemorrhagic tumor tissue. Hemorrhagic glioblastoma shows complex signal on T1-weighted (left) and T2-weighted (center) images, due to hemorrhagic components with different ages, debris–fluid levels indicating cystic or necrotic parts of the tumor, and enhancing nonhemorrhagic tumor tissue on postcontrast T1-weighted image (right, arrow).

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FIGURE 10.35 Hemorrhagic necrosis in tumor, anaplastic oligodendroglioma. Extensive heterogeneous hemorrhagic anaplastic oligodendroglioma in the right frontal lobe (A–C) shows multiple debris–fluid levels and extensive “edema” with irregular enhancement (D), all findings typical of hemorrhagic neoplasm with necrosis.

FIGURE 10.36 Hemorrhagic neoplasm with absence of hemosiderin adjacent to chronic hematoma. Hemorrhagic glioblastoma shows mainly subacute-to-chronic hemorrhage on T1-weighted (left) and T2-weighted (center) images. Note persistent mass effect and adjacent hyperintensity, despite chronic hemorrhage. Also, note the absence of a hypointense rim of storage iron on both T2-weighted (center) and gradient-recalled echo image (right) on the ventromedial border of the lesion.

A less well-known clue to discerning the true cause of a lesion that appears to represent an acute hematoma containing intracellular deoxyhemoglobin is the signal change when comparing the T2 scan to the gradient-echo image. If the cause of the low signal on T2 is compartmentalized paramagnetic deoxyhemoglobin, then such a lesion would necessarily also be markedly hypointense to brain on a T2*weighted gradient-echo image; indeed, this is seen in the clinical setting. The exception is the clue to the mimic of acute hemorrhage due to mucin-containing tumor. In that case, mucinous masses are only moderately low signal or nearly isointense to gray matter on gradient-echo images rather than show the expected profound hypointensity of acute hematomas (Fig. 10.38). These lesions also enhance internally after gadolinium, which of course excludes simple acute hematoma. A consistent feature of hemorrhagic tumors is a lack of a well-defined, complete, markedly hypointense rim (47), a characteristic finding in nonneoplastic hematomas in their subacute and chronic 684

stages. It has been postulated that the persistent blood–brain barrier disruption known to occur in intracranial malignancies allows more efficient removal of iron storage products (47). As a result, this marker of prior intracranial hemorrhage, which persists indefinitely in nonneoplastic intracranial hematomas (12), is not consistently observed in the subacute and chronic stages of intratumoral hemorrhage (Fig. 10.36). A similar lack of hypointensity on T2-weighted images in the follow-up of prior intrapituitary hemorrhage (Fig. 10.39) can also be explained by the absence of a blood–brain barrier. Finally, an important finding in hemorrhagic neoplasms on unenhanced MRI is the persistent and prominent perilesional high intensity (representing edema and tumor) on T2-weighted MR images, even when the hemorrhage is in the chronic stage (Fig. 10.40). Edema is a well-documented prominent feature on CTs of intracranial metastases (94). The depiction of “edema” by MR images in the presence of a chronic intracranial hematoma precludes the radiologist from confidently ascribing a benign etiology to the hemorrhage. An important role for intravenous contrast is in distinguishing hemorrhagic tumor from hematomas without underlying lesions. This diagnosis can be revealed by any of the following findings: (a) intrahematoma enhancement in a presumed acute or hyperacute hematoma (Figs. 10.38 and 10.41), whereas benign hematomas do not show enhancement until they evolve into the subacute stage, when a thin rim of peripheral enhancement is seen; (b) irregular or nodular enhancement outside the area of the hemorrhage (Fig. 10.33); or (c) within a focal portion of the hematoma itself, regardless of age (Fig. 10.42).

FIGURE 10.37 Hemorrhagic metastasis, delayed evolution. The hematoma is still displaying the intensity pattern of intracellular methemoglobin on T1 (A) and T2 (B) images despite the fact that it is more than 3 weeks old. This delayed evolution is a feature of intratumoral hemorrhage.

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FIGURE 10.38 Mucinous metastases. The left cerebellar mass is isointense on T1 (A) and hypointense on T2 (B) images, a pattern suggestive of acute hematoma. However, gradient-echo image (C) does not display the expected marked hypointensity of paramagnetic deoxyhemoglobin within the lesion, signifying nonparamagnetic mucin as the cause of low signal. After gadolinium (D), note the intralesional enhancement, eliminating acute hematoma and in fact proving the underlying lesion (neoplasm) in mucinous metastasis.

FIGURE 10.39 Pituitary hemorrhage without iron storage hypointensity on follow-up. A: Coronal T1-weighted magnetic resonance (MR), initial study. B: Coronal T2-weighted MR, initial study. C: Coronal T1-weighted MR, 6 weeks later. D: Coronal T2-weighted MR, 6 weeks later. High-intensity methemoglobin (1) within a complex pituitary adenoma is demonstrated initially (A,B). Note the resolution of methemoglobin (C) 6 weeks later, without evidence of the hypointensity on T2-weighted image from iron storage forms (D). (From Barkovich AJ, Atlas SW. Magnetic resonance imaging of intracranial hemorrhage. Radiol Clin North Am 1988;26:801–820, with permission.)

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FIGURE 10.40 Hemorrhagic astrocytoma, suggested by persistent perihematoma hyperintensity. A: T1-weighted magnetic resonance (MR), initial scan. B: Axial long–repetition time/echo time MR image (2500/80), initial scan. C: Coronal T1-weighted MR, 1-month follow-up. D: T2-weighted MR, 1-month follow-up. E: T1-weighted MR, 13-month follow-up. F: T2-weighted MR, 13-month follow-up. Initial MR (A,B) showed right parietal hemorrhage composed of central deoxyhemoglobin and peripheral methemoglobin surrounded by high intensity on T2-weighted image (B), a universal finding in acute/early subacute hemorrhage. One-month follow-up scan (C,D) shows evolution into the appearance of chronic hematoma, with central methemoglobin, peripheral ferritin/hemosiderin, and collapse of mass with resolution of the bulk of the mass effect. However, the persistence of adjacent high intensity (D, arrows) precludes the diagnosis of benign hematoma because there should be complete resolution of the “edema” in the chronic stage. The delayed follow-up scans (E,F) finally revealed growth of the underlying large astrocytoma, which eventually spread aggressively into both hemispheres via the corpus callosum.

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FIGURE 10.41 Early hematoma with underlying metastatic tumor. Heterogeneous lesion on T1 (A) and T2 (B) shows striking intralesional contrast enhancement (C) indicating the presence of an underlying tumor in this early stage hematoma.

MR Mimics of Intracranial Hemorrhage Signal intensity alone is rarely sufficient for a correct diagnosis by a radiologist. Even intracranial hemorrhage, with its characteristic signal intensity pattern, can be mimicked by other entities. The radiologist should be aware of the list of entities other than hemorrhage that can be associated with high intensity on T1-weighted images (Table 10.13) or marked hypointensity on T2-weighted images (Table 10.14, Figs. 10.43–10.47). The distinction between hemorrhage and its mimics is successfully made when one considers the associated features of the signal intensity alterations, including, most important, the anatomic distribution of the abnormal signal, notably symmetry, which is highly unusual in hemorrhage; the absence of mass effect, which must be present in early stages of hemorrhage; the presence or absence of symptoms; and the course of onset of symptoms, in relation to the “stage of the hemorrhage.” One exception may be in tissue characterization of signal alterations in brain tumors, where intratumoral calcification can appear in a variety of ways that mirror signal changes seen in intratumoral hemorrhage (Figs. 10.48 and 10.49). Note that paying attention to the detail of the signal intensity pattern on all MR images, including GRE and FLAIR, typically permits the radiologist to be accurate in diagnosing acute hematomas in virtually all cases. The reader is referred to other sections in this text for more complete discussions of these entities.

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FIGURE 10.42 Hemorrhagic tumor revealed by gadolinium. Left occipital hyperacute hematoma on computed tomography (A) and T1 (B) and T2 (C) images shows focal irregular ring enhancement after gadolinium (D), proving the neoplastic etiology of the hemorrhage.

TABLE 10.13 Mimics of Hemorrhage: Hyperintensity on T1-Weighted Images

TABLE 10.14 Mimics of Hemorrhage: Hypointensity on T2-Weighted Images

Extraaxial Central Nervous System Hemorrhage Subarachnoid Hemorrhage 689

The diagnosis of acute SAH has been a mainstay of neuroradiology since the advent of CT. There can be no question that it is absolutely essential to diagnose SAH with the highest degree of sensitivity and specificity. The most common atraumatic cause of SAH in the adult is a ruptured aneurysm (Table 10.15), a devastating event if left untreated, with a 60% to 70% morbidity and mortality (95). Adding to the extraordinary risk of missing the diagnosis is the knowledge that neurosurgical treatment of unruptured aneurysms is associated with very low morbidity and mortality (96) (i.e., this is a “treatable” disease). Imaging with CT plays an indispensible role in acute SAH today, notwithstanding the often stereotypical clinical presentation of the patient to the emergency room physician. First, the confirmation of the diagnosis (with or without lumbar puncture) is readily made by CT, so that clinical mimics of SAH, such as migraine headache or intraparenchymal bleed, can be quickly dispensed with. The identification of acute SAH then immediately leads to an accompanying CT angiogram (CTA) for the diagnosis and full characterization, or the exclusion, of an intracranial aneurysm. The triage of the patient after CT and CTA is then rapidly initiated and directed toward either endovascular or neurosurgical aneurysm treatment, often occurring within 24 hours of the initial ictus to avoid the risks of early rebleeding. Second, the localization of the subarachnoid blood is useful to suggest the location of the aneurysm that had ruptured and to direct the surgical approach, particularly in cases of multiple aneurysms. Third, the identification of acute hydrocephalus is important to prioritize therapeutic intervention. Overall, the diagnosis of acute SAH on CT is well established in clinical practice (97–99), where the sensitivity for acute SAH is believed to approach 100%.

FIGURE 10.43 Fahr disease. Extensive bilateral deep gray matter and white matter calcification on computed tomography (A,B) is seen as hyperintensity on T1-weighted axial (C) and coronal (D) magnetic resonance.

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FIGURE 10.44 Hyperintensity on T1-weighted magnetic resonance due to subarachnoidal Pantopaque. Small foci of hyperintensity in the right sylvian fissure on T1-weighted image (A, arrows) are hypointense on T2-weighted image (B) and represent droplets of Pantopaque from a prior myelogram. In this case, the signal intensity pattern resembles that of intracellular methemoglobin.

FIGURE 10.45 Chronic liver disease. T1-weighted images (A,B) show hyperintensity in the upper brainstem and globus pallidus, characteristic locations for chronic liver disease, as well as hyperalimentation. These are believed to be related to manganese deposition. Note that T2-weighted images (C,D) in these regions are typically normal when the signal changes are due to chronic liver disease.

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FIGURE 10.46 Hypoparathyroidism. Dense bilateral calcification in the basal ganglia and dorsal thalami on computed tomography (A) is hyperintense on sagittal T1-weighted images (B,C) and markedly hypointense on T2-weighted image (D).

FIGURE 10.47 Mucinous adenocarcinoma metastases. Two masses, isointense to brain on T1-weighted images (top) and hypointense on T2-weighted images (middle), with edema and mass effect, suggest either acute hemorrhage or mucinous content. On close inspection, there is irregular intralesional hyperintensity on T2-weighted images within both of the lesions, which would not be consistent with acute hematomas and raises the suspicion of necrosis. The irregular, thick, ringlike enhancement of the cerebellar mass is highly suggestive of neoplasm rather than infection or any other cause of enhancing ring lesions (bottom). The temporal lobe mass also enhances in a nearly solid fashion. The patterns of enhancement exclude simple acute hematomas.

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FIGURE 10.48 Calcification, intratumoral (ependymoma). The intraaxial mass in the left frontal lobe shows high intensity on T1 (A) and irregular, marked hypointensity on T2* gradient echo (B), findings that in this case indicate irregular calcification within this ependymoma.

FIGURE 10.49 Calcification, intratumoral (pleomorphic xanthoastrocytoma [PXA]) computed tomography shows a heavily calcified mass with noncalcified portions (A). The T2 image (B) demonstrates solid tumor but fails to demonstrate any signal suggestive of calcification, whereas the gradient-echo image (C) shows the marked signal loss of calcification in this proven PXA.

Although brain MR has clearly replaced, or at least obviated, CT for most neurologic diseases, one of the most important uses of head CT remains suspected acute SAH. Arguably, the most important exception to the superiority of MR over CT in neuroradiology has been in this setting (18,100,101). Chakeres and Bryan (102), using an in vitro model, reported that, theoretically, conventional MR should be more sensitive to acute SAH than CT. Although some clinical studies have claimed that conventional MR has high sensitivity and therefore is a reliable imaging technique for acute SAH (103–107), these 693

have been highly controversial (101). In fact, despite in vitro relaxation rate changes and scattered clinical reports, it has been generally accepted that the use of conventional T1- and T2-weighted MR evaluation for acute SAH is very limited (Figs. 10.50 and 10.51). It has been suggested from in vitro experiments that the cause of the insensitivity of conventional MR for acute SAH is the relatively oxygen-saturated hemoglobin present in the subarachnoid space (106) (Fig. 10.52). The conversion of oxyhemoglobin to deoxyhemoglobin (and subsequently to methemoglobin) requires a relatively narrow range of oxygen tension (72,73). This state is rapidly achieved in isolated intracranial hematomas, resulting in characteristic marked hypointensity on T2-weighted images in the acute stage, and it is also seen in isolated clots in the subarachnoid space (Fig. 10.53). Additional factors that have been invoked to explain the insensitivity of MR for acute SAH include lack of hemoconcentration and clot retraction in diffuse SAH, confounding motion (circulation) of subarachnoid space contents and brain and vascular pulsations during the cardiac cycle. TABLE 10.15 Etiologies of Subarachnoid Hemorrhage

More recently, fluid-attenuated inversion recovery (FLAIR) imaging, now part of routine brain MR protocols, has been shown to be highly sensitive to acute, subacute, and chronic SAH. FLAIR MR uses an inversion recovery pulse sequence with an inversion time that effectively nulls the high signal intensity of CSF. A long TE is used to produce a heavily T2-weighted sequence but without the high signal typically associated with CSF on T2-weighted images. Clinical studies have suggested FLAIR is highly sensitive for the detection of acute SAH, even when diffuse and even in the absence of clot (Figs. 10.50 and 10.51) (107,108). In a small subgroup of patients with acute SAH among a larger group of patients with proven subarachnoid space disease of varying etiologies, a blinded reader study (109) found FLAIR to be 100% sensitive for acute SAH (Fig. 10.54 and 10.55). However, FLAIR is nonspecific (110) in terms of differentiating subarachnoid space diseases related to blood, inflammation, or tumor, because the signal intensity of CSF on FLAIR images changes with protein concentration (111). Studies suggest that FLAIR may even be more sensitive to CT for acute SAH (112,113), although this may be less relevant than the practical issues like near-universal 24-hour availability of CT in the emergency clinical setting (Figs. 10.56 and 10.57). After recurrent or chronic SAH, subpial deposition of hemosiderin sometimes occurs, resulting in superficial hemosiderosis (or superficial siderosis) (Figs. 10.58 and 10.59) (41). This entity may be clinically incidental, but patients often demonstrate cranial nerve palsies, hearing loss, and cerebellar ataxia. Intracranial hemorrhage from tumors that continue to bleed, or aneurysmal hemorrhage (Fig. 10.60), can result in superficial hemosiderosis. Regardless of the source of the recurrent bleeding, the entity is manifested as marked hypointensity along the parenchymal surfaces on T2-weighted images. The cerebellum is a particularly common site for hemosiderin deposition in siderosis and is typically more severely affected with hypointensity and concomitant parenchymal loss (cerebellar atrophy) on MR. This relative localization of imaging findings correlates with the relative predilection of symptoms referable to the posterior fossa in these patients, the most common of which are sensorineural hearing loss and ataxia. In the absence of an intracranial cause for the siderosis, an ependymoma of the conus medullaris or other spinal source of bleeding should be explored as the etiology of the recurrent hemorrhage. Intraventricular siderosis is a common sequela of neonatal intraventricular hemorrhage (114) in the pediatric population, whereas intraventricular siderosis in an adult is usually from intracranial vascular malformations and aneurysms.

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FIGURE 10.50 Acute traumatic subarachnoid hemorrhage with contusion, computed tomography (CT) versus magnetic resonance (MR). A: CT shows a left temporal hemorrhagic contusion with very subtle temporal-occipital acute subarachnoid hemorrhage (SAH). B, C: Respective T1- and T2-weighted MR demonstrate acute intraaxial hematoma with edema but no clear evidence of acute SAH. D: Fluid-attenuated inversion recovery shows contusion and obvious acute SAH in the left temporal and occipital regions and very thin right subdural hemorrhage posteriorly.

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FIGURE 10.51 Acute aneurysmal subarachnoid hemorrhage, computed tomography (CT) versus magnetic resonance (MR). Top: Left sylvian cistern acute hemorrhage extends into the left sylvian fissure on CT. Middle: Proton density–weighted MR shows no definite abnormality. Bottom: Fluid-attenuated inversion recovery clearly defines abnormal hyperintensity within subarachnoid spaces of the left hemisphere.

Subdural and Epidural Hematomas Subdural and epidural hematomas can be easily identified by T1- and T2-weighted MR images, because the contrast between calvarium (marrow and cortical bone) and blood is high (Fig. 10.61), regardless of what pulse sequence is used. Traditional morphologic criteria that are based on CT can also be applied to MR images for the precise compartmentalization of these extraaxial collections. The problem of “isodense” subdural hematomas on CT is not an issue at all on MR because these hematomas are subacute, and methemoglobin (their main constituent) is typically hyperintense on MR (Figs. 10.60 and 10.61). Perhaps the most common pitfall of evaluating extraaxial hematomas by MR is potential confusion of marrow fat with hyperintense blood. The solution for such dilemmas is simply consciously to identify each component of the extracerebral tissue, starting from extracranial subcutaneous fat and moving layer by layer inward.

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FIGURE 10.52 Acute subarachnoid hemorrhage, spinal. Intermediate signal intensity filling the subarachnoid space on T1 (A) is heterogeneous and consistent with acute subarachnoid hemorrhage on T2 (B). Note that a subarachnoid hemorrhage is often not clotted and therefore does not necessarily demonstrate the signal of deoxygenated blood on T2 magnetic resonance imaging.

FIGURE 10.53 Acute intraventricular hemorrhage with isolated clot, ruptured arteriovenous malformation. Sagittal T1weighted image (A) shows abnormal signal within the fourth ventricle. Also note abnormal signal in the lateral ventricle and prominent vessels in the midline and along the superior vermis, suspicious for arteriovenous malformation. Axial proton density–weighted (B) and T2-weighted (C) magnetic resonance shows acute intraventricular clot, which is more hypointense on GRE image (D).

FIGURE 10.54 Benign perimesencephalic subarachnoid hemorrhage. CT scan (A) and FLAIR image (B) both clearly demonstrate blood in the prepontine cistern. However, flow-related artifacts often plague FLAIR around the basal cisterns and could mimic or obscure acute blood in this region.

FIGURE 10.55 Intraventricular hemorrhage, nonclotted, on fluid-attenuated inversion recovery (FLAIR). T2-weighted (left), FLAIR (middle), and GRE (right) images all show layered blood in the dependent parts of the occipital horns. Acute intraventricular blood is easily identified as hypointense to CSF on all T2-weighted images, including FLAIR.

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FIGURE 10.56 Acute subarachnoid hemorrhage, computed tomography (CT) versus fluid-attenuated inversion recovery (FLAIR). Traumatic acute subarachnoid hemorrhage is not clearly seen on CT (A,B) but is obvious as marked hyperintensity within the subarachnoid spaces of the right posterior temporal and occipital regions on FLAIR (C,D).

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FIGURE 10.57 Acute subarachnoid hemorrhage, computed tomography (CT) versus fluid-attenuated inversion recovery (FLAIR). Acute subarachnoid hemorrhage proven by lumbar puncture was not identifiable on CT (A,B) but was shown as abnormal hyperintensity within several scattered sulci on FLAIR (C,D).

The signal intensity patterns of evolving subdural hematomas on conventional MR have been reviewed (45) and generally appear similar to intraparenchymal hematomas in the acute and subacute stages (Figs. 10.61 and 10.62). Note that chronic subdural hematomas, which show low attenuation on CT (and thereby are indistinguishable from CSF collections), are hyperintense on T1 MR because of methemoglobin content (Fig. 10.63). Chronic subdurals can be only minimally hyperintense to CSF on T1-weighted MR, reflecting either a very low concentration of paramagnetic methemoglobin or a high concentration of nonparamagnetic protein. The distinction between a chronic subdural hematoma and a subdural hygroma (a CSF collection in the subdural space) is easily discerned on proton density– weighted images and FLAIR images due to the signal suppression of CSF by that technique (Fig. 10.61). As chronic subdurals evolve, progressive breakdown, resorption, and dilution effects on methemoglobin result in a gradual decrease in intensity on T1-weighted images (Fig. 10.64).

FIGURE 10.58 Superficial siderosis, left sylvian fissure. Subacute left sylvian fissure hemorrhage on T1-weighted (A), proton density–weighted (B), and T2-weighted (C) images is associated with diffuse hypointensity in the superficial brain adjacent to the hemorrhage on gradient-recalled echo (D), indicating localized superficial siderosis.

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FIGURE 10.59 Progressive ataxia in 59-year old with spinal ependymoma. GRE images from inferior to superior (A) demonstrate patchy but extensive hypointensity along surfaces of the cerebellum, brainstem, and sylvian fissures in this patient with diffuse superficial hemosiderosis from conus ependymoma (B). Note the hemosiderin deposition also along the lower spinal cord and conus (B).

Hemosiderin and other iron storage from accumulation in the adjacent dural structures are not a consistent feature of subdural and epidural hemorrhage (45), presumably because of the absence of a blood–brain barrier in dura. Rebleeding into a subdural collection should be suspected if irregular hypointense membranes loculating areas of different ages of subdural are found (Fig. 10.65) or if there are debris–fluid levels seen within the collection (Fig. 10.66). An important role in MR of extraaxial hemorrhage, with its unique ability to stage intracranial hemorrhage temporally, lies in the documentation of suspected child abuse because the depiction of multiple sites of intracranial hemorrhage at different stages of evolution can be an important clue to this diagnosis (Fig. 10.65). The clinical etiologies of subdural and epidural hematomas are few in the absence of head trauma (Table 10.16).

FIGURE 10.60 A,B: Focal superficial hemosiderosis from prior aneurysmal hemorrhage. Note the thin superficial hypointensity along the left sylvian fissure and opercular regions (B, arrows) seen on the T2-weighted image in a patient who had had prior surgical clipping of a left-sided aneurysm (manifested by temporal lobe encephalomalacia and ferromagnetic clip artifact).

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FIGURE 10.61 Isodense subdural hematoma, computed tomography (CT) versus magnetic resonance (MR). A: CT shows a very subtle, relatively isodense extraaxial collection along the right temporal region. B,C: Respective T1and T2-weighted MR images both show obvious subdural hematoma consistent with subacute-to-chronic methemoglobin. D: Fluid-attenuated inversion recovery also clearly demonstrates the subdural hematoma, as well as minimal high signal within several adjacent sulci, suggestive of a small amount of otherwise invisible subarachnoid blood.

FIGURE 10.62 Acute subdural hematoma, computed tomography (CT) versus magnetic resonance MR. A: Acute subdural hematoma in the left frontal region. B,C: respective sagittal T1-weighted and axial T2-weighted MR images show an extraaxial clot consistent with intracellular deoxyhemoglobin (i.e., acute subdural hematoma). D: The calculated apparent diffusion coefficient map demonstrates marked hypointensity, indicating restricted diffusion within acute hematoma.

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FIGURE 10.63 Subdural hematomas, intracranial hypotension. Sagging brain with bilateral subacute-chronic subdural hematomas on T1 (A,B) and fluid-attenuated inversion recovery (C) shows extensive dural enhancement after gadolinium (D,E). This constellation of findings is characteristic of secondary subdural hematomas due to intracranial hypotension.

Coagulopathies, either due to a disease state or by virtue of over-anticoagulation, can present as subdural hematoma. Certain dural-based metastases, including those from renal cell carcinoma, breast carcinoma, and melanoma, can bleed into the subdural space. Meningiomas can bleed acutely and occasionally can be the source of a subdural hematoma. Dural arteriovenous malformations should also be considered in the differential diagnosis of subdural hematoma. Added MR scans with intravenous contrast should be performed in those cases in which no identifiable cause for a subdural hematoma can be recognized or in those cases in which an unexpected and remarkable heterogeneity of signal intensity is seen on MR. A similar list of entities can be invoked in consideration of multicompartmental hemorrhages (i.e., those cases in which intraparenchymal hematoma is accompanied by subdural hematoma) (Table 10.16). The most common, aside from trauma, is simply a large superficial intraparenchymal hematoma that dissects out into the subarachnoid and subdural space. Dural arteriovenous malformation and then very peripheral aneurysms (e.g., traumatic or mycotic) are probably the next most likely diagnoses in cases with both intraparenchymal and subdural hematoma, with or without epidural hemorrhage.

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FIGURE 10.64 Eventual decrease in intensity of chronic subdural hematoma over time. A: T1-weighted magnetic resonance (MR). B: T2-weighted MR. C: T1-weighted MR, 2 months later. D: T2-weighted MR, 2 months later. Chronic right-sided subdural hematoma (1) is markedly hyperintense on T1-weighted (A) and T2-weighted (B) images. Over time, the intensity on the T1-weighted image (C) decreased dramatically, but it still remained hyperintense to ventricular cerebrospinal fluid (2). This effect is due to dilution of the concentration of methemoglobin with degradation of the hematoma.

FIGURE 10.65 Complex subdural hematomas with parenchymal injury, nonaccidental trauma. Extensive mixed signal complex subdural hematomas are shown bilaterally in a child on T1-weighted (top) and T2-weighted (middle) images. Also note right parietal parenchymal encephalomalacia and extensive signs of atrophy in the right hemisphere. T2-weighted (middle) and gradient-recalled echo (bottom) images also allow detection of superficial siderosis in the left frontal region, indicative of previous subarachnoid hemorrhage.

FIGURE 10.66 Intrahematoma level suggestive of recent rebleeding. A: T1-weighted magnetic resonance (MR). B:

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T2-weighted MR. Dependent intracellular deoxyhemoglobin (1) layers posteriorly, with anterior methemoglobin (2). (From Barkovich AJ, Atlas SW. Magnetic resonance imaging of intracranial hemorrhage. Radiol Clin N Am 1988;26:801–820, with permission.)

TABLE 10.16 Etiologies of Subdural or Epidural Hematomas

TABLE 10.17 Determination of Hematoma Etiology

CONCLUSION With the evolution of MRI scanning methods, it has become apparent that signal changes of intracranial hemorrhage are seen that vary from what can be strictly stereotyped because protocols vary more than ever among medical imaging facilities. Furthermore, the trend toward higher–field-strength scanners, although still representing the minority of MR scanners, has added yet another variable for the clinical radiologist to consider. Higher-field systems result in earlier and more prevalent hypointensity on T2weighted scans. That said, nothing has changed the role of the neuroradiologist in assessing MR images of patients who are suspected to have had intracranial hemorrhage: to recognize and localize the hemorrhage and to discern its etiology. Understanding the basis for the appearance of hematomas aids significantly in accomplishing these goals for two reasons: clinical cases not infrequently show signal intensities that vary slightly from the stereotyped stages of the evolving hematoma as presented in this chapter, and different etiologies of bleeding can show important but sometimes subtle variations from the temporal patterns characteristic of simple hematomas. Because new motivations for brain imaging continue to develop, including in the emergency setting, it has become even more important to recognize and understand the MR appearance of hematomas at their earliest stages. Moreover, it appears that newer techniques now permit the confident identification of extraaxial hemorrhage, including subarachnoid blood. Finally, although the optimal interpretation of MR images clearly requires correlation with the clinical history, there are a variety of clues (Table 10.17) that lead the radiologist to the specific etiology of intracranial hematomas that are identifiable on careful inspection of images and on comparison with the characteristic signature of simple benign evolving hematomas.

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11 Intracranial Vascular Malformations and Aneurysms Nicholas A. Telischak and Huy M. Do

Since the last edition of this chapter, magnetic resonance imaging (MRI) has firmly established itself in depiction of lesions of the cerebral vasculature. In addition to now routine standard techniques, many new sequences are pushing the envelope such that physiologic information such as cerebral blood flow is easily acquired noninvasively. It is well established that MRI is the most specific and sensitive noninvasive modality for the detection of intracranial vascular malformations of all types, whether angiographically demonstrable or angiographically occult. Even the detection of subarachnoid hemorrhage (SAH), for which computed tomography (CT) was previously felt to be superior (1), has been shown to be equally or better depicted by MRI (2,3). MR is widely held to be more sensitive to the documentation of the sequelae of vascular lesions and complications of their treatment than CT. As a general rule, MR has replaced CT as the screening modality of choice for intracranial vascular malformations and their complications in all clinical settings, although CT will still prove useful when artifact plagues MRI or when a patient has a contraindication to MRI. In certain clinical settings and pathologies, it has even become apparent that the complete preoperative assessment of some types of vascular malformations (generally those without arterial or high-flow components), as well as all secondarily related intracerebral pathology, can be made with MR alone. The continued refinement and development of high-field (3 Tesla [T] and beyond) MR scanners, newer pulse sequences, such as diffusion tensor imaging (DTI) and arterial spin labeling (ASL), and improvements to MR angiography (MRA) promise even more sensitive and sophisticated methods for detecting and specifically defining these lesions based on anatomic and pathophysiologic criteria and temporal evolution. Functional MR (fMRI) (see Chapter 33) techniques are no longer nascent and are well suited to the regional mapping of brain functions in the presence of vascular malformations that occupy “eloquent” cortex (4). The role of fMRI in the study of vascular malformations, for both preoperative mapping and more detailed investigations of anomalous development of cortical representations in the presence of congenital space-occupying lesions like arteriovenous malformations (AVMs), has been better elucidated as the techniques have matured. Although MR has become part of the standard workup of patients suspected (or known) to harbor vascular lesions, catheter angiography continues to be the definitive imaging modality and is still the mainstay of diagnosis in the preoperative and postoperative evaluations of AVMs and aneurysms. Multidetector CT angiography (CTA) has had a significant effect on the imaging of aneurysms, but for vascular malformations, especially AVMs, CTA lacks the temporal resolution accurately to depict these lesions (5). Concurrent with the improvements in MR have been dramatic improvements in CTA, such that both modalities are now complimentary. It should be emphasized that despite all of the improvements in these techniques, intracranial aneurysms in particular still cannot be definitively excluded by any noninvasive modality, including CTA, leaving conventional intra-arterial catheter angiography as the gold standard for aneurysm diagnosis. Three-dimensional (3D) rotational angiography has improved the diagnostic quality and safety of intracranial diagnostic and endovascular treatment procedures for both AVM and aneurysm diagnosis and therapy. The 3D rotational angiography images are obtained by reconstruction of a series of images that are acquired while the Carm rotates in a continuous movement around the region of interest. Computer-automated reconstruction algorithms then enable the physician to view vascular morphology in any direction, including cut-planes and “flythrough” modes (6–10). The 3D digital subtraction angiography (DSA) and rotational C-arm CT images are now obtainable in nearly all rotational angiography units and are 708

indispensable in the neurovascular setting (11,12).

VASCULAR MALFORMATIONS Vascular malformations of the brain have been classified by McCormick (13) and Russell and Rubinstein (14) into four major pathologic types: AVM, cavernous malformation, capillary telangiectasia, and developmental venous anomaly (DVA). The basis for these classifications is that each entity has its distinct pathologic abnormalities. In addition, each has its unique clinical presentation, treatment, and, in most cases, MR characteristics. Although not typical, clinical imaging studies and necropsy specimens have demonstrated that mixed vascular malformations having pathologic characteristics of two or more of the major types may also occur (15–19). Aside from these congenital (developmental) lesions, a distinct entity is the dural arteriovenous fistula (DAVF). The DAVF represents an acquired vascular lesion, characterized by arteriovenous (AV) shunting involving vessels within the dural venous sinuses and coverings of the brain. Estimates of the overall incidence of vascular malformations involving the brain range from 0.1% to 4%. Arteriovenous Malformations The most common clinically symptomatic cerebrovascular malformation is the AVM. AVMs have an estimated incidence of about one-seventh that of intracranial aneurysms (20), which corresponds to approximately 0.14% of the population. AVMs represent congenital anomalies of blood vessel development and result from preservation of direct communication between arterial and venous channels without an intervening capillary network (21).

FIGURE 11.1 Arteriovenous malformation, artist’s depiction. Tangle of vascular nidus receives supply from multiple enlarged tortuous arteries. Markedly enlarged proximal draining veins carry arterialized blood.

The focus of all therapy involving any surgical or catheter treatment in the management of a patient harboring an AVM is the tangle of abnormal vessels representing the site of this primitive communication—the nidus—which replaces the normal arterioles and capillaries with a low-resistance, high-flow vascular bed (Fig. 11.1). The nidus permits increased flow through the arterial feeding vessels to the AVM and delivers increased blood volume under relatively high pressure into the cerebral venous system. Therefore, it is of paramount importance in pretherapy imaging to delineate this vascular nidus in those patients for whom intervention is planned. Clinical Features Although they are congenital, AVMs most commonly are not clinically apparent until the second through the fourth decades of life, with most having become symptomatic by the time the patient reaches age 40 years (22). In adults, the most common initial symptom is related to acute intracranial hemorrhage, although larger AVMs are more likely to present with seizures rather than acute hemorrhage (23). Seizures and progressive neurologic deficits follow hemorrhage in frequency, and other, less common clinical manifestations may also occur. In those cases in which the AVM becomes apparent in the pediatric age group, hemorrhage is more likely than seizures to be the initial clinical event (24). From historical literature, intracranial hemorrhage heralds the existence of the AVM in 30% to 55% of patients and most often occurs during the second or third decade (25–28). More than 70% of patients who become symptomatic due to acute intracranial hemorrhage do so before age 40 years. Intracranial 709

hemorrhage associated with AVMs is most often intraparenchymal, with the presumed site of bleeding being the nidus or proximal arterialized venous drainage. Intraventricular hemorrhage and SAH may also occur, although AVMs represent the etiology of only some nontraumatic SAHs. On the other hand, the occurrence of nontraumatic isolated intraventricular hemorrhage (i.e., without SAH) in an adult should always suggest the presence of an underlying AVM (Fig. 11.2). The rate of bleeding from AVMs has received much attention in the clinical literature for decades, and the appropriate management of unruptured AVMs has now become newly controversial. It was generally believed that the incidence of bleeding from cerebral AVMs was much lower than that of intracranial (saccular) aneurysms. Over the past couple of decades, data, however, had suggested a high rate of hemorrhage, in the range of 2% to 4% per year. It had become conventional wisdom that the rate of hemorrhage from an AVM is at least as high as (28) and probably exceeds that of aneurysmal hemorrhage from long-term follow-up studies (26,27). Data suggest that AVMs in deep gray matter have a higher bleed rate than those in other cerebral locations (29). Estimates of annual bleed rates have ranged from 0.9% per year for patients without hemorrhagic AVM presentation, deep location, or deep venous drainage to 34.4% per year in patients having all three risk factors (30). In 2014, a randomized study (the ARUBA trial) of adults with nonruptured AVMs was published comparing medical management to interventional plus medical management in 223 patients from 39 sites in 9 countries (31). The ARUBA trial showed that medical management alone is superior to medical management with interventional therapy for the prevention of death or stroke in patients with unruptured brain AVMs followed up for 33 months. The randomized study was halted due to the superior outcome in the medical management alone group. The trial specifically showed a more than threefold increased risk of stroke and death after the initiation of interventional therapy compared with medical management alone in these patients. At the time of this writing, the continued funding of a longer-term study was denied, partly based on the disparity in outcome events between the two treatment arms in the trial. Statisticians calculated a range of 12 to 30 years might be needed for events in the medical arm to reach that of the intervention group, assuming no further events occur in the intervention group. As J.P. Mohr wrote in May 2015, “the current status of the data from ARUBA leaves unsettled both the long-term rate of hemorrhage and hemorrhage severity for those in the medical arm,” but concluded “In adult patients (>18 years) with an unruptured AVM, addition of interventional therapy (ie, neurosurgery, embolization, or stereotactic radiotherapy, alone or in combination) to medical management alone (ie, pharmacologic therapy for neurologic symptoms as needed) is probably harmful” (32).

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FIGURE 11.2 Isolated intraventricular hemorrhage on sagittal (A) and axial images (B–D) was due to proven arteriovenous malformation.

From the literature prior to the ARUBA study, each occurrence of hemorrhage from an AVM is associated with a mortality of 10% to 15%, with an overall annual mortality rate in the range of 1%. In addition, permanent neurologic deficit associated with hemorrhage has been estimated to be approximately twice the risk of death, that is, 20% to 30% per episode of hemorrhage, for an annual incidence in the vicinity of 2%. The risk of rebleeding after the initial hemorrhage from cerebral AVM has been estimated to be 6% during the first year (33). After the first year, the rebleeding rate decreases to that of the rate of initial hemorrhage in patients with symptomatic AVMs who had no clinical history of bleeding, estimated to be 2% to 4% per year (20,25). In the analysis of the ARUBA 711

study for patients followed up without interventional therapy, the data demonstrated a low spontaneous rupture rate of 2.2% per year (95% CI, 0.9% to 4.5%). In the past, no significant increase in the risk of AVM hemorrhage was considered to be associated with hypertension or specific situations, such as physical activity, pain, or trauma (20,25,34). However, others have found that hypertension is positively associated with hemorrhage in patients harboring intracranial AVMs (35). The dominant single predictor of future AVM hemorrhage is initial hemorrhagic presentation; that is, if a patient originally presents with hemorrhage, they are at higher risk of repeat hemorrhage than a patient with an identical-appearing, unruptured AVM. Several anatomic and physiologic factors are associated with increased hemorrhage from an AVM: exclusively deep venous drainage, periventricular/intraventricular or basal ganglia location of the AVM, arterial supply from perforating vessels or from the vertebrobasilar system, intranidal aneurysm(s), and high intranidal pressure, which is reflected by high pressures in the feeding arteries or restriction of venous outflow (36–39). In a recent large, individual patient data meta-analysis of three large AVM databases, identified risk factors for hemorrhage included hemorrhagic presentation (hazard ratio 3.86), increasing age (hazard ratio 1.34 per decade), female sex (hazard ratio 1.49), and exclusively deep venous drainage (hazard ratio 1.60) (40). The ARUBA study secondary analyses argue against a predictive spontaneous hemorrhage effect from the Spetzler–Martin AVM grade, however. Although investigators have reported that smaller AVMs (less than 2.5 cm) present more frequently with hemorrhage than larger ones, the absolute effects of small size may be overestimated. Smaller malformations may be less likely to cause other symptoms such as seizures, headaches, and steal phenomena than are larger AVMs and therefore are more likely to present with bleeding (41). A high incidence of underlying AVM has been reported by many investigators in patients presenting with intracranial hemorrhage after cocaine abuse (42,43), and so the diagnosis must be aggressively pursued in that specific clinical setting. Seizures are also a common clinical manifestation of intracranial AVMs, reported as an initial symptom in 20% to 60% of cases in several large series (20,23,33,44). More often associated with AVMs situated in the temporal and frontal regions, seizures affect more than half of AVM patients younger than 30 years. Acute or progressive neurologic deficits may result from the presence of an intracranial AVM. Although acute neurologic deficits have been reported to accompany 90% of AVM-associated intraparenchymal hemorrhages, neurologic deficits may arise in the absence of bleeding. In fact, the risk of significant morbidity and mortality is high in AVMs, whether or not the lesion has ruptured. Crawford et al. (26) followed 217 patients who had conservative management of their AVMs for a mean period of more than 10 years. They estimated that aside from the risk of hemorrhage, the risk of seizure disorder was 18% and the risk of neurologic dysfunction was 27% during the 20-year follow-up in conservatively treated patients. In the study by Anderson et al. (45), there was a 25% risk of a patient becoming disabled because of intellectual impairment, even without hemorrhage. Progressive and transient deficits have been ascribed to a number of potential pathophysiologic mechanisms. Among those proposed is “steal” of blood flow from adjacent normal regions of brain into the low-resistance, high-flow vessels feeding the AVM. Dilation of arterial supply to the AVM or enlarged draining veins may result in mass effect with resultant compression and neurologic dysfunction. Hydrocephalus may develop, either as a result of prior hemorrhage or by compression of adjacent cerebrospinal fluid (CSF) pathways. Venous hypertension represents an additional cause of neurologic dysfunction that may affect brain adjacent to or at a distance from the AVM nidus. Headache is another frequently described clinical manifestation of intracranial AVMs; it affects more than half of patients at some time during their clinical course (46). Although no characteristic headache pattern is consistently observed in AVM patients, a number of authors have reported atypical migrainelike pain with associated visual complaints. The incidence of true migraine, however, appears no higher in patients with AVMs than in the general population. AVMs with arterial supply from dural arteries may cause headache as a result of involvement of the pain-sensitive dura. Other mechanisms of pain include increased intracranial pressure, hemorrhage, hydrocephalus, and mass effect. Additional clinical associations of AVMs include subjective bruit, which was noted in nearly 30% of patients in one series (25). Objective cranial bruit is an infrequent finding in adult patients with AVMs. Compression of cranial nerves is a rare symptom, most often reflected by atypical facial pain from involvement of cranial nerve V. Hemifacial spasm and glossopharyngeal neuralgia due to involvement of the seventh and ninth nerves have also been described (46). Pathologic Findings 712

Although AVMs can be found throughout the central nervous system, intracranial AVMs are located in the supratentorial compartment in approximately 80% to 93% of cases. Supratentorial AVMs usually arise over the convexities and involve the distribution of the middle cerebral artery (MCA), typically visible over the surface of the cerebral hemisphere. However, deep-seated lesions are not uncommon. When AVMs are situated within deep structures, their venous drainage typically enlarges the deep venous system; in children, this may result in a massive enlargement of the vein of Galen (“vein of Galen aneurysm”), which should not be confused with a vein of Galen malformation, a misnomer that describes an AV fistula occurring in infants and children resulting in an enlarged draining median vein of the prosencephalon. AVMs are most often solitary lesions, but they can be multiple when part of certain syndromes (47), including hereditary hemorrhagic telangiectasia (Rendu–Osler–Weber disease) and mesencephalon-oculor facial angiomatosis (Wyburn–Mason syndrome).

FIGURE 11.3 Arteriovenous malformation, intraoperative photograph. Note the well-circumscribed arteriovenous malformation with vessels of varying caliber and states of thrombosis. (Courtesy of Dr. E. Flamm, Philadelphia, PA.)

On direct inspection, the gross pathologic appearance of an AVM is a tangled cluster of irregularly dilated vessels with varying wall thicknesses and luminal sizes (Fig. 11.3). Classically, AVMs appear as wedge-shaped clusters of vessels, with the apex of the wedge directed toward the ventricular surface and the base located at the cortical margin. Intervening brain parenchyma is not found within the vascular nidus itself, but feeding and draining vessels are separated by parenchyma when examining the malformation in its entirety (48). Typically, neither displacement nor mass effect on adjacent structures is present unless hemorrhage has occurred or there has been development of large venous varices involved in the drainage of the lesion. With time, feeding arteries of the AVM gradually enlarge with increased flow, and venous drainage pathways undergo progressive dilation and tortuosity. Approximately 10% of AVMs have associated arterial aneurysms, most of which occur on arteries hemodynamically related to the lesion (49,50). In one recent series, more than 98% of aneurysms originated from arteries hemodynamically or anatomically related to the AVM (50). On histopathologic examination, arterial channels in AVMs usually show well-defined elastic laminae, a feature absent in the venous channels. Wall thickening of both arterial and venous channels is often present with hyperplasia of smooth muscle cells, fibroblasts, and connective tissue. In many cases, focal areas of wall thinning may be found, representing sites of possible hemorrhage. Regions of thrombosis and recanalization are often present. Intervening and adjacent brain parenchyma frequently exhibit degenerative changes, seen as mild or extensive gliosis and demyelination (Fig. 11.4), often with concomitant parenchymal atrophy (48,51). Evidence of prior hemorrhage is also frequently present, as evidenced by ferritin, hemosiderin, and other iron-storage forms (Fig. 11.5). Calcification may involve not only vessel walls, but also adjacent brain parenchyma due to chronic ischemia or old hemorrhage (Fig. 11.4). Pretreatment Grading of Arteriovenous Malformations Grading systems have been developed in an effort to rank individual AVMs into groups predictive of the difficulty associated with a specific treatment and the probable response to that treatment. Ideally, such a system should be sufficiently simple for easy application yet comprehensive enough to permit grading of all AVMs. It should, therefore, encompass all features of the lesion that influence risks of the specific treatment modality and accurately predict the degree of risk associated with the treatment. Although such an ideal grading system does not exist, a number of systems have been proposed. Surgical grading scales are based on clinical, anatomic, and/or physiologic characteristics of the AVM 713

and the patient. Features studied have included the age and sex of the patient, the presence of neurologic deficits, and the occurrence of prior hemorrhage. The number and location of feeding arteries, site and size of the AVM nidus, and pattern of venous drainage have also been included in various grading systems (52–56). A relatively simple and widely used AVM grading system (although not widely used in diagnostic neuroradiology reports) is that proposed by Spetzler and Martin (55). This system assigns a numerical grade to the AVM, with higher grades indicating lesions that are more surgically difficult. It requires evaluation of three features: the size of the nidus, the location of the nidus, and the venous drainage pattern. The nidus size is scored as small (less than 3 cm), medium (3 to 6 cm), or large (greater than 6 cm), with 1, 2, or 3 points given, respectively. Venous drainage is categorized as either superficial (score of 0) if drainage is entirely into the cortical venous system or deep (score of 1) if any or all drainage enters the deep system. The location of the nidus is determined to be within either “eloquent” (score of 1) or “noneloquent” (score of 0) regions of brain, where eloquent areas are those with readily identifiable neurologic function and resultant disabling neurologic deficit when injured (Table 11.1). By this definition, eloquent areas include sensorimotor, visual, or language cortex; internal capsule; thalamus; hypothalamus; brainstem; cerebellar peduncles; and deep cerebellar nuclei (Table 11.2).

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FIGURE 11.4 Right hemispheric arteriovenous malformation, computed tomography (CT) versus magnetic resonance (MR) versus digital subtraction angiography (DSA). A: CT before contrast administration. B,C: CT after contrast administration. D: T1-weighted postcontrast MR. E,F: T2-weighted MR. G–I: Three-dimensional time-of-flight MR angiography. J,K: Anteroposterior (AP) and lateral DSA arterial phase. L,M: AP and lateral DSA venous phase. CT before contrast (A) shows a relative hyperdense mass with punctate and curvilinear calcifications with surrounding edema and mass effect. There is dense enhancement of the anterior round tubular component representing the draining venous aneurysm and mottled spongiform enhancement of the posteriorly located nidus after contrast administration (B,C). On MR, prominent flow void (E,F) and pulsation artifact along the phase-encoding axis (D, arrows) denote the arteriovenous malformation and venous varix. Note the surrounding high signal intensity on T2weighted images (E,F) representing gliosis in adjacent brain. Three-dimensional time-of-flight MR angiography (G–I)

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demonstrates right middle cerebral arterial feeders, nidus, and large tortuous draining vein of Trolard (arrows) but fails to demonstrate the huge proximal draining venous aneurysm confirmed on angiography (L,M, curved arrows) due to slow flow and intravoxel phase dispersion.

FIGURE 11.5 Arteriovenous malformation (AVM), evidence of prior hemorrhage by magnetic resonance. Axial T2weighted (A) and gradient-recalled echo (GRE) (B) images show a region of mixed signal on T2 that appears to be hemorrhagic on GRE in the left basal ganglia. The abnormality was confirmed to be an AVM with deep venous drainage at angiography (C).

TABLE 11.1 Spetzler–Martin Determination of Arteriovenous Malformation (AVM) Grade

The numerical score from these features is added to give the overall grade of the AVM. For instance, a grade I lesion would be small, located in noneloquent cortex, and have only superficial venous drainage. A grade V AVM would be large, involve eloquent cortex, and have deep drainage. In this system, large or diffuse AVMs encompassing the entirety of critical structures are classified as grade VI because surgical resection of such lesions would be associated with unavoidable disabling neurologic deficit or death. Therapy

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Because AVMs have been thought to hold a grim prognosis if left untreated, the goal of management (in the appropriate clinical setting) has been complete obliteration of the nidus for cure. Various therapeutic arms are available for patients with intracranial AVMs, including surgery, intravascular embolotherapy, and radiotherapy, often used in some combined approach. Traditional treatment for AVMs has been surgical excision of the nidus. Complete surgical excision can be achieved in approximately 80% of AVMs with mortality and morbidity better than that arising from the natural history of the lesion if left untreated. Combined operative morbidity and mortality rates equal approximately 10% when taking into account all AVMs, regardless of grade (28). With the ARUBA study, however, the treatment of unruptured AVMs is now newly controversial. TABLE 11.2 “Eloquent” Areas of Braina

Most postoperative morbidity in the series by Heros and Korosue (28) occurred in very large AVMs, AVMs that were immediately adjacent to critical anatomy, and AVMs with deep venous drainage (i.e., those that would be classified as Spetzler grade V). If one only considered AVMs of grades I through IV, morbidity and mortality were only 4.5% in the series by Heros and Korosue. To evaluate the proposed Spetzler–Martin grading system, Hamilton and Spetzler (57) prospectively studied 120 patients with brain AVMs who underwent surgery and showed no permanent deficits in grade I, II, and III patients. For grade IV and V patients, permanent neurologic deficits were found in 21.9% and 16.7%, respectively. This AVM grading system accurately correlated with both new temporary (p < 0.0001) and new permanent (p = 0.008) neurologic deficits. Thus, this evaluation confirms the accuracy and utility of this grading system for assisting with management decision-making. Because the rates of immediate rebleeding and mortality and morbidity associated with hemorrhage from AVMs are lower than those associated with aneurysmal hemorrhage, acute or emergent surgical intervention is limited to patients with life-threatening intracranial hemorrhage. Timing of surgery is determined by the characteristics of the lesion and the judgment of the surgeon. Depending on the risk associated with surgical treatment alone, adjunctive or alternative forms of therapy may be used. Radiosurgery or stereotactic external beam radiation therapy uses focused irradiation directed at the AVM nidus. Radiosurgery is usually pursued in those cases considered unsuitable for resection because of either location of the AVM nidus or overall operative risk. Generally, the size of the nidus must be less than 3.5 cm for the AVM to be considered suitable for treatment by these methods. Radiotherapy techniques cause obliteration of the nidus secondary to radiation damage to vessel endothelium (58), with minimal radiation exposure of the surrounding brain parenchyma. A single dose is used that is larger than the typical fractionated doses used to treat brain tumors. Obliteration rates in the range of 75% to 90% have been reported with permanent neurologic complications (due to radiation necrosis) in the range of 3% to 10% (59–62). Significant controversy over the role of radiotherapy for AVMs continues, however, as some studies have questioned the efficacy of any form of radiotherapy based on worse reported outcomes from radiotherapy than from microsurgery in some hands (63). Among the advantages of radiotherapy are its relatively noninvasive nature (for some radiosurgical systems stereotactic frames need to be placed on the patient’s skull while others utilize a thermoplastic mask) and its absence of visible effects on the head. Unlike microneurosurgical resection, the effect of radiosurgery takes months to years. Therefore, the risk of hemorrhage is still present until the lesion entirely disappears (64). Endovascular treatment is usually an adjunctive measure to either surgery or radiation. Complete endovascular obliteration of brain AVMs occurs in only approximately 5% of cases and in general occurs in AVMs that are small and with one or two arterial feeders (65–67). Embolization usually precedes surgery or radiosurgery. Surgery most frequently benefits from embolization when deep feeding vessels are eliminated. Reduction in the AVM nidus size decreases venous outflow, which can be helpful, especially when the venous drainage is deep. The goal of preradiosurgical embolization is to reduce the 717

size of the radiosurgical target (AVM nidus) to 3.0 cm or less in all dimensions. The efficiency of AVM obliteration is low when the AVM nidus exceeds 3.0 cm when treated with γ radiation (“gamma knife”) or x-ray photon radiation (“LINAC radiosurgery”). Large AVMs greater than 3.0 cm may benefit from stereotactic heavy–charged-particle Bragg peak radiation (68). Aneurysms associated with AVMs are at risk for rupture before, during, and immediately after the treatment of the AVMs. New aneurysms may arise in patients with high-flow AVMs. The risk of intracranial hemorrhage from either source is higher in female patients. To reduce the complications of intracranial hemorrhage in these patients, these aneurysms should be treated by either surgical or endovascular means before administering definitive therapy for the AVMs (69). Magnetic Resonance Imaging Complete imaging evaluation of an AVM requires the acquisition of sufficient information on which to select, plan, and carry out therapy. Features of the lesion to be evaluated include (a) the number, location, and specific identification of arterial supplies to the AVM (including collateral circulation to the AVM and vascular steal from adjacent normal brain); (b) associated vascular lesions (e.g., aneurysms); (c) the presence of hemorrhage (acute or chronic); (d) the location, size, and flow characteristics of the nidus; (e) venous drainage of both the AVM and the normal brain, including the presence of venous thrombosis, outflow restriction, or mass effect; and (f) follow-up of any prior therapy (55,70). Although cerebral angiography clearly remains the definitive method of fully characterizing the vascular supply and venous drainage of intracranial AVMs, recent advances with MR allow specific diagnosis of these lesions in most cases. It has been recognized that improved anatomic delineation of the AVM nidus, its relationship to vital cerebral structures, and improved definition of the lesion in 3D space with the use of MR (Fig. 11.6) has contributed significantly to optimizing surgical approach (71) and has allowed treatment of some lesions that previously would have been believed to be inoperable (28). Associated hemorrhage and other parenchymal changes and posttherapy follow-up are best evaluated with the use of MR in conjunction with supplemental MRA. MR information derived from these types of studies is complementary to the angiographic evaluation and clearly contributes significantly to accurate diagnosis and optimal therapeutic decisions (Figs. 11.5 and 11.6). The typical AVM on conventional fast spin-echo or spin-echo (SE) MR is depicted as a cluster of focal round, linear, or serpentine areas of signal void (Figs. 11.4–11.7), representing dilated vascular channels containing relatively rapidly flowing blood (72). Although large high-flow AVMs are usually obvious diagnoses on MRI, subtle enlargement of deep veins occasionally may be the only clue to the diagnosis of these high-flow lesions. Note that certain MR sequences can result in high intensity in areas of flowing blood (Fig. 11.6) because of either flow-related enhancement or even echo rephasing (73) or because of the now routine incorporation of gradient moment nulling into SE imaging. High intensity from these phenomena is generally a reflection of slower flow. Gadolinium enhancement of the enlarged vessels also occurs in those vessels with relatively slow flow, that is, mainly the venous side of the lesion. AVM nidi can partially enhance after gadolinium (Figs. 11.8–11.10), but the rapidly flowing blood within arterial feeding vessels generally does not enhance. Despite the traditional teaching stating that intraparenchymal AVMs demonstrate little or no mass effect on imaging studies unless hemorrhage has occurred, enlargement of draining veins can result in fairly significant mass effect (Fig. 11.10), even in the absence of hemorrhage, in up to one-third of cases (25).

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FIGURE 11.6 Arteriovenous malformation (AVM), complete anatomic delineation by magnetic resonance. Right internal carotid angiogram in anteroposterior (A) and lateral (B) projections demonstrate two AVMs in the right thalamic region fed by hypertrophied lenticulostriate arteries and a smaller AVM in the right orbit fed by small branches from the ophthalmic artery. The precise location of the thalamic AVM is well depicted by axial T1-weighted (C,D), T2-weighted (E), and three-dimensional time-of-flight magnetic resonance angiography (F,G). The enlarged deep draining basal vein of Rosenthal is well seen. Both AVMs are also well depicted on multidetector computed tomography angiography with coronal (H,I) and sagittal (J) reformations.

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FIGURE 11.7 Extensive holohemispheric racemose arteriovenous malformation with dilated feeding arteries and enlarged cortical venous drainage (A,B) is associated with chronic parenchymal changes, including atrophy of the corpus callosum. Note the enlarged leptomeningeal vessels well seen after gadolinium (C), as well as markedly feeding arteries outlined on magnetic resonance angiography (D).

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FIGURE 11.8 Spetzler–Martin grade III arteriovenous malformation (AVM) in a 14-year-old girl with severe headache and altered mental status. Sagittal T1-weighted image demonstrates frontotemporal acute hemorrhage with mass effect (A). Coronal T2-weighted image shows dark acute blood products in the left temporal lobe. MIP image of the MRA does not show clear vascularity, obscured by blood products (C). Ferraheme blood pool T1-weighted image shows clear abnormal vascularity along the medial border of the hemorrhage (D). 3D reconstructions of the Ferraheme contrast-enhanced T1 images show the venous drainage patter into the basal vein of Rosenthal and straight sinus (E,F). AP and lateral views of the catheter angiogram in the early arterial (G,H) and late arterial phase (I,J) show the supply to the AVM from branches of the left anterior choroidal artery and from a lateral lenticulostriate artery with venous drainage into the left basal vein of Rosenthal.

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FIGURE 11.9 Deep thalamic arteriovenous malformation with deep venous drainage (A,B) shows heterogeneous enhancement limited to slower-flowing components (C); magnetic resonance angiography shows vascular relationships to the lesion (D).

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FIGURE 11.10 A 17-year-old female with headache, found to have a Spetzler–Martin grade IV arteriovenous malformation with mass effect in the absence of hemorrhage. T1-weighted sagittal (A) and T2-weighted axial (B) MRI show flow voids from a right parieto-occipital AVM. T1-weighted postcontrast image shows minimal enhancement (C). There is evidence of blood products on the axial GRE sequence (D). ASL demonstrates arteriovenous shunting into an enlarged cortical vein. MIP image from the MRA shows the arterial supply. Note the presence of mass effect on the occipital horn of the right lateral ventricle in the absence of hemorrhage. In a 21-year-old female with a left parietal Spetzler–Martin grade IV arteriovenous malformation as identified on sagittal T1-weighted (A), axial T2-weighted (B), sagittal FLAIR image (C), axial GRE images (D). ASL image shows increased cerebral blood flow and early venous shunting. Axial and sagittal postcontrast BRAVO images (L,H), and MRA (G) delineate the arterial supply and draining veins.

Aside from the features of the intracranial AVM itself, associated findings on MR may provide further insight into the natural history of these lesions and aid in predicting the development of secondary clinical deficits in individual patients. The presence and age of any associated intraparenchymal hemorrhage (Figs. 11.8 and 11.11) and its resultant mass effects are clearly seen on MR. Associated intraparenchymal hemorrhage can be aged on the basis of signal intensity patterns (see Chapter 13). Staining of adjacent brain by iron-storage products can suggest prior subclinical hemorrhage from a clinically asymptomatic AVM. Intraventricular or superficial cortical hemosiderosis from prior (or recurrent) SAHs is a frequent accompaniment to vascular malformations. This entity, not usually seen on CT, is often an incidental MR finding, but patients can develop cranial nerve palsies, most commonly 726

sensorineural hearing loss, or extraventricular obstructive hydrocephalus. Long–repetition time/echo time (TR/TE) (T2-weighted) SE and gradient-recalled echo (GRE) images demonstrate marked hypointensity along the surface of the brain parenchyma or along the ependymal surface of the ventricle in this entity (Fig. 11.12) (74). Venous occlusive disease, probably an important pathophysiologic feature of many AVMs, should be sought on MR. This can be suggested by massively dilated vessels (nearly always representing veins) of either the deep or superficial venous system. Enlargement of the medullary veins, even in the contralateral hemisphere from the site of the AVM, is an important clue to venous occlusive disease (particularly in dural AV fistulas; see Dural Arteriovenous Fistulas). Signal intensity alterations representing gliosis and/or secondary demyelination in the vicinity of the AVM are easily demonstrated and imply chronic vascular ischemia, perhaps because of steal from adjacent brain.

FIGURE 11.11 A 23-year-old male with acute left temporal lobe hemorrhage from a Spetzler–Martin grade I AVM as shown on T1-weighted (A) and T2-weighted (B) images. Sagittal contrast-enhanced T1-weighted BRAVO image shows abnormal vascularity along the base of the hematoma (C), and there is increased CBF with shunting on the ASL image (D). MRA fails to show abnormal vascularity adjacent to the hematoma (E), which was evident on the lateral projection of the catheter angiogram with arterial supply from temporal branches of the left MCA and venous drainage to an infratemporal vein to the left lateral sinus (F).

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FIGURE 11.12 Intraventricular arteriovenous malformation with intraventricular siderosis. A: T1-weighted magnetic resonance (MR) (600/20). B: T2-weighted MR (2,800/80). C: Gradient-echo MR (150/15/50 degrees). Right ganglionic and intraventricular arteriovenous malformation is unambiguously depicted as round and serpentine regions of signal void on spin-echo images (A,B) and as high intensity on gradient-echo image (C). Note the marked hypointensity lining the right lateral ventricle (C, arrows), more obvious on the gradient-echo image (C), indicating prior intraventricular hemorrhage. (From Atlas SW, Fram EK, Mark AS, et al. Vascular intracranial lesions: applications of fast scanning. Radiology 1988;169:455–461, with permission.)

To determine the precise role of MR in the diagnostic workup of intracerebral AVMs, several investigators have studied patients with these lesions and compared MR findings with those of other imaging modalities (71,75,76). MR has been shown to be competitive with both CT and catheter angiography for demonstrating the neuroanatomic location of the nidus and the relationship of its supplying and draining vessels to deep ganglionic structures, the ventricular system (Figs. 11.6 and 11.13), and the corpus callosum (Fig. 11.14 and 11.15). This information is critical to treatment planning, whether surgical, endovascular, or radiosurgical (72).

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FIGURE 11.13 Arteriovenous malformation adjacent to hemorrhage in the left lateral ventricle. Axial T2-weighted image shows hemorrhage in the left lateral ventricle (white arrow) with flow voids (white arrow) from the adjacent Spetzler–Martin grade IV arteriovenous malformation (A,B). Blood products in the ventricle and AVM show blooming artifact on axial GRE images (black arrow) (C,D). Axial T1-weighted image before (E) and after (F) gadolinium contrast demonstrates intense hematoma (white arrow) and mild enhancement of the nidus. MRA shows the left frontal AVM with supply from left anterior cerebral artery, middle cerebral artery, and lateral lenticulostriate branches (G,H). Closer inspection of the MRA (A) and T2-weighted axial images identifies a perinidal aneurysm as the cause of hemorrhage (arrows), confirmed on the AP view of the catheter angiogram (arrow, K) and on a selective injection of the lateral lenticulostriate artery (arrow, L). This was treated with targeted embolization with n-BCA (native image, M), with exclusion of the aneurysm on the postembolization angiogram (N).

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FIGURE 11.14 Arteriovenous malformation involving the corpus callosum. T1-weighted sagittal (A) and T2-weighted axial (B) images demonstrate serpentine signal voids within the genu and anterior body of the corpus callosum, which adjacent to the nidus shows thinning. After administration of gadolinium, partial enhancement of the nidus occurs (C). MRA in the lateral projection demonstrates the callosal AVM with supply from numerous small branches of the paricallosal artery. Early drainage into the deep venous system is into the inferior sagittal sinus and an ectatic ependymal vein draining to the vein of galen. AP and lateral projections of the catheter angiogram better define the arterial supply, nidus, and draining veins (E,F).

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FIGURE 11.15 A 36-year-old man with a corpus callosum arteriovenous malformation that extends into the left lateral ventricle. A: Axial T2-weighted (2,900/87.5/2) image through the level of the nidus with setup acquisition block for lateral projection magnetic resonance (MR) digital subtraction angiography (DSA). B: T2-weighted image shows the nidus extending into the left lateral ventricle. C: Left carotid selective conventional catheter angiogram shows the arteriovenous malformation. D–F: Several stages of MR DSA during passage of a contrast bolus in a lateral projection. Early arterial phase (D), late arterial phase (E), and early venous phase (F). (From Griffiths PD, Hoggard N, Warren DJ, et al. Brain arteriovenous malformations: assessment with dynamic MR digital subtraction angiography. AJNR Am J Neuroradiol 2000;21:1892–1899, with permission.)

MR and CT allow for accurate representations of lesion volumes, and are often used as an adjunctive study to both MR and angiography for treatment planning purposes, although the gold standard that we use for radiosurgical planning is that of fused 3D rotational angiograms (Figs. 11.16 and 11.17). The size of the AVM nidus is important for many reasons, including an overall increase in operative grade (and risk) with increasing nidus size and the potential for normal perfusion pressure breakthrough after a large nidus is resected (77). The potential for hemorrhage is also related to AVM size: smaller AVMs tend to present more often with hemorrhage than larger AVMs, perhaps because by definition they are less likely to cause symptoms related to mass effect (78). MR is also superior to CT for demonstrating the degree of nidus obliteration after intra-arterial embolization. In such cases, MR often allows clear depiction of the thrombosed portion of the lesion and accurate differentiation of patent from thrombosed vessels, a distinction that even conventional arteriography may not make with certainty because of the many physiologic changes in flow after endovascular therapy (71). MR is more sensitive than either CT or angiography at delineating hemorrhagic complications of AVMs, especially those that are subacute or chronic (Figs. 11.5 and 11.8). Conventional catheter angiography remains superior to MR in depicting the specific arterial supply and venous drainage of the AVM. Even thin-section, high-resolution MR can only implicate abnormal veins or arteries in an AVM on the basis of enlargement, a feature that may not be present in all involved vessels. Similarly, 3D time-of-flight (TOF) MRA is a nonselective technique that cannot define with certainty the specific feeding arteries and draining veins, although approaches to selective timeresolved MRA or MR DSA techniques have been developed (Fig. 11.16) (see Chapter 28). These timeresolved techniques include both noncontrast ASL sequences (79), and bolus tracking sequences with gadolinium. Even newer contrast agents such as ultrasmall superparamagnetic iron oxide particles (USPIO) (e.g., Ferraheme) may further improve what MR can show (80). Currently, the spatial and temporal resolution of these sequences still cannot match a catheter directed DSA. Moreover, one must detect and characterize aneurysms that are associated with the AVM because certain types are reported to have an extremely high risk of rupture (81). Obliteration of symptomatic intranidal or perinidal aneurysms is now considered a part of the surgical or endovascular management of AVMs (50,69), and so these lesions must be defined on imaging studies (Figs. 11.13, 11.17–11.19). If MRA is performed in these patients, then the region of interest is not limited to the AVM itself and must include the circle of 732

Willis and feeding arteries into the nidus. Differential Diagnosis Because AVMs are frequently associated with intracranial hemorrhage, the question of the diagnosis is often raised when the patient presents after an episode of intracranial hemorrhage. In the presence of any intracerebral hematoma, the radiologist must search for evidence of large vessels to suggest AVM, which can be detected with either CT or MR (Fig. 11.20). It is important to realize that the failure to identify large vessels on MR in the presence of an acute hematoma does not entirely exclude an AVM as the cause of the hemorrhage (Fig. 11.21). Small AVMs occasionally can be angiographically occult because of a variety of factors, including compression of the lesion by adjacent hematoma, vasospasm, extremely slow flow, and thrombosis. These lesions are often referred to as “cryptic” AVMs.

FIGURE 11.16 Right frontal AVM in a 22-year-old man. Main arterial feeder from the anterior cerebral artery (arrows), medium nidus (arrowheads), and superficial drainage. (A) Time-resolved SL MR angiographic images over two cardiac cycles in axial (top), sagittal (middle), and coronal (bottom) planes: two short early-draining veins are located on the superior portion of the nidus, posteromedial (white arrows) and anterolateral (black arrows), and then converge into a single vein toward the superior sagittal sinus; there was no artifact, although the anterior cerebral artery is close to the nasal fossa and ethmoid sinus. (B) TOF MR angiography in axial (top) and sagittal (bottom) planes does not allow venous drainage analysis. (C) Time-resolved CE MR angiography in axial (top) and sagittal (bottom) planes. Nidus delineation is less accurate than at time-resolved SL MR angiography over two cardiac cycles; complete venous drainage is better detected, with an anastomotic vein toward the right lateral sinus (gray

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arrows), but the two short early-filling draining veins are not distinguished. (D) Reference DSA in sagittal (top) planes and in comparison with time-resolved SL MR angiography over two cardiac cycle (bottom) planes. The two short early-filling draining veins are distinguishable with DSA. (From Raoult H, Bannier E, Robert B, et al. Time-resolved spin-labeled MR angiography for the depiction of cerebral arteriovenous malformations: a comparison of techniques. Radiology 2014;271(2):524–533.)

FIGURE 11.17 Radiosurgical planning for residual AVM. AP native image (A) demonstrates a large Onyx cast within the patient’s left cerebellar AVM, with a lateral DSA image (B) showing residual arteriovenous shunting through remnant AVM nidus. Images from the 3D rotation angiogram show the embolization material cast and the residual nidus, which were subsequently used to create a radiosurgical treatment volume (C,D).

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FIGURE 11.18 Flow-related aneurysms. Sagittal T1-weighted image (A), axial GRE (B), postcontrast axial T1weighted (C), and axial T2-weighted images show a large Spetzler–Martin grade IV right frontoparietal arteriovenous malformation with increased cerebral blood flow on the ASL image (E) and rapid T-max on bolus perfusion imaging (F). MRA identifies multiply dysplastic aneurysms of the feeding anterior cerebral arteries and anterior communicating artery, confirmed on the lateral projection catheter angiogram (I) and reformatted 3D rotational angiogram (J).

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FIGURE 11.19 Acute arteriovenous malformation (AVM) hemorrhage from an intranidal aneurysm in a 38-year-old woman with sudden severe headache and mental status change. Noncontrast computed tomography (A) and T1weighted (B) and gradient-recalled echo (C) images demonstrate casting of the lateral and third ventricle by blood products. Sagittal reformatted image (D) from computed tomography angiography shows a vascular lesion in the quadrigeminal plate region suspicious for a small AVM with a possible nidal aneurysm, which was confirmed at angiography (E,F) from lateral left vertebral injection. This small AVM was supplied by a branch of the medial posterior choroidal artery, which was superselectively embolized, resulting in cure (G,H).

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FIGURE 11.20 Ruptured intranidal aneurysm. A,B: Sagittal and coronal T1-weighted magnetic resonance (MR). C– E: Axial T2-weighted MR. F,G: Computed tomography angiogram (CTA). H,I: Anteroposterior and lateral right internal carotid artery angiogram. Subacute parenchymal hematoma (arrows) is seen inferior and anterior to the arteriovenous malformation nidus (A–E). Note the prominent flow voids in the enlarged central draining veins on T2weighted sequence (C,D). Sagittal maximum intensity projection image from CTA (F) is suspicious for an aneurysm arising from a feeding right middle cerebral artery branch in the same location as the hematoma (white arrow). Variceal draining cortical and galenic system veins are well depicted on three-dimensional reformatted CTA (G, black arrows). At angiography (H,I), which was done for confirmation and stereotactic presurgical localization, the aneurysm is again demonstrated (arrows). The aneurysm was surgically clipped and was found to be the cause of the bleed.

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FIGURE 11.21 Hyperacute hematoma with cryptic arteriovenous malformation (AVM). A: Sagittal T1-weighted magnetic resonance (MR) (600/11). B: Axial T2-weighted MR (3,000/80). C: Lateral view, arterial phase, angiogram. D: Anteroposterior view, arterial phase, angiogram. Parietal mass (A,B,1) represents hyperacute hematoma (see Chapter 9), with no definite evidence of AVM on MR. Arteriogram shows posterior parietal AVM with small nidus (C,D, closed arrows) and draining vein (D, open arrows).

A major part of the role of the radiologist once the identification of an intracerebral hemorrhage has been made on MR is the search for any associated enlarged vessels because the diagnosis of an underlying AVM is of paramount importance in these cases. A point of confusion may arise when a cavernous hemangioma is identified but vascular channels are noted in contiguity with the lesion (Fig. 11.22). The keys to the diagnosis of the “mixed malformation,” composed of cavernous hemangioma plus venous angioma (discussed later in this chapter), are the recognition of two features of the associated vessels: the characteristic “spoke-wheel” morphology of the enlarged vessels and the very slow flow through these vessels (shown by either SE intensities or with gadolinium enhancement) (Figs. 11.23 and 11.24). Occasionally, a hypervascular neoplasm with markedly enlarged vessels manifests as an acute hematoma. The only potential source of confusion with AVM might be a hemangioblastoma, which can certainly be associated with markedly enlarged vascular channels and intraparenchymal hematoma. The typical macrocystic component and the identification of the enhancing mural nodule of hemangioblastoma separate this entity from AVM in most cases. Moreover, hemangioblastomas do not generally bleed. Although the diagnosis of AVM is usually unambiguous on MR, one other lesion can superficially masquerade as an AVM because it too is depicted as abnormally dilated vascular channels. Moyamoya disease is characterized by the occurrence of progressive symmetric occlusion involving the bifurcations of the internal carotid arteries (ICAs) and the proximal anterior and middle cerebral arteries. The occlusive process stimulates the development of an extensive network of enlarged basal, transcortical, and transdural collateral vessels. The angiographic appearance of the innumerable tiny collateral vessels, termed “puff of smoke” or “moyamoya” in Japanese, gives the condition its name. Moyamoya disease has a bimodal age presentation, with the first peak occurring in the first decade of life, associated with cerebral infarction as progressive carotid occlusion develops. Adult patients most often present in the fourth decade with intracranial hemorrhage arising from the rupture of the delicate network of collateral vessels. Hemorrhage from moyamoya is intraparenchymal in 60% of cases, with 738

intraventricular hemorrhage accounting for nearly all the rest (82,83). Occasionally, isolated SAH is the initial manifestation of the disease.

FIGURE 11.22 Hemorrhage involving dorsal medulla cannot be dismissed as cavernous malformation due to subtle vessels in adjacent subarachnoid space, later proven as arteriovenous malformation.

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FIGURE 11.23 Incidentally discovered developmental venous anomaly with arteriovenous shunting. Axial T2weighted (A) and gradient-recalled echo (GRE) images (B) show numerous linear small channels oriented perpendicularly to the cortical surface which show minimal intrinsic hyperintensity on the axial T1-weighted image likely secondary to slow flow (C) and enhance on the postcontrast T1-weighted axial image (D). An unusual finding in this case is the presence of arteriovenous shunting on the arterial spin labeling (ASL) image which signifies a transitional type of developmental venous anomaly. In a second patient with a left occipital developmental venous anomaly shown on an axial T1-weighted contrast-enhanced image (F), there is ASL signal abnormality with early shunting into the superior sagittal sinus (G).

Characteristically, flow voids representing large collaterals and the markedly enlarged striate vessels are seen on MR amid the deep ganglionic structures (84,85). Absence of the expected flow void within the cavernous and supraclinoid portions of the ICAs is a consequence of narrowing and ultimately occlusion of these vessels. Changes resulting from ischemia or rupture of the fragile, enlarged network of collateral vessels, including regions of infarction or hemorrhage, may also be seen (Fig. 11.25). This diagnosis is clearly defined by MR when evidence of the occlusive disease of the distal ICAs is apparent in conjunction with the flow voids representing the enlarged striate vessels. Associated enhancing leptomeningeal collaterals after gadolinium and hyperintensity within these surface collaterals and small arterial branches on FLAIR images should suggest this diagnosis.

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FIGURE 11.24 Hemorrhagic mixed malformation in a middle-aged woman who presented with mild headache. Noncontrast computed tomography (CT) (A) shows no acute findings, only a region of calcification in the right cerebellum. She presented several months later with sudden acute loss of consciousness. Repeat head CT (B) and T1-weighted (C), T2-weighted (D,E), gradient-recalled echo (F,G), and T1 postcontrast (H) magnetic resonance (MR) studies show a large acute left cerebellar hematoma with upward transtentorial herniation. MRI demonstrates multiple smaller chronic-appearing bleeds consistent with multiple cavernous malformations. Enhanced MR sequence suggests a linear enhancement in the right cerebellum, which was confirmed to be a developmental venous anomaly at angiography (I).

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FIGURE 11.25 Young woman with bilateral moyamoya disease. Hyperintense slow-flow leptomeningeal collaterals with right hemispheric deep chronic infarctions on fluid-attenuated inversion recovery (A) were verified as patent collaterals after gadolinium (B). Arterial spin labeling (ASL) images performed before (C), and after the administration of diamox (D) show worse cerebral perfusion to the left hemisphere at baseline. Poor perfusion to the right frontal lobe at baseline shows augmentation of cerebral blood flow following diamox administration. Right internal carotid artery (ICA) catheter angiogram shows classic findings of moyamoya disease, including occlusion of the supraclinoid segment of the ICA and innumerable leptomeningeal collateral vessels (E,F).

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FIGURE 11.26 Computed tomography (A) shows subtle hyperdensity in the right parietal region without mass effect. Fluid-attenuated inversion recovery (FLAIR) (B) and T2 (C) demonstrate abnormal right parietal white matter; especially note the hyperintense subarachnoid space on FLAIR. After gadolinium, characteristic leptomeningeal enhancement and enhancing intrachoroidal vascular malformation (D) prove a diagnosis of Sturge–Weber syndrome.

Most often, the underlying occlusive process is idiopathic and is more commonly seen in Asian patients. An identical picture may result from progressive distal internal carotid occlusion arising from any other etiology that is accompanied by collateral development, termed moyamoya syndrome. Such causes include neurofibromatosis and sickle cell disease and as a delayed effect of radiation therapy to the suprasellar region. An increased incidence of moyamoya changes may also be present in patients with Down syndrome. Another entity associated with marked enhancement of surface vessels that should not be confusing is Sturge–Weber syndrome (Figs. 11.26 and 11.27). On close inspection, the MR changes associated with moyamoya are usually quite characteristic and should not be confused with the findings of an AVM or any other entity. Posttherapy MR In addition to the initial pretreatment evaluation of the patient harboring an intracranial AVM, MR has gained increasing importance in the assessment of these patients after treatment has been completed. Several investigators have studied the effects of radiosurgery on intraparenchymal AVMs based on imaging (86–88). Expected pathologic changes after therapy include deposition of collagen within the subendothelial space of the nidus, resulting in gradual narrowing and thrombosis of the lesion. A significant reduction in nidus size after therapy is usually clearly recognized on MR, even without MRA. This is depicted as a decrease in previously recognizable flow void with increased signal intensity on T2weighted images and persistent contrast enhancement in the area of the nidus. Significant evidence of reductions in AVM flow generally does not occur until at least 12 months after the initial treatment (Fig. 11.28) (89). It should be noted that CT is inaccurate in evaluating residual AVM nidus size after radiosurgery because persistent contrast enhancement is demonstrated even after complete obliteration. Complications of this treatment may also be monitored by MR. Changes in the surrounding parenchyma have been noted as early as 3 months after treatment and include transient vasogenic edema and radiation necrosis. Most often, asymptomatic vasogenic edema is a frequent finding in these patients and is characterized by hyperintensity on T2-weighted images in white matter surrounding the nidus. Symptomatic radiation necrosis occurs in an estimated 3% to 4% of patients and is seen as high intensity with mass effect and irregular enhancement (Fig. 11.29). Hemorrhage can be concomitant 743

with radiation necrosis. In an in vitro study, liquid cyanoacrylate mixtures used for superselective endovascular embolization of AVMs demonstrated signal characteristics similar to fat secondary to the iophendylate component that is added to make the mixture more radiopaque. After the addition of blood to simulate in vivo postembolization and polymerization conditions, the signal characteristics of clotted blood predominated (90). MRI of patients after staged transarterial flow-directed embolization with N-butyl cyanoacrylate demonstrated the region of the “glue” cast as mixed regions of alternating high and low signals on conventional images (Figs. 11.30–11.32).

FIGURE 11.27 Atrophy in the right parietal lobe, calvarial thickening, and right lateral ventricle choroid plexus mass on T2 and fluid-attenuated inversion recovery (A,B) are accompanied by parenchymal hypointensity on T2* gradientecho images (C), making the diagnosis of unsuspected Sturge–Weber syndrome obvious. Confirmation was achieved on gadolinium-enhanced sagittal and axial images (D).

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FIGURE 11.28 Arteriovenous malformation (AVM) pre- and postcyberknife radiosurgery in a 7-year-old girl who presented with right-sided weakness. Anteroposterior left internal carotid artery angiogram (A) shows a large but compact AVM nidus in the right thalamus fed by multiple lateral lenticulostriate arteries. Pretreatment fluid-attenuated inversion recovery (B) and three-dimensional time-of-flight magnetic resonance angiography (C) show a discrete nidus in the thalamus. Repeat magnetic resonance (D,E) done 1 year after radiosurgery demonstrates obliteration of previously seen prominent flow voids and flow-related enhancement consistent with a favorable response to treatment.

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FIGURE 11.29 Arteriovenous malformation with extensive radiation necrosis after treatment. A: Pretherapy magnetic resonance (MR). A supraventricular arteriovenous malformation is clearly seen as signal voids in this patient without neurologic deficit. B,C: Posttherapy MR. Severe edema (B) with marked contrast enhancement (C) indicates extensive radiation necrosis in the patient, who developed hemiparesis.

FIGURE 11.30 Postembolization magnetic resonance (MR). The N-butyl cyanoacrylate “glue” cast is hyperdense on computed tomography (A), predominantly isointense on T1-weighted MR (B), and of mixed signal intensity on T2weighted MR (C, arrows).

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FIGURE 11.31 Vein of Galen malformation. Infant with pulmonary hypertension and enlarging head circumference. Sagittal T1-weighted (A), axial T2-weighted (B,D), and arterial spin-labeled (C) (ASL) MR images show numerous small choroidal branches supplying a choroidal type vein of Galen malformation draining into an enlarged median vein of the prosencephalon (black arrow, A), with clear evidence of rapid arteriovenous shunting on the ASL image (white arrow, C). Following multiple sessions of n-BCA embolization, a glue cast can be clearly seen in the venous pouch on sagittal T1-weighted (A), coronal T2-weighted (B), axial T2-weighted (C), and axial gradient-recalled echo (GRE) MR images.

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FIGURE 11.32 Arteriovenous malformation with adjacent hematoma, magnetic resonance (MR) versus time-of-flight MR angiography. Sagittal T1-weighted (700/12) (A) and axial T2-weighted (2,300/80) (B) images demonstrate intraparenchymal hemorrhage with adjacent areas of signal void. Three-dimensional time-of-flight MR angiography (C) shows feeding vessels originating from the left posterior cerebral artery and their relationship to the area of highsignal hematoma. Lateral (D) and anteroposterior (E) vertebral artery injections show the arterial supply, nidus, and superficially draining vein.

Specialized MR Techniques in Arteriovenous Malformations MR ANGIOGRAPHY. Since the initial publication by Wedeen et al. (91) showing intravascular flow as high signal intensity on in vivo MR images, intense scientific and clinical interest has focused on imaging the cerebral vasculature and its pathology with MR. The various methods of imaging vascular flow and displaying it in multiple projections have been termed “MR angiography” because of the similar appearance of these images to conventional catheter angiography using iodinated contrast agents and xrays. MRA for the brain and spine consists of three principal techniques of data acquisition: TOF, phase contrast (PC), and contrast-enhanced TOF (92–98). The major impetus for the development of MRA as a potential replacement for catheter angiography in the diagnosis of neurologic diseases is the morbidity and mortality of cerebral catheter angiography. The historical literature reports that aside from local complications due at the puncture site itself, there is approximately a 4% incidence of neurologic event, a 1% fixed neurologic deficit incidence, and a small but definable (less than 0.1%) incidence of death from these procedures (99). It should be recognized, however, that in competent and well-trained hands, cerebral angiography is well documented to be a safe procedure and has become much safer with the improvement in equipment, contrast agents, and techniques (100,101). In fact, in a meta-analysis of the risk of angiography in patients with SAH, cerebral aneurysm, and AVMs, Cloft et al. (102) found that the risk of permanent neurologic complication is only 0.07%, much lower than that found in patients presenting with transient ischemic attacks or ischemic stroke (0.7%; p = 0.004). The second motivation for developing MRA for the workup of neurologic disease, particularly in the United States in the current healthcare climate, is the hospital cost of catheter angiography, a factor that varies widely and is too complex a subject for this review. More specific characterization of regions of signal void on (fast) SE images as regions of blood flow rather than from dense calcification or hemorrhage can be obtained by using gradient-refocused limited flip-angle techniques (94,103). These techniques form the basis of TOF and PC MRA (see Chapter 16). 748

On these sequences, regions of flowing blood are most often demonstrated as high signal intensity. These techniques can be relatively rapid methods of clarifying ambiguous regions of signal intensity on SE images as flowing blood (such as subependymal vessels or vessels near cortical margins). The presence of major venous sinus occlusion accompanying the AVM can also be clarified with MRA techniques. It is clear that at least some familiarity of the physics of flow is essential to the appropriate design and implementation of these techniques (104) (see Chapter 32). While not generally thought of as an MRA sequence, blood pool imaging with 3D postcontrast acquisitions (e.g., BRAVO) is excellent at delineating the venous side of the cerebral circulation and can be performed either following gadolinium contrast or USPIO which has a strong T1 shortening effect and yields exquisite images of the blood pool (Fig. 11.8). The fundamental role for such flow imaging techniques as MRA in the diagnostic workup of the patient with an AVM is controversial at this point in the evolution of these techniques (105). Interesting early results have been reported on the utility of 3D volume-rendered surface anatomy displays of 3D TOF MRA for staging of AVMs (106–108). This display technique has been used together with catheter cerebral angiography for the treatment planning and targeting of AVMs for radiosurgery. Although no one doubts that MRA can demonstrate the vascular nature of a high-flow AVM, the importance of simply showing the tangle of vessels on an image is arguable because the mere identification of the lesion is usually accomplished even with conventional MR. In fact, the AVM can sometimes be even more clearly separated from adjacent hematoma by MR rather than by MRA (Figs. 11.11 and 11.31). MRA in those AVMs that are fed by enlarged dural vessels is a valuable tool because dural feeding arteries are often not seen well on conventional SE MR because of their intrinsic signal void superimposed against the background of signal void of skull base and calvarium. The search for dural vessels involved in AVMs is a clear indication for supplemental MRA rather than MR alone (see Dural Arteriovenous Fistulas). One could make a strong argument that the assessment of AVM nidus size might be an appropriate indication for MRA of these lesions, whether pretreatment or posttreatment, for several reasons. First, in terms of prognosis, many neurosurgeons classify AVMs at least in part based on nidus size (55,78). Second, it is common practice to evaluate these patients after radiotherapy and/or embolization to determine the residual nidus, particularly if one desires to avoid exposing these patients to invasive catheter angiograms multiple times. Third, most institutions that treat some AVMs with a form of radiotherapy triage these lesions based on the size of the nidus, among other factors, where lesions less than 3.5 cm are more difficult to treat with such therapy (59–62). MRA does represent a potentially effective way to demonstrate a quantifiable nidus size in 3D space (Fig. 11.32). Reports of the utility of time-resolved projectional MRA and dynamic MR DSA for depiction of intracranial AVM and dural AVM have been encouraging (109–111). Recently, a comparative study demonstrated that 3D TOF MRA at 3 T is superior to the same technique at 1.5 T in terms of image quality, detection rates of feeding arteries, and draining veins (112). More important, however, the same study found that both MRA techniques are equal in nidal size evaluation and both are inferior to DSA in all assessment criteria. Unfortunately, these techniques are plagued by lack of spatial and temporal resolution when compared with catheter cerebral angiography, and it can be difficult to separate nidus vascularity from draining veins in many cases. Quantification of intravascular flow in AVMs may be a future indication for MRA as an adjunct to the multifaceted treatment plan and follow-up of patients harboring these lesions by using PC MRA techniques (113). A further indication for MRA in AVM patients is the search for associated aneurysms. The sensitivity and specificity of MRA for aneurysms are not clear, but indications are that more than 90% of circle of Willis aneurysms larger than 3 mm are detected by intracranial MRA if state-of-the-art acquisition and postprocessing methodology are used (108,114), with evaluation at 3 T having a sensitivity of greater than 98% (115) (see Intracranial Aneurysms). Detection of intra- and perinidal aneurysms, however, is made more difficult by virtue of surrounding abnormal vessels of the AVM nidus (Fig. 11.13). Important pitfalls in using MRA for documenting flow must be recognized by the radiologist. If flow is turbulent (116), as is often the case in high-flow AVMs (117) in-plane, or extremely slow (104), flowing blood may be manifest as low intensity on all “white blood” MRA methods. Furthermore, a subacute–chronic intravascular clot is often difficult or impossible to distinguish from intravascular flowing blood on the GRE images (117) that comprise TOF MRA (Fig. 11.13). Other MRA methods have been used with more success in differentiating flowing blood from clot, including, most important, both 2D and 3D PC MRA techniques. In the clinical setting of an intracranial hematoma, and, in fact, in any search for the source of an intracranial hemorrhage, the major advantage of PC MRA is its specificity 749

for flow because this technique is based on differences in phase between moving and stationary spins rather than simply the T1 differences that characterize TOF methods. PC MRA, however, has its unique limitations and artifacts (see Chapters 2 and 28). Therefore, we believe that in the hunt for intracranial AVMs, MRA techniques should be used only in conjunction with conventional SE imaging (as an adjunctive MR method) rather than as the sole pulse sequence (118). Generally speaking, although MR better delineates AVM nidus localization and conventional arteriography is clearly superior in depicting overall angioarchitecture, the potential usefulness and noninvasiveness of MRA should encourage its use in cases of suspected intracranial AVM (Fig. 11.33). FUNCTIONAL MR. Blood oxygen level–dependent contrast (BOLD) imaging (118) is a noninvasive fMRI technique for localizing regional brain signal intensity changes in response to task performance. This technique uses no intravenous contrast agents and depends mainly on regional changes in endogenous intravascular paramagnetic deoxyhemoglobin. Signal intensity changes in BOLD fMRI are attributed to the documented mismatch between increases in regional cerebral blood flow and cerebral blood volume and to the much less profound increase in oxygen extraction in response to regional activation (119,120). As opposed to contrast bolus MR techniques (121) and positron emission tomography, the performance of BOLD fMRI measurements is not limited by contrast agent dose or radiation limits, and so several activation experiments can be performed without these considerations. The use of fMRI for the localization of definable cortical functions in relation to the site of AVM nidus as an aid to operative planning has been explored (91). Investigators have also demonstrated that aberrant mapping of cortical functions can occur in the presence of an AVM that is situated in the expected location of primary sensorimotor cortex (Figs. 11.34 and 11.35) (117,118), implying neural plasticity in response to the physiologic impact of the AVMs. Schlosser et al. (122) demonstrated that displacement of the activated region and hemispheric asymmetry in the number of activated voxels in the functional regions is in part due to anatomic displacement from the mass effect of the lesion or from associated hemorrhage. However, fMRI results are often inconclusive (Fig. 11.35). The disordered hemodynamics in the presence of high-flow AVMs can cause false negatives for “activation” on fMRI, so that if activation is not seen, it is not necessarily because the function has moved. We now use this routinely for pretreatment planning, and can be very helpful anecdotally, although no studies support its use in the setting of AVM treatment. Conventional MRI depicts cerebral white matter as a relatively homogeneous structure even though it is composed of multiple tightly compact and intertwined white matter bundles. DTI is a technique capable of delineating and reconstructing fiber tracts in 3D images and has been used to study the modification of white matter tracts in numerous medical conditions, including patients with AVMs (Fig. 11.31) (123–126).

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FIGURE 11.33 Young woman with unruptured right frontal arteriovenous malformation, who presented with headache. Sagittal T1-weighted (A), coronal T2-weighted (B), axial gradient-recalled echo (C), arterial spin labeling (D), and T1-postcontrast images both after gadolinium (E) and Ferraheme (F) show the improved signal to noise that can be achieved with blood pool imaging using Ferraheme. MIP images of the magnetic resonance angiogram (MRA) in the AP (G) and lateral projection (H) show that MRA is excellent for identifying feeding vessels from the anterior cerebral and middle cerebral arteries including lateral lenticulostriate branches, but that the nidus itself is better defined by the AP (I) and lateral (J) images from the catheter digital subtraction angiogram.

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FIGURE 11.34 Functional magnetic resonance imaging (fMRI) in arteriovenous malformation in two patients without neurologic deficit. Right frontal AVM with fMRI localizing language to the left hemisphere (Broca’s area, pink, A). A left hand motor task shows that the motor strip is posterior to the right frontal AVM (orange, B). In a patient with a right occipital AVM the optic pathways are highlighted in yellow in the right hemisphere and orange in the left hemisphere, routed below the AVM (C–E). The superior longitudinal fasciculus (pink) and corticospinal tracts (blue) are identified for procedure planning (F).

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FIGURE 11.35 False-negative functional magnetic resonance (fMRI) in a patient with left frontal parietal arteriovenous malformation (AVM). A: fMRI with left-hand passive task. B: fMRI with right-hand passive task. C: fMRI with left-hand active task. D: fMRI with right-hand active task. E: Raw signal intensity values of the same regions of interest with the left-hand active task. Activation is seen in the appropriate location on the side without the AVM (C, arrow) but is not seen on the side of the AVM (D). E: Raw signal intensity values of the same regions of interest with the left-hand active task. Activation is seen in the appropriate location on the side without the AVM (C, arrow) but is not seen on the side of the AVM (D). E: Raw MR signal intensity values plotted over the time for both tasks show a significant increase in noise and marked variation in signal on the same side as the lesion (lower graph tracings) compared to the nonaffected hemisphere (higher graph tracings). (Images courtesy of Gary Glover, PhD.)

TABLE 11.3 Cerebral Proliferation Angiopathy (CPA) vs. AVM

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Cerebral Proliferative Angiopathy Cerebral proliferative angiopathy (CPA) is a rare hypervascular lesion marked by diffuse intravascular shunting, which is distinguished from AVM by several characteristics, including that normal brain is interspersed between abnormal vascular channels, thereby limiting its surgical treatment. CPA is only found in an estimated 3.4% that of brain AVM’s, making it an extremely uncommon diagnosis. However, it is essential that this diagnosis is distinguished from AVM, because it has markedly different management implications (Table 11.3). The “nidus” in CPA is a misnomer, because it is not a discrete conglomeration of vessels as in an AVM; instead, the abnormality is a more diffuse region of multiple small-caliber feeding arteries and draining veins often in a region larger than 6 cm. Arterial supply is often transdural (127). Clinical Features Seizures are most frequently the presenting symptom of CPA, occurring in 45% of patients, far more frequent the presenting symptom than in AVM patients. Other symptoms include severe headache (41%), hemorrhage (12%), or TIA or other strokelike neurologic deficit (16%). Hemorrhage is exceptional (128). Two-thirds of patients diagnosed with CPA are female (127). These lesions are typically found in young adults (mean age 22 years). An effective treatment regimen is not yet established. Pathologic Findings The hallmark pathologic finding of CPA is normal neural tissue dispersed between a diffuse network of abnormal arteries and veins with altered internal elastic laminae and thickened veins with overexpressed type IV collagen. Perivascular gliosis is typically only mild, distinguishing CPA from the classical AVM (127). Diffuse angiogenesis is characteristic of this lesion. vascular endothelial growth factor (VEGF) levels in the CSF may be elevated. Imaging Characteristics On MRI, CPA appears as a large network of densely enhancing vessels with intermixed normal brain parenchyma. Small flow voids may fill a whole hemisphere or multiple lobes with a predilection for frontal, temporal, and parietal lobes, less commonly seen in the occipital lobes and below the tentorium. Compared with AVM, shunting is relatively slow and thus time to peak perfusion values will be only mildly elevated while cerebral blood volume will be strikingly increased. MRA will show a conspicuous absence of a dominant feeder, with all arteries of the region contributing equally to the malformation (Figs. 11.36 and 11.37). Stenosis of the feeding arteries is common (39%), reminiscent of the vascular narrowing seen in moyamoya disease, and the risk of feeding artery aneurysms is thought to be significantly less than that seen in AVM. Transdural supply is common relative to classical AVM’s, seen in 59% of patients. Catheter angiography will show puddling of contrast in the late arterial and early venous phases (127). A distinguishing feature of CPA is that changes, including the proximal intracranial arterial occlusive disease, may be progressive over time (129).

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FIGURE 11.36 Cerebral proliferative angiopathy. Axial T2-weighted MR images at the level of the basal ganglia at presentation (A), two years later (B) and three years later (C) show the progressive development of new intraparenchymal flow voids (B) involving the temporal and occipital lobes with some involvement of the thalamus and internal capsule (note preservation of tissue signal suggesting that there is not an accompanying gliosis). This process is progressive, with enlargement of the cortical arteries and new midline shift thought to be due to vascular engorgement (C).

FIGURE 11.37 Left common carotid artery angiograms in anteroposterior (A) and lateral (B) projections demonstrating poorly defined hypervascular ‘nidus’ with some early venous filing seen on the anteroposterior projection. Left internal carotid artery angiograms performed 4 months later in anteroposterior (C) and lateral (D) projections demonstrate more extensive ‘nidus’ and more rapid shunting with more prominent venous filling compared with the prior angiogram.

Cavernous Malformations Cavernous malformations (or cavernous angiomas, cavernomas) account for approximately 8% to 16% of all cerebrovascular malformations from postmortem studies. It is estimated that 4% of the population harbors this lesion. They represent a distinct pathologic subtype of vascular malformation, typically appearing as discrete, compact, honeycomblike masses of endothelial-lined sinusoidal vascular spaces that contain essentially thrombosed blood (48,51). This lesion is believed to be congenital, although the peak incidence of symptom onset is between the third and fifth decades of life. Cavernous 756

malformations may occur in either the brain or spinal cord. Intracranial lesions affect male and female patients equally, whereas those in the spine show a female predominance. Most cavernous malformations occur in the cerebral hemispheres, in either a superficial or subcortical location, but a superficial location with proximity to either the subarachnoid space or ventricle is particularly common. Involvement of the deep cerebral structures, including basal ganglia, thalamus, and internal capsule, occurs in only 10% of cases. Roughly one-fourth of the lesions involve the infratentorial compartment, with the cerebellum and brainstem equally affected. The pons is the most common brainstem location. Extra-axial locations have been described infrequently, including lesions arising from leptomeninges (130,131) or cranial nerves. The lesions are frequently multiple (approximately 20% to 30% of cases), with a familial pattern in 10% to 15% of patients, suggesting that a genetic basis may be present in some cases (132–134). When familial, the lesions have a very strong tendency to be multiple (134). MR has also documented that cavernous malformations change in size, morphology, and composition over time. Moreover, the de novo development of these lesions has also been described in patients with the familial type (135). Clinical Features The increased sensitivity of MR (134) for the detection of cavernous malformations has highlighted the relatively high number of lesions that are asymptomatic. In fact, these lesions are not uncommonly found incidentally at postmortem (48). In one study of familial cavernous malformations, 61% of patients were symptomatic, but it can be inferred that a higher percentage of lesions evoke no symptoms (135). If symptoms do occur, the clinical presentation may include seizures, hemorrhage, or progressive neurologic deficit. Cavernous malformations represent the second most common type of vascular malformation to be symptomatic. Seizures are the most common symptom associated with cavernous malformations, occurring in 40% to 60% of those patients with symptoms, and are the most frequent manifestation of those lesions that are situated in the supratentorial compartment. Patients may have a longstanding seizure disorder and relate no acute episode to indicate hemorrhage in the past. Seizures associated with cavernous malformations are most often focal and are believed to arise from the irritative effects of hemosiderin, gliosis, and compression on adjacent cortex. The lesions vary considerably in their responsiveness to medical management, and refractory seizures are a rather common indication for surgical excision. Clinically evident hemorrhage is the most concerning consequence of cavernous malformations. Like other symptoms of these lesions, hemorrhage occurs with the highest incidence in the second and third decades of life and affects male and female patients equally. Limitations in the imaging of these lesions in the pre-MR era made it difficult to estimate accurately the frequency of hemorrhage associated with their presence. It is now clear that subclinical hemorrhage is a common occurrence, but the size of the hemorrhage is usually small and it is most often not accompanied by the devastating effects of AVMassociated hemorrhage (48). Recent studies using MR suggest that clinically significant hemorrhage occurs in 10% to 13% of patients. Several investigators have estimated that the risk of hemorrhage from a cavernous malformation is in the range of 0.1% to 1.1% per year for each lesion (103–105,136–138). Hemorrhage may be associated with seizures or with the acute development of neurologic deficits. Most often, intraparenchymal hemorrhage occurs with similar frequencies, regardless of the location of the lesion. Clinical consequences vary, so that small hemorrhages in critical locations (e.g., brainstem) are more likely to produce symptoms. Extension of hemorrhage into subarachnoid or intraventricular space is not common. Repeat hemorrhages, each with clinically evident sequelae, are not infrequent, and some evidence suggests that cavernous malformations become more aggressive after an episode of bleeding (137). Progressive neurologic deficit is an uncommon manifestation of supratentorial cavernous malformations but occurs more often with those in the infratentorial space. Although sometimes arising from an episode of frank hemorrhage, progressive deficits are more likely to be caused by slow enlargement of the malformation secondary to chronic or recurrent extravasation of blood, thrombosis, or other poorly understood mechanisms (Fig. 11.35). Pathologic Findings Pathologically identical regardless of their location in the central nervous system, cavernous malformations are typically dark blue, well-circumscribed, lobulated mass lesions with a grapelike or mulberry configuration on gross inspection. Less commonly, identical lesions on histopathology are found that differ only in their racemose, rather than compact appearance (48). The lesions are nearly 757

always intraparenchymal and are often found in a subpial location, protruding into the subarachnoid space, or adjacent to a ventricle. Leptomeningeal sites of origin have been reported (Figs. 11.38 and 11.39). Rarely, cavernous malformations are extradural (Fig. 11.40), with most reported cases of such lesions involving intraspinal sites (139,140). Most range in diameter from a few millimeters to a few centimeters. Within the lesion is subacute-to-chronic clotted blood. Although virtually always well demarcated by a rim of gliotic brain stained by hemosiderin pigment from prior hemorrhages (Fig. 11.41) or diffusion of red cell pigment from prior intracavernous sequestration (13), the lesions are not encapsulated.

FIGURE 11.38 Rare location of a common cavernous malformation in the left optic chiasm and tract (A,B) in a patient with progressive visual field defect, corresponding to reduced activation on functional magnetic resonance imaging in the left visual cortex (C) and reduced visual pathway fiber density by diffusion tractography diffusion tensor imaging scan (D).

FIGURE 11.39 Extra-axial origin of a cavernous malformation. The infratemporal cavernous malformation arises from meninges and elevates the temporal lobe. (Courtesy of Dr. P. Burger, Charlottesville, VA.)

On microscopic examination, a honeycomb of multiple, partially collagenized, endothelial-lined sinusoidal vascular channels is seen that varies in caliber. The walls of these channels may be thin, irregularly thickened and hyalinized or partially calcified. Even when thickened, no muscularis or elastica is present in vessel walls, differentiating the vessels of cavernous malformation from those of AVM. Another distinguishing feature of the vessels found in cavernous malformations is their close 758

apposition within the substance of the lesion, reflecting the absence of interposed brain tissue (Fig. 11.42). Intraluminal thrombosis of varying stages is frequently identified, reflecting the extremely slow flow or stagnation through the lesions in vivo. Staining of the lesions and adjacent parenchyma with hemosiderin and iron-storage products within macrophages and astrocytes (48) provides evidence of chronic low-grade seepage of blood in virtually all cases. Adjacent parenchymal atrophy and gliosis may also be found. In some cases, mixed forms of vascular malformations have been identified that share features of both cavernous malformation and capillary telangiectasia (21,141). In addition, the coexistence of cavernous malformation DVA can be seen (15,16,18).

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FIGURE 11.40 A–C: Right temporal extra-axial mass with heterogeneous hemorrhage also involves the temporal bone (B, most inferior slice location). D: The intraosseous portion and other parts of the lesion enhance. E: Pathology specimen showed a clear intraosseous cavernoma.

Imaging Characteristics These lesions are typically angiographically occult and hence have also been called “occult cerebrovascular malformations” as a reflection of the normal cerebral angiogram seen in most cases, except for the mass effect if acute hematoma is present. Occasionally, a late minimal contrast stain is seen, but AV shunting is never a feature of cavernous hemangioma.

FIGURE 11.41 Cavernous malformations with surrounding hemosiderin, necropsy specimen. Gross examination reveals classic staining of adjacent brain by hemosiderin.

CT demonstrates these lesions as focal high-attenuation masses with variably present calcification in the absence of edema or mass effect (142). Enhancement is typically mild on CT but may not be identifiable. Rigamonti et al. (134) studied nine relatives harboring pathologically proven cavernous malformations using both CT and MR. CT allowed the detection of 11 lesions, whereas MR showed 38 lesions, illustrating the increased sensitivity of MR for the detection of cavernous malformations. Given the advances MRI has made since that time in the arena of susceptibility-weighted imaging, these differences have only been magnified. 760

FIGURE 11.42 Cavernous malformation, low-power section. Thrombosed vascular spaces in the superficial subpial location without intervening brain parenchyma characterize the cavernous malformation. (From Okazaki H, Scheithauer B. Atlas of Neuropathology. New York: Gower Medical, 1988, with permission.)

MR features of cavernous malformations are characteristic and are considered diagnostic of these lesions (143), obviating angiography in most cases (Figs. 11.43–11.45). These key features are focal central heterogeneity containing areas corresponding to subacute–chronic hemorrhage (methemoglobin), circumferential complete rings of markedly hypointense iron-storage forms around these high-intensity central areas, and the absence of mass effect or edema (16). The presence of remote blood-breakdown products within and around these lesions is often demonstrable in patients who relate no history of clinical hemorrhagic event, supporting the idea that this appearance is more often due to seepage of blood pigments from intracavernous sequestration rather than from frank hemorrhage. On MR, cavernous hemangiomas typically show contrast enhancement (Figs. 11.46 and 11.47). A prospective MRI study with volumetric analysis in 68 patients harboring 114 cavernous malformations shows that these lesions exhibit a wide range of behaviors, including enlargement, regression, and de novo formation. Serial examinations on MR demonstrate a trend for maturation of blood products from a subacute to a mixed, and, finally, to a chronic appearance (Fig. 11.48) (144).

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FIGURE 11.43 Cavernous malformation. Left thalamic cavernous malformation with high signal intensity on sagittal T1-weighted MRI (A), axial T2-weighted MRI (B), pre- and postcontrast T1-weighted MRI (C,D), and GRE with hemosiderin rim (E). Color fractional anisotropy map shows the relationship of the cavernous malformation with white matter tracts (F) for surgical planning.

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FIGURE 11.44 Familial multiple cavernous malformations. Axial T2-weighted MRI shows hypointense lesions with central hyperintensity in the bilateral frontal lobes (arrows) (A,B) which show little enhancement (C,D) on postcontrast T1-weighted images. GRE MRI (E,F) show blooming associated with these cavernous malformations, and also identify smaller cavernous malformations not seen on T2-weighted MRI (arrows) (G,H).

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FIGURE 11.45 Multiple cavernous malformations. A: T1-weighted magnetic resonance (MR) (600/20). B: T2weighted MR (2,500/80). Left subinsular and periatrial hemorrhagic lesions (A,B, arrows) have typical features of occult cerebrovascular malformation, with focal methemoglobin, a complete rim of markedly hypointense iron-storage products, and no edema. (From Atlas SW. Intracranial vascular malformations and aneurysms: current imaging applications. Radiol Clin N Am 1988;26:821–837, with permission.)

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FIGURE 11.46 Cavernous malformation, enhancement characteristics on magnetic resonance (MR). Sagittal T1weighted MRI (A), sagittal T2-weighted MRI (B), axial T2-weighted MRI (C) and fluid-attenuated inversion recovery (D), axial T1-weighted pre- and postcontrast (E,F) administration demonstrate a cavernous malformation located in the pons with heterogeneous signal with a rim of hypointensity and mild contrast enhancement (F). Color fractional anisotropy map (G), and diffusion tractography (H,I) show the relationship of the malformation with the descending white matter tracts—corticospinal tract (blue), middle cerebellar peduncle (yellow), medial lemniscus (orange).

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FIGURE 11.47 Cavernous malformation with associated developmental venous anomaly. Unenhanced axial T1weighted (A) (700/20) and T2-weighted (B) (3,500/93) images demonstrate heterogeneous signal intensity adjacent to the right temporal horn without associated mass effect. The rim of decreased signal intensity surrounding the cavernous malformation is best seen on the T2-weighted images (arrows), as are linear areas of decreased signal (developmental venous anomaly) within the temporal lobe (open arrows). C: Enhanced T1-weighted image (700/20) with diffuse enhancement of the cavernous malformation (arrows) and improved visualization of linear vascular structures of the developmental venous anomaly (open arrows). D: Venous phase of the right internal carotid injection demonstrates developmental venous anomaly (open arrows). E: Very late (greater than 20 seconds) phase shows contrast stagnation within the cavernous malformation (arrows).

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FIGURE 11.48 Axial T2-weighted images taken initially (A) and 3 years later (B) demonstrate de novo cavernous malformation in the left temporal lobe. A smaller right occipital malformation in the right cerebellum is stable. (From Clatterbuck RE, Moriarity JL, Elmaci I, et al. Dynamic nature of cavernous malformations: a prospective magnetic resonance imaging study with volumetric analysis. J Neurosurg 2000;93(6):981–986, with permission.)

TABLE 11.4 Differential Diagnosis of Cavernous Malformation

Aside from the potential confusion from the associated venous anomaly, other pitfalls occur in the interpretation of MR when a cavernous malformation is suspected (Table 11.4). The distinction of cavernous malformation from hemorrhagic neoplasm on MR images may be difficult if a relatively recent hemorrhage has occurred, but the absence of edema, the absence of identifiable nonhemorrhagic tumor tissue, complete rings of extensive ferritin/hemosiderin in the adjacent parenchyma, and the presence of expected temporal evolution of the hematoma on serial MR scans usually allow confident differentiation from neoplasm (145) (also see Chapters 6 and 7). Focal hypointensity on T2-weighted images in isolation can be due to a variety of pathologic conditions, including cavernous malformation, residua of remote hypertensive hemorrhage, treated toxoplasmosis, prior radiation therapy, disseminated intravascular coagulopathy (Fig. 11.49), and amyloid angiopathy (Fig. 11.50). The use of GRE imaging (see Chapter 5) for its heightened sensitivity to hemorrhage and, therefore, cavernous malformations occasionally presents two problems in diagnosing this entity (Fig. 11.51). First, the hypointensity arising from the heterogeneity of magnetic susceptibilities when the lesion is present can mask all intrinsic signal characteristics, thereby precluding the specific diagnosis. Second, focal susceptibility artifacts from any cause may uncommonly appear as peripheral rings of hypointensity with central artifactual hyperintensity (146), thereby mimicking the characteristic appearance. Tractography and fMRI have proved useful for delineation of critical eloquent brain regions and white matter tracts for preoperative planning, and is routinely used when cavernous malformations are located in eloquent regions of brain (Figs. 11.43 and 11.46). Capillary Telangiectasia Capillary telangiectasias (sometimes called capillary angiomas) are usually small, solitary lesions that most commonly occur in the pons. These represent a collection of pathologically dilated capillaries, which on histologic examination reveal aneurysmal enlargement with marked variability within a delicate network of these vessels. Intervening brain parenchyma is identifiable within the lesion (in distinction from cavernous hemangiomas) (8,51). In most cases, the intervening and adjacent brain tissue is normal on pathologic examination, without gliosis or residua of prior hemorrhage (48). Although most of these lesions are clinically silent and, therefore, incidental findings on both imaging and necropsy, they occasionally can be associated with hemorrhage and can also be found in concert with other vascular malformations (as can cavernous hemangiomas) (16). 767

FIGURE 11.49 Disseminated intravascular coagulopathy as multiple focal hypointensities in T2-weighted magnetic resonance (MR). A: T1-weighted MR. B: T2-weighted MR. Multiple punctate foci of marked hypointensity in subcortical and deep white matter are seen best on a T2-weighted image (B). Absence of any hyperintensity on the T1-weighted image (A) and the location of the lesions make cavernous malformations less likely.

FIGURE 11.50 Amyloid angiopathy as subcortical focal hypointensities. Numerous focal hypointensities in subcortical white matter and in the deep grey nuclei with evidence of prior left parietal hemorrhage as seen on axial T2-weighted (A), GRE (B,C) MRI. Arterial spin labeling sequence shows a border zone pattern of cerebral blood flow (D).

It can be difficult to differentiate cavernous malformations from capillary telangiectasias when the lesion is in the pons and is an incidental finding if hemorrhage has occurred (although the fact that hemorrhage has indeed occurred implies the diagnosis of cavernous malformation rather than capillary telangiectasia). Therefore, as noted earlier, an often-used term for this group of entities for clinicians that is more descriptive is occult cerebrovascular malformation because these lesions are usually angiographically occult (147). More importantly, cavernous malformation and capillary telangiectasia typically have different clinical manifestations (cavernous malformations commonly declare themselves with seizures or intracranial hemorrhage, whereas capillary telangiectasias are most often clinically silent) and consequently different management issues. Therefore, it is important to recognize those instances when the MR findings are specific for capillary telangiectasia. Capillary telangiectasia should be suspected when there is a lacelike region of stippled contrast enhancement with no (or only subtle) abnormality 768

on unenhanced SE images (Figs. 11.52 and 11.53). There occasionally may be a minimal hypointensity associated with the lesion, presumably representing residua of subclinical bleeding. This may be detected only with highly sensitive GRE techniques. The diagnosis can be confidently made when the lesion demonstrates all of these features and is asymptomatic and particularly when it is situated in its classic location, that is, the pons (Fig. 11.54). It should be noted that capillary telangiectasias are occasionally found in the cerebral hemispheres and other locations (Fig. 11.52). The key to distinguishing the enhancement of capillary telangiectasia from other, similar enhancing lesions, notably lymphoma when periventricular, is the absence of any signal abnormality on the unenhanced images. The associated findings of other portions of a mixed vascular malformation are also helpful, when present (Fig. 11.55).

FIGURE 11.51 Heterogeneous left cerebellar hematoma on T1 and T2 images (A) was ascribed to underlying cavernoma when multiple cavernomas were shown by gradient-echo images (B).

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FIGURE 11.52 Capillary telangiectasia, basal ganglia. A lesion in the left basal ganglia is not evident on fluidattenuated inversion recovery (FLAIR) but shows blooming on GRE (B) and faint reticular enhancement on axial postcontrast T1-weighted MRI (D). Arterial spin labeling MRI shows no associated perfusion abnormality.

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FIGURE 11.53 Virtually specific magnetic resonance pattern in pontine capillary telangiectasia shows very subtle signal abnormality without mass effect in the body of the pons (A) with subtle hypointensity on T2* gradient-echo images (B) and lacelike enhancement (C). This lesion also has increased cerebral blood volume on bolus perfusionweighted MRI. These lesions are incidental and should not be interpreted as the source of a patient’s symptoms.

FIGURE 11.54 Capillary telangiectasia, necropsy specimen. An axial section from a necropsy specimen shows typical morphology of capillary telangiectasias, with abnormally ectatic vessels and interposed brain parenchyma in lesions involving the brainstem and cerebral hemisphere. (From Okazaki H, Scheithauer B. Atlas of Neuropathology. New York: Gower Medical, 1988, with permission.)

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FIGURE 11.55 Capillary telangiectasia, cavernous malformation, and developmental venous anomaly (DVA), pons. Serial axial T1-weighted (A), T2-weighted (B), GRE (C), and T1-weighted postcontrast (D) images from inferior to superior in the pontine regions illustrate all three types of nonhigh-flow vascular malformations in this patient. The most inferior lesion is a capillary telangiectasia, the middle entity is a DVA, and a small cavernous malformation is in the most superior position.

Developmental Venous Anomalies DVAs (also known as venous angiomas or venous malformations) are considered to be incidental malformations of venous drainage patterns. There is no arterial component in this entity. Intervening brain tissue is present between the veins comprising the lesion, and this brain tissue is usually normal without evidence of hemosiderin staining or gliosis (48). DVAs may represent the most common cerebrovascular malformation, accounting for 63% of vascular malformations in one large autopsy study, with an overall incidence of 2% (148). They are generally believed to be clinically silent, although there is some controversy regarding their possible association with hemorrhage. They may be associated with cortical dysplasias and masquerade as more significant lesions if their characteristic appearance is not recognized (Figs. 11.56 and 11.57). 772

DVAs occur throughout the cerebrum and cerebellum; Burger and Scheithauer (48) stated that they can also involve the spinal cord. This lesion consists of a tuft of abnormally enlarged medullary venous channels that are radially arranged around, and drain into, a central venous trunk (Fig. 11.58). The common trunk drains intracerebrally into the deep or superficial venous system (149). In the spinal cord, the enlarged draining veins associated with a DVA must be considered in a differential diagnosis with normally prominent veins seen along the dorsal aspect of the lumbar cord and enlarged draining veins of a dural spinal AVM (see Chapter 28) (48).

FIGURE 11.56 Mixed capillary telangiectasia/cavernous malformation/developmental venous anomaly. A–C: T2weighted magnetic resonance (MR). D–G: T1-weighted MR after intravenous contrast. Very minimal signal abnormality can be detected in the right medial temporal lobe and basal ganglia on unenhanced MR (A–C). Mixed regions of enhancement, including areas typical of capillary telangiectasia, developmental venous anomaly, and cavernous malformation, are seen after gadolinium (D–G). The pattern of enhancement in an essentially normal noncontrast region is typical of capillary telangiectasia.

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FIGURE 11.57 High-resolution 3-T imaging on T2 (A), T1 (B), and fluid-attenuated inversion recovery (C) demonstrates cortical dysplasia with slight signal alteration. Note the enhancing developmental venous anomaly and capillary telangiectasia (D), the source of the signal intensity abnormality. (Courtesy of M. Leonardi, Bologna.)

Because they represent anatomically variant but physiologically competent venous drainage pathways of a normally functioning region of brain, only rarely have neurologic symptoms been attributed to DVAs. Nonetheless, clinical symptomatology, particularly intracranial hemorrhage, has been reported in patients with DVAs (150). It should also be noted that MR perfusion abnormalities have been identified in most DVA cases using contrast bolus methods, although the significance of this finding remains uncertain (152). Although the potential may exist for the increased blood flow through the normally tiny medullary veins to cause rupture, most cases are believed to remain asymptomatic throughout life. Most cases of symptoms associated with DVAs have been found in patients who also harbor cavernous malformations in contiguity with the DVA, that is, mixed vascular malformations (151). Perhaps the most important issue in the setting of DVA accompanying cavernoma is that the neurosurgeon must know about the DVA prior to resection of the cavernoma, since interruption of the DVA would cause hemorrhage and unnecessary, serious morbidity. For the diagnostic radiologist, therefore, it is essential to administer intravenous contrast when cavernoma is identified specifically to also identify the DVA for preoperative planning.

FIGURE 11.58 Developmental venous anomaly, artist depiction. Radially arranged veins along the roof of the lateral ventricle drain into an enlarged cortical vein in the pattern characteristic of this anomaly.

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The link between DVA and clinical symptoms is controversial. It has been noted that DVAs occur frequently with solitary cavernous malformations yet only very rarely when multiple cavernous malformations are present. More recently, with the increasingly frequent clinical use of MR perfusion imaging techniques, a transitional type of DVA has been described which exhibits rapid AV shunting and thus has features of a high-flow vascular malformation (152). The clinical import of this, if any, is not known. Angiography, contrast-enhanced CT, and contrast-enhanced MR delineate typical curvilinear vascular channels receiving drainage from a spoke wheel–appearing collection of small, tapering veins arranged in a radial pattern (Figs. 11.55 and 11.59). The larger central draining vein empties into a large cortical vein, a dural sinus, or a subependymal ventricular vein. Angiographic characteristics also include normal arterial and capillary phases, with opacification of the lesion usually occurring during the normal venous phase and remaining opacified through the late venous phase. DVAs may be overlooked on first pass on unenhanced MR (Fig. 11.55), where sometimes only the large central vein is obvious as a linear flow void. The venous nature of the vascular channel is implied on unenhanced long-TR MR when the venous slow flow is high intensity because of gradient moment nulling techniques (often misregistered because of oblique flow) (Fig. 11.60), and on close inspection the radially arranged veins are also revealed. An anatomic clue to the diagnosis is the location of the DVA, typically intimately associated with the lateral ventricle (Figs. 11.59 and 11.61) and draining into a subependymal vein. As already stated, DVAs can coexist with other occult cerebrovascular malformations, an association that should be actively sought with GRE techniques in symptomatic patients. GRE MRI allows rapid confirmation of flowing blood within these incidentally discovered malformations when necessary, although they have a characteristic appearance on conventional SE images (153). GRE imaging can occasionally show marked hypointensity within DVAs. This should not be mistaken for hemorrhage; it is simply a reflection of the paramagnetic deoxyhemoglobin within venous blood (Fig. 11.61). MRA is unnecessary in most cases.

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FIGURE 11.59 Developmental venous anomaly. Axial T2-weighted MRI (A) shows a linear hypointense vascular channel in the left temporal lobe draining to the superficial middle cerebral vein without evidence of hemorrhage on GRE (B). Axial T1-weighted MRI before and after contrast administration (C,D) shows marked enhancement consistent with DVA. Increased CBF on bolus perfusion weighted MRI is a function of the large size of the lesion (E).

FIGURE 11.60 Developmental venous anomaly as high intensity with gradient moment nulling. A: Proton density– weighted magnetic resonance (MR). B: Long–repetition time/echo time MR. Flow-compensated images (A,B) show

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slightly misregistered hyperintensity in cerebellar developmental venous anomaly because of the oblique orientation of the vessels.

Dural Arteriovenous Fistulae DAVF are vascular malformations that have different angioarchitecture, clinical presentation, natural history, imaging features, and therapy than parenchymal AVMs of the brain. DAVFs comprise about 10% to 15% of all intracranial vascular malformations (154). Approximately 35% of posterior fossa AVMs are purely dural in supply; more than half of DAVFs are in the posterior fossa. They represent AV shunts located within the dura or tentorium, most often involving the walls of the large dural venous sinuses (Fig. 11.62). Arterial supply is primarily via meningeal branches of the external carotid artery, ICA, or vertebral artery. DAVF drainage is into the dural venous sinuses or other dural or leptomeningeal venous channels. There is a higher incidence in women, with a peak incidence occurring between the third and sixth decades (155,156). Thrombosis or obstruction of the involved venous sinus has frequently been associated with DAVFs. Retrograde filling of the involved venous sinus and reflux into pial veins, which is considered a risk factor for subsequent hemorrhagic sequelae, may also be present. When drainage into pial veins is present, the veins may be tortuous and enlarged, often with variceal dilation.

FIGURE 11.61 Developmental venous anomaly with intravascular hypointensity on gradient-echo image and associated hemorrhage presumably secondary to an associated cavernous malformation. Axial T1-weighted MRI (A) shows mild linear hyperintensity and a large linear hypointense central portion. A hypointense chronic evolving hemorrhage is located posterior to the malformation. T2-weighted MRI (B) highlights the large developmental venous anomaly with surrounding signal abnormality, with blooming on GRE MRI (C). Postcontrast T1-weighted MRI (D) shows mild linear enhancement.

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FIGURE 11.62 Dural arteriovenous malformation, artist depiction. The posterior fossa dural arteriovenous malformation has enlarged vessels because of high-flow shunt within the dural margin at the skull base.

Clinical Features Most DAVFs present later in life and are believed to be acquired lesions (157). The pathophysiology of DAVF development and the temporal course of vasculopathic changes in the lesions are somewhat controversial. Proposed predisposing factors in the development of these lesions include trauma, prior surgery, infection, pregnancy, and vascular disease entities such as the hereditary hemorrhagic telangiectasia syndrome (158–161). It has been postulated that veno-occlusive disease affecting the dural venous sinus results in enlargement of normally present microscopic AV shunts within the sinus wall (162). Initially, drainage from the shunts is into the involved venous sinus. Recruitment of additional arterial feeding vessels occurs with increasing AV shunting and venous hypertension within the sinus. In some cases, the increased venous pressure and sinus obstruction favor retrograde filling and enlargement of leptomeningeal and pial veins communicating with the involved sinus (Fig. 11.63). In such cases, compromise of venous drainage from regions of involved brain may occur, as may rupture of the delicate enlarged pial veins. It has also been shown in an animal model that acquired DAVFs can occur after chronic intracerebral venous hypertension, even without veno-occlusive disease (163). The natural history and clinical symptomatology of DAVFs are highly variable and to a large extent dependent on the location of the lesion and its venous drainage pathways (159). Cranial bruit, tinnitus, and headache are frequent and reflect increased flow, often involving pain-sensitive regions of dura. Spontaneous regression of the lesions has been reported without intervention (Fig. 11.64). Many patients do not come to medical attention because of the frequently benign clinical course. In approximately 15% of cases, however, patients sustain intracranial hemorrhage, most commonly intraparenchymal or subarachnoid in location (Fig. 11.65). A smaller number of cases are identified as a result of parenchymal deficits or seizures arising from venous infarction or impairment of venous drainage and ischemia.

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FIGURE 11.63 Dural arteriovenous malformation of the left transverse–sigmoid sinus. Subtle flow voids are seen adjacent to the wall of the left transverse sinus (arrow, A) which show mild flow-related enhancement on the fluidattenuated inversion recovery (FLAIR) (arrow, B). There is no evidence of hemorrhage on GRE (C). MIP image of the time of flight magnetic resonance angiogram shows the marked vascularity in and around the wall of the left transverse sinus (D), with note of hypertrophied branches of the left occipital artery, posterior auricular artery, and middle meningeal artery. Early arteriovenous shunting is present into the left transverse sinus and into the cavernous sinus on the arterial spin labeling sequence (E,F). AP views in the mid-arterial (G) and late arterial (H) phases demonstrate a transverse sigmoid sinus dural AV fistula supplied by the left occipital, posterior auricular, and middle meningeal arteries with anterograde drainage into the transverse–sigmoid sinus as well as retrograde cortical venous drainage into the vein of Labbe.

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FIGURE 11.64 Spontaneous regression of dural arteriovenous fistula (DAVF). Axial arterial spin labeling MR image (A) shows high-signal arteriovenous shunting into the right sigmoid sinus (white arrow). The only evidence of this on anatomic MR images is pulsation artifact from this region as seen on the axial postcontrast T1-weighted image (arrow, B). AP and lateral projections (C,D) from a right external carotid artery (ECA) angiogram performed following the MRI demonstrate a DAVF supplied by ascending pharyngeal artery and occipital artery branches. When the patient was brought back for treatment of pulsatile tinnitus two months later, the fistula had spontaneously resolved as shown on the right ECA injection, AP and lateral projections (E,F).

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FIGURE 11.65 Dural arteriovenous fistula with intraparenchymal hemorrhage. Axial T2-weighted magnetic resonance image shows an acute left temporal hematoma (arrow) with surrounding parenchymal edema (A). Serpentine flow voids represent dilated cortical draining veins (arrowhead). On the axial fluid-attenuated inversion recovery (FLAIR) MR image (B,D), there is bright signal within these dilated channels consistent with slow venous flow. Prominent cortical draining veins enhance on the axial T1-weighted postcontrast image (arrow, C). Axial magnetic resonance angiography (MRA) shows flow-related enhancement from the patient’s transverse–sigmoid DAVF (E), which is clearly depicted on the maximum intensity projection (MIP) (arrow). Arterial spin labeling (ASL) color cerebral blood flow (CBF) map (G) and grayscale image shows rapid arteriovenous shunting into a cortical vein.

Hemorrhage from DAVFs has been demonstrated to occur through leptomeningeal venous connections 781

rather than through the nidus itself. Hemorrhage has been reported only in lesions with reflux into leptomeningeal veins and not in those cases in which drainage is confined to the dural sinuses. Consequently, the risk of hemorrhage in DAVF is related to the venous drainage pattern, with the presence of leptomeningeal venous drainage conferring an increased risk of hemorrhage, which in turn is a factor of the location of the lesion (164). DAVFs may sometimes manifest as progressive encephalopathy and dementia (165). At angiography, patients were found to have high flow through the DAVFs with the additional observation of venous outflow obstruction, thus causing impairment of cerebral venous drainage. Brain parenchymal abnormalities are found at cross-sectional imaging. On MR, diffusely increased signal on T2-weighted images with mass effect are noted. Clinical deficits and MR signal abnormalities may resolve or improve after treatment (Fig. 11.66) (162,165). DAVFs may be classified according to the dural sinus or region of dura involved by the shunt. DAVFs involving the sigmoid–transverse sinuses are the most common, making up nearly two-thirds of cases in Awad and Little’s review of 377 reported cases in the literature (166). Because of the tendency for drainage to remain confined to the transverse and sigmoid sinuses, reflux into leptomeningeal veins is rare in this location. Consequently, the incidence of hemorrhage in sigmoid–transverse DAVFs is lower. The cavernous sinus is the second most common location, with nearly 12% of DAVFs involving this region, often referred to as carotid-cavernous fistulae (CCFs). DAVFs of the cavernous sinus comprise a unique group of intracranial vascular malformations. These lesions are usually found in middle-aged women, often with hypertension. Leptomeningeal venous drainage is uncommon in this location, and consequently intracranial hemorrhage from this lesion is rare. In CCF, symptoms are highly suggestive of the diagnosis, a situation distinctly different from that with noncavernous DAVFs. Blood supply to CCFs in this location is derived from multiple branches of the internal and external carotid arteries. From the ICAs, the meningohypophyseal trunk, the inferolateral trunk, recurrent branches of the ophthalmic artery, and infrequently McConnell capsular branches may be recruited. From the external carotid arteries, the middle and accessory meningeal arteries, the artery of the foramen rotundum, the ascending pharyngeal artery, and, rarely, the posterior auricular and occipital arteries may be involved. Both internal and external carotid arteries need to be evaluated at angiography because there may be recruitment from the contralateral or from bilateral fistulas (167).

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FIGURE 11.66 Dural arteriovenous fistula (DAVF) causing venous hypertension and dementia. A,B: Axial fluidattenuated inversion recovery (FLAIR) magnetic resonance (MR) before treatment. C–F: Right common carotid angiogram (CCA) images before treatment. G: Anteroposterior right CCA angiogram during transvenous embolization. H,I: Axial FLAIR MR 2 months after endovascular therapy. This 58-year-old woman presented with a 1-year history of progressive deterioration of memory, judgment, and orientation that culminated in the inability to drive a car. Pretreatment MR (A,B) shows severe periventricular white matter edema. Diagnostic cerebral angiography (C–F) shows DAVF of the right transverse/sigmoid sinus region. The distal right transverse sinus and the entire left transverse sinus are occluded (D,E), likely due to longstanding high-flow venopathy. Note retrograde drainage to the galenic system, torcular herophili, superior sagittal sinus, cavernous sinuses, and multiple cortical vein (D,E). Markedly delayed cerebral transit time with persistent contrast staining of the brain parenchyma is noted (F) well after washout of contrast from the DAVF is seen. Because of the lack of transfemoral transvenous access demonstrated on diagnostic angiography, a combined treatment approach with neurosurgical craniotomy over the torcular herophili followed by direct transdural sinus puncture and endovascular coil embolization of the receiving draining venous component was successfully performed (G). Note the craniotomy defect (closed arrows) and the catheter in the right transverse sinus (open arrows). The patient’s neurologic impairment significantly improved. Clinical findings are corroborated by the regression of periventricular edema seen on follow-up MR done 2 months after treatment (H,I) compared with pretreatment findings (A,B).

Once the arterial supply has been elucidated, it is possible to assign CCFs according to the Barrow classification system. Four types of CCFs are recognized: type A, direct fistula between the intracavernous ICA and the cavernous sinus; type B, shunt between dural branches of the ICA and the cavernous sinus; type C, shunt between meningeal branches of the external carotid artery and the cavernous sinus; and type D, shunt between branches of both internal and external carotid arteries and the cavernous sinus. Type A lesions are usually traumatic in origin or secondary to spontaneous rupture of an aneurysm of the cavernous ICA with near-universal high-flow shunt associated with easily recognizable signs and symptoms (Fig. 11.67). Types B, C, and D tend to present spontaneously or after trauma, and the associated symptoms are usually more insidious in onset and evolution (Fig. 11.68) (168,169). Drainage into the cavernous sinus often results in compromise of cranial nerves III, IV, and VI, with secondary diplopia. Drainage into the ophthalmic veins, most notably the superior ophthalmic vein, is extremely common in CCFs, and red eye with proptosis secondary to engorgement of the veins of the orbit is a frequent complaint (170). Secondary glaucoma from impairment of venous drainage from the globe may also occur. DAVFs of the tentorial–incisural region, anterior fossa, convexity–sagittal sinus, and sylvian–middle fossa represent additional DAVF locations (171). Although these lesions are much less common, the 783

incidence of leptomeningeal venous drainage is very high with DAVFs in these regions. Consequently, most lesions in these locations have a very aggressive course, and most commonly present with intracranial hemorrhage (Figs. 11.69 and 11.70). MR Characteristics The role of MR in DAVFs has been reviewed (172). The actual site of the fistulous communication in DAVF is virtually never seen on MR. The failure to visualize the site of shunting is ascribed to the small size of the area of AV communication, the location within the leaves of dura, and the lack of contrast between the signal void of rapidly flowing blood and that of adjacent bone. MR is extremely useful in the evaluation of patients with DAVF (Table 11.5), particularly those with the potential for an aggressive course because of pial venous drainage. MRA can usually depict the feeding arteries with accuracy. ASL is of particular use because of its ability to show AV shunting so clearly, and in our experience may be the only MRI abnormality prompting a catheter DSA which confirms the diagnosis. Additionally, 4D MRA sequences have been shown to depict the feeding arteries and draining veins of DAVFs with good agreement with DSA (173). Susceptibility-weighted angiography (SWAN) also highlights the AV shunt inherent to DAVF, although in our experience this finding can be more subtle (174). Because the clinical presentation of these patients is often nonspecific and vague, the often subtle clues to the diagnosis on MR can play an extremely important role in the management of these patients.

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FIGURE 11.67 Direct cavernous carotid fistula. Sagittal T1-weighted MRI shows an enlarged and tortuous superior ophthalmic vein (arrow) (A), which can be seen (arrow) and traced back to flow voids in the right cavernous sinus (arrowheads) on the axial T2-weighted images (B,C). There is associated asymmetric enhancement of the cavernous sinus on T1-weighted axial MRI before (D) and after (E) gadolinium contrast. Magnetic resonance angiography shows marked flow-related enhancement in the right more than left cavernous sinus and superior ophthalmic vein (arrows) (F,G). Arterial spin-labeled MRI shows early arteriovenous shunting into the right superior ophthalmic vein (arrow, H) and via the inferior petrosal sinus to the internal jugular vein (arrow, I). AP and lateral catheter angiogram show a direct carotid-cavernous fistula with venous drainage into the cavernous sinus and bilateral inferior petrosal sinuses, as well as the right superior and inferior orbital veins (J,K).

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FIGURE 11.68 Indirect carotid-cavernous fistula. Axial fluid-attenuated inversion recovery (A) and T2-weighted (B) MRI demonstrate small abnormal vessels surrounding the cavernous segment of the right internal carotid artery (arrows). There is mild asymmetric enhancement of the cavernous sinus and the axial contrast-enhanced T1weighted image (C). Arterial spin-labeled image demonstrates early arteriovenous shunting into the right cavernous sinus (D). Magnetic resonance angiography shows flow-related enhancement within multiple small abnormal vessels in the cavernous sinus (E,F). AP and lateral projections (E,F) of the catheter angiogram demonstrates early filling of the cavernous sinus on this right internal carotid artery injection supplied by the meningohypophyseal trunk and inferolateral trunk. External carotid artery injection (not shown) also supplied the fistula, consistent with a Barrow type D cavernous carotid fistula.

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FIGURE 11.69 Dural arteriovenous malformation of the posterior fossa with intracranial venous drainage. A: Computed tomography of a patient presenting with cerebellar deficits and loss of consciousness demonstrates highdensity acute blood within the fourth ventricle. B: Axial T1-weighted magnetic resonance shows multiple areas of flow void along the tentorium. Lateral view of right (C) and left (D) external carotid artery injections demonstrates dural arteriovenous malformation with shunting into the posterior fossa venous system (arrows). E: Additional supply originated from the posterior meningeal branch (arrow) of the vertebral artery.

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FIGURE 11.70 Dural arteriovenous malformation (DAVF) of the anterior fossa. Axial T2-weighted image (A) demonstrates mass with a signal void and a signal abnormality affecting the entire right hemisphere from a compromise of venous drainage. Axial T1-weighted image (B) shows that the spherical lesion enhances after administration of gadolinium. Lateral views of right (C) and left (D) external carotid artery injections demonstrate DAVF of the anterior fossa (arrows) with drainage into intracranial veins and filling of a large venous varix (open arrow). No supply from the internal carotid arteries was present.

TABLE 11.5 Magnetic Resonance Findings in Dural Arteriovenous Fistulas

DAVF should be suspected when large draining veins and feeding vessels are found exclusively in superficial dural-based locations (Figs. 11.71 and 11.72). Dilation of cortical veins in the absence of visualization of a parenchymal vascular nidus should suggest the diagnosis of DAVF. In one study (172), MR was able to define accurately all cases of cortical vein dilation associated with veno-occlusive disease that were seen at catheter angiography. A highly suggestive, if not specific, MR sign of DAVF with veno-occlusive disease is the finding of prominent medullary veins. The enlarged medullary veins are frequently found in both hemispheres and often in supratentorial and infratentorial locations. This sign is more obvious on postcontrast MR and is a reflection of the venous hypertension that frequently accompanies these lesions. The enlarged medullary veins are often seen in conjunction with edema, presumably reflecting venous congestion (170). We believe that the demonstration of medullary vein enlargement on MR is a specific sign of venous hypertension due to DAVF with venous outflow obstruction. It is an indication of significant venous hypertension and may correspond to clinically apparent encephalopathy in these patients. The documentation of thrombosis of the major dural sinuses is usually clear on conventional images, but MRA can play an adjunctive role. Parenchymal changes secondary to venous hypertension (venous infarction and parenchymal 789

hemorrhage) are also well evaluated by MR. One study showed that nearly 80% of DAVF cases with MR evidence of abnormal venous drainage had parenchymal complications.

FIGURE 11.71 Dural arteriovenous malformation with cortical venous drainage and venous hypertension in a 55year-old man with headache and memory loss. Left external carotid injection shows extensive dural shunting in the occipital region with retrograde leptomeningeal venous drainage. The posterior dural sinuses are occluded (A). Sagittal T1-weighted (B) and axial T2-weighted (C,D) images shows these same abnormal veins as markedly enlarged, tortuous, serpentine flow voids.

MRA has been of use in demonstrating AV shunting in DAVFs in a variety of intracranial locations. This has been particularly true in cases with extensive involvement of the sigmoid–transverse sinuses, which may be characterized by large areas of visible nidus and relatively high flow. MRA may be useful in DAVFs near the skull base, where MR even with gadolinium is often unremarkable. Although the diagnosis of DAVFs of the cavernous sinus has also been documented by the finding of abnormal drainage patterns into the orbit or across the intercavernous sinuses, the nidus in cavernous DAVFs is small and usually not visualized directly, even on MRA. Although MR cannot delineate the small vessels supplying these lesions, depiction of cavernous sinus or superior ophthalmic vein thrombosis is exquisite on MR images (175) (see Chapter 22). Thrombosis of cavernous DAVFs can occur spontaneously. Historically, the roles of MR in DAVFs have been to document parenchymal complications of these lesions, to suggest veno-occlusive disease by defining abnormal cortical venous drainage, to indicate venous hypertension and thereby implicate DAVF with venous outflow obstruction by delineating enlarged deep medullary veins, and to exclude other causes of venous dilation (e.g., parenchymal AVM, isolated dural sinus thrombosis). MR is also useful in defining the relationship of the components of the DAVF to neuroanatomic structures, particularly in lesions with both intracranial and extracranial involvement (Fig. 11.65). With the more recent commonplace utilization of ASL and/or SWAN sequences, MR has been used to both confirm the presence of AV shunt, as well as document its disappearance following treatment, although data on the positive predictive value and negative predictive value are lacking to date (Fig. 11.73). An entity distinct from DAVF is the scalp arteriovenous fistula, or cirsoid aneurysm. This entity is often traumatic in origin, and develops as an AV fistula between the external carotid artery branches and the scalp veins, resulting in marked dilatation of the venous drainage systems and a visible anomaly with a palpable thrill (Figs. 11.74 and 11.75) (176). The superficial temporal artery is involved in 90% of cases, and treatment is best accomplished by transarterial embolization. 790

FIGURE 11.72 Dural arteriovenous malformation with venous hypertension. Edema in the left occipital region is well depicted by sagittal T1-weighted (A), coronal T2-weighted (B), and axial T1 postcontrast-weighted (C) sequences. This process involves both gray and white matter but has prolonged apparent diffusion coefficient (not shown), consistent with vasogenic edema. Angiography from a left occipital artery selective injection (D) demonstrates an extensive dural AVM with occlusion of the normally antegrade draining dural sinus, resulting in retrograde flow of contrast through multiple cortical venous channels.

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FIGURE 11.73 Middle cranial fossa dural arteriovenous fistula (DAVF). Axial T2-weighted MR images demonstrate a flow void from a dilated and tortuous superficial middle cerebral vein at the anterior pole of the left temporal lobe which can be traced posteriorly to the Sylvian fissure (A). Axial and maximal intensity projection (MIP) magnetic resonance angiogram shows asymmetric external carotid artery middle meningeal (arrow) and internal maxillary (arrowhead) branches, suggesting supply to the fistula (B). Axial MIP MRA images show flow-related enhancement within the dilated venous pouch at the site of fistula along the sphenoid wing (C). AP and lateral projections of the left external carotid artery (ECA) catheter digital subtraction (DSA) angiogram show the fistula with early venous drainage (D). The post n-BCA embolization DSA from a left ECA injection demonstrates closure of the fistula without evidence of early venous drainage (E). Posttreatment axial T2-weighted MRI (F), gradient-recalled echo (GRE) (G), T1weighted images pre- and postcontrast (H,I), arterial spin labeling (J), and MIP MRA (K) show susceptibility artifact without abnormal enhancement or evidence of arteriovenous shunting on ASL, confirming a cure.

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FIGURE 11.74 Child with posttraumatic scalp arteriovenous fistula. Sagittal T1-weighted magnetic resonance (MR) image (A), axial T2-weighted MR image (B), axial fluid-attenuated inversion recovery (FLAIR) (C), and axial postcontrast BRAVO T1-weighted MR image (D) show dilated, enhancing vascular channels overlying the left mastoid. The selective left external carotid artery (ECA) injection in early and late arterial phases show enlarged occipital and posterior auricular arteries supplying the fistula (E,F), with early venous drainage (G,H).

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FIGURE 11.75 Adolescent cervicofacial vascular malformation involving the scalp, calvarium, and dura. A: Axial T2weighted magnetic resonance (MR). B: Axial T2-weighted MR. C: Sagittal precontrast (left and middle image) and

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coronal postcontrast (right image) T1-weighted MR. D: Source and maximum intensity projection images from contrast-enhanced three-dimensional time-of-flight MR angiography. E: Right internal carotid angiogram, lateral view, arterial phase. F: Right external carotid angiogram, lateral view, arterial (left and middle images), and venous (right image) phases. This vascular malformation enlarged significantly, as evidenced by the interval growth from age 11 years (A) to age 16 years (B–F) with involvement of not only the right frontal scalp, but also the underlying calvarium and dura. Prominent flow voids are evident on both T1-weighted (C) and T2-weighted sequences. There is prominent enhancement of this lesion after administration of gadolinium (C, right image). MR angiography (D) shows prominent flow in this vascular malformation. The arterial supply is primarily from the distal anterior falcine branches of the ophthalmic artery (E) and from superficial, transosseous, and dural branches of the external carotid artery (F, left and middle images). Drainage of this high-flow lesion is primarily from a tortuous superficial vein, which is well seen on both MR angiography (D) and angiography (F, right image).

INTRACRANIAL ANEURYSMS Cerebral aneurysms are found in 1% to 14% of the population (177), suggesting that approximately 11 million people in the United States harbor this lesion. Intracranial aneurysms represent the most common atraumatic cause of SAH; indeed, SAH is the most frequent presenting manifestation of intracranial aneurysm (177). Unruptured aneurysms are most often asymptomatic. Assuming a maximum prevalence of unruptured aneurysms of 0.5% and an incidence of SAH of 1 per 10,000 per year, an annual risk of aneurysm rupture of 2% has been calculated. Operation on incidentally discovered unruptured aneurysms is recommended because of the serious morbidity (20% to 25%) and mortality (50% to 60%) of SAH and because the morbidity and mortality of surgery for unruptured aneurysms are low (178,179), with the best outcomes being for those less than 25 mm, that is, nongiant aneurysms. However, much controversy exists due to the findings of the recent International Study of Unruptured Intracranial Aneurysms (ISUIA), which found that the rupture rate of small (less than 10 mm in diameter) aneurysms was only 0.05% per year in patients with no prior SAH and 0.5% per year for large (greater than 10 mm in diameter) aneurysms and for all aneurysms in patients with previous SAH (180). The rupture rates of aneurysms analyzed in this study is much lower than the respective 2% and 0.7% risks of rupture for all aneurysm types and small aneurysms (181). Of note, the cohort studied for annual risk of rupture in the ISUIA study was analyzed in a retrospective fashion, and 17% of the aneurysms in the group of patients with no previous history of SAH were located in the cavernous segment of the ICA. Aneurysms in this location typically are not at risk for SAH. Rather, they tend to present with mass effect due to enlargement or CCF or epistaxis due to rupture. While the ISUIA study showed that in patients with no prior history of SAH, the rupture risk for an aneurysm DWI imaged in the first 7 hours after stroke has demonstrated greater lesion expansion than a pattern in which PWI ≤ DWI (Figs. 12.22 and 12.23) (128,180). Monitoring of patients before and after intravenous tPA suggested that reversal of the perfusion deficit significantly improves the imaging and clinical outcome (167,207–209). In one study, 21 of 35 patients showed a mismatch in which PWI > DWI by a ratio greater than 2:1 (208). Eleven of these 21 received intravenous tPA. Eight of the 21 patients with mismatch demonstrated early recanalization (6 treated with intravenous tPA and 2 spontaneously). In the 8 with recanalization there was significantly better outcome clinically, and MR showed significantly smaller infarctions with less growth in infarction size from baseline scanning.

FIGURE 12.23 Demonstration of infarction evolution in the absence of vessel recanalization. A: DWI at 4 hours following symptom onset demonstrates an acute infarction involving the right caudate head and body and the right frontal operculum (arrowhead) in a patient with occlusion of the right middle cerebral artery (M1 segment). B: Occlusion of the right M1 segment (arrowhead) at angiography shortly after presentation; however, the vessel could not be successfully recanalized by mechanical thrombectomy or endovascular thrombolysis. C: DWI obtained at 26 hours following symptom onset demonstrates increased size of volume of cerebral infarction into a larger portion of the right frontal and parietal lobes (arrowhead) in the absence of vessel recanalization.

FIGURE 12.24 Schematic representation of two groups of hyperacutely imaged stroke patients. One group shows a mismatch such that perfusion-weighted imaging (PWI) > diffusion-weighted imaging (DWI), and in the other group PWI ≤ DWI. The area of the PWI deficit is believed to represent tissue at risk for an infarction. When this PWI region is larger than the area that is already demonstrating cytotoxic edema (the DWI lesion) so that PWI > DWI, the patient may benefit from reperfusion to salvage that area in the PWI region that is at risk for infarction. If reperfusion occurs, the infarction would presumably be smaller than if no reperfusion occurs. In those patients in whom the PWI deficit is already smaller than the DWI deficit, reperfusion is not likely significantly to affect the eventual infarction size.

The use of DWI–PWI mismatch criteria may identify patients who will benefit from early reperfusion with acute stroke therapies (Figs. 12.21, 12.24, and 12.25). Parsons et al. (209) showed that mismatch patients receiving intravenous tPA had higher rates of reperfusion on follow-up imaging and a greater proportion of hypoperfused acute mismatch tissue not progressing to infarction than controls (82% vs. 25% in controls). A prospective study evaluated intravenous tPA in the 3- to 6-hour time window and 850

demonstrated better outcome (measured as improvement in stroke scale scores) in those patients with a mismatch versus those without a mismatch (167). This study repeated MRI evaluations in an early time interval (3 to 6 hours after treatment) and found that mismatch patients with early recanalization (seen on MRA) and early reperfusion (seen with PWI) did significantly better than patients without mismatch (Fig. 12.25). More recently, Lansberg et al. (169) prospectively demonstrated that patients with a mismatch had a better outcome (measured as an improvement in stroke scale scores and 90-day modified Rankin score) after endovascular reperfusion compared to reperfused patients without a target mismatch group. Therefore, there are multiple studies that validate the use of perfusion imaging selection of acute stroke reperfusion candidates (167,169,170,209).

FIGURE 12.25 A 62-year-old patient imaged 3 hours after the acute onset of a left hemispheric stroke. The patient’s National Institutes of Health (NIH) stroke scale score was 19 at the time of presentation. The top row shows pretreatment (Pre-Tx) magnetic resonance (MR) imaging, including perfusion-weighted imaging (PWI) with a prolonged time to maximum (Tmax) in the left MCA territory (A), a subtle small area of acute infarction on the DWI sequence in the left caudate head and left lentiform nuclei (B,C, arrows), occlusion of the left middle cerebral artery M1 segment on time-of-flight MR angiography (MRA) (D, arrow) and digital subtraction angiography (E, arrow). The bottom row shows posttreatment (Post-Tx) imaging following endovascular reperfusion therapy. DWI (F,G) demonstrates increased high signal in the left caudate head and left lentiform nuclei (arrows), but the overall volume of infarction is unchanged. MRA (H) and digital subtraction angiography (I) show recanalization of the left MCA occlusion (arrows). The patient did very well and had an NIH stroke scale of 1 at the time of discharge 5 days after treatment.

Two trials evaluated the use of a screening MRI to select patients for a thrombolytic drug (desmoteplase) in a 3- to 9-hour window (210,211). The studies selected patients with a perfusion– diffusion mismatch of greater than 20% and found improved outcome in this time window when these patients were treated with the thrombolytic compared to the same group treated with placebo. However, a more recent randomized control trial failed to show a clinical benefit of intravenous thrombolysis using desmoteplase in patients with a similar PWI–DWI mismatch (212). Additional trials 851

using PWI–DWI mismatch as a selection criterion in acute ischemic stroke are required to validate the use of PWI in ischemic stroke treatment. Interestingly, the size of cerebral infarction may not correlate with the time since symptom onset, which suggests that viability of the penumbra in acute ischemic stroke may be significantly influenced by collateral vessel supply to the ischemic territory, patient blood pressure, and other factors (193). In support of this observation, penumbra viability may be influenced by perfusion secondary to collateral vessels arising from patent vascular beds. In one study, the degree of collateral flow to an area of ischemia was measured by digital subtraction angiography (213). Patients with good collaterals had a lower stroke scale, a smaller penumbra volume, and better reperfusion after endovascular stroke therapy compared with those with poorer collateral vessels. There are ongoing efforts to determine whether collateral vessel robustness, as assessed by vascular imaging, PWI, and FLAIR, may be used in the triage of reperfusion therapy and in the outcome prediction in patients with acute ischemic stroke (214–216). Determining the site of vascular occlusion by in acute ischemic stroke may be important in determining the best revascularization treatment (87,217). Internal carotid artery terminus or M1 segment of the MCA occlusions recanalize following intravenous tPA around 10% and 30% of the time, respectively (218). By contrast, these vessel segments may be recanalized by the current generation of mechanical thrombectomy devices in 61% to 86% of patients, which suggests that these patients may benefit from endovascular reperfusion (90,91,219). The location of vascular occlusion may be determined by either MRI or MRA. The “artery susceptibility sign” on a GRE sequence identifies an arterial thrombus with a sensitivity of 82% to 83% and a specificity that approaches 100% (117,220). MRA detects intracranial arterial occlusions with a sensitivity of 80% to 92% and a specificity of 85% to 98% when compared to DSA (221–222). Underscoring the importance of noninvasive vascular imaging, the absence of CT angiography or MRA is criticized as a methodologic flaw in recent studies that failed to demonstrate a benefit of endovascular reperfusion therapy compared with medical management (95,224,225). There are emerging data that suggest the degree of thromboembolic clot burden as assessed by clot length or morphology may predict the likelihood of vessel recanalization following intravenous thrombolysis (226,227).

MR APPEARANCE OF INFARCTION BY ETIOLOGY Large-Artery Infarction Disease intrinsic to an artery in the cerebrovascular circulation or cardiac disease can result in a large thromboembolic occlusion of the cerebrovascular anatomy. The size of the ensuing infarction depends on the length of occlusion time and the degree to which the vessel is and remains occluded and the collateral circulation to the ischemic territory. A general knowledge of the cerebrovascular arterial anatomy and the brain parenchyma supplied by these arteries is helpful in surmising the arteries that are involved in the thromboembolic episode. This knowledge can sometimes help the radiologist to differentiate between a thromboembolic event intrinsically involving the cerebrovasculature and a cardioembolic event. In addition, it alerts the radiologist to atypical presentations that do not follow vascular territories and may suggest another mechanism such as venous infarction. The cerebral hemispheres are supplied by three major arteries: the anterior and middle cerebral arteries, which are derived from the carotid artery in the anterior circulation, and the posterior cerebral artery, which is derived from the basilar artery in the posterior circulation. These arterial territories and the territories of major branches of these arteries are shown in Figure 12.26. The anterior cerebral artery is the smaller of the two terminal branches of the supraclinoid carotid artery, which courses immediately toward the interhemispheric fissure and generally supplies the medial portion of the hemisphere. It gives rise to a series of small perforating branches, the medial lenticulostriate arteries, and the recurrent artery of Huebner, which is generally the largest perforating branch from the proximal anterior cerebral artery. It then gives rise to a series of cortical branches as it courses superiorly in the interhemispheric fissure. The perforating branches of the anterior cerebral artery in general supply the head of the caudate and the anterior portions of the putamen and globus pallidus and the anterior limb of the internal capsule. The cortical branches provide blood supply to the inferior and medial portions of the frontal lobe and medial portions of the parietal lobe (Fig. 12.27).

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FIGURE 12.26 Arterial vascular territories. Diagrams of the major arterial territories. MCA, middle cerebral artery; PCA, posterior cerebral artery.

The MCA is the larger of the two terminal branches of the supraclinoid internal carotid artery. It has a horizontal segment that extends laterally from the bifurcation of the carotid to the sylvian fissure. This segment gives rise to a series of perforating arteries known as the lateral lenticulostriate arteries. The MCA generally bifurcates or trifurcates in the sylvian fissure, giving rise to a series of secondary and tertiary cortical branches that extend from the insula and supply the lateral portion of the hemisphere. The lenticulostriate arteries from the MCA supply much of the globus pallidus and putamen and the internal capsule. The cortical branches of the MCA supply the lateral portions of the frontal and parietal lobes and the anterior and lateral portions of the temporal lobe (Figs. 12.28 and 12.29). One additional artery from the supraclinoid carotid, the anterior choroidal artery, is important in understanding patterns of large-artery stroke. This relatively constant artery arises from the posterior wall of the internal carotid artery just proximal to its bifurcation point. It courses posteriorly initially and then extends into the choroidal fissure. It can supply branches that feed the optic track, cerebral peduncle, medial portions of the temporal lobe, and the lateral geniculate body. The posterior cerebral branches are the terminal bifurcating branches of the basilar artery. These vessels course around the brainstem in the interpeduncular cistern, giving rise to perforating branches that supply the brainstem and thalamus (Figs. 12.30 and 12.31). The artery then extends posteriorly just above the tentorium, giving rise to a series of cortical branches. The perforating branches from the proximal posterior cerebral artery are known as the posterior thalamoperforating arteries. The anterior thalamoperforating (or tuberothalamic) arteries by definition arise from the posterior communicating artery segment, bridging the internal carotid and posterior cerebral artery in the circle of Willis. In 853

general, these thalamoperforating arteries supply the anterior thalamic nuclei. The paramedian perforating arteries arise from the basilar apex or the P1 segment of the posterior cerebral artery, and these vessels supply the medial thalamic nuclei and portions of the midbrain. Occasionally, a dominant thalamoperforating artery that gives rise to a single vessel that supplies the medial thalamus bilaterally and is referred to as the “artery of Percheron” or the paramedian thalamic artery (Fig. 12.32) (228,229). A third set of perforating arteries, the thalamogeniculate arteries, arises from the P2 segment of the posterior cerebral artery as it courses around the brainstem. These arteries supply the medial geniculate body and the inferior and lateral thalamic nuclei. The final set of perforating arteries, the medial and lateral posterior choroidal arteries, arises from the P2 segment of the posterior cerebral artery. These arteries supply the pulvinar of the thalamus, the posterior rim of the internal capsule, and the parahippocampal gyrus. The cortical branches of the posterior cerebral artery supply the medial and posterior portions of the temporal lobe and the posterior medial portion of the parietal lobe and the occipital lobe (Fig. 12.33). The largest of the arteries of the posterior fossa are the right and left vertebral arteries that fuse in the midline to form the basilar artery. The vertebral arteries enter the skull through the foramen magnum, where they pierce the dura. Here they wind around the medulla and meet at the midline anteriorly at the pontomedullary junction. The vertebral arteries give rise to a series of medial and lateral branches, many of which would be classified as perforating or penetrating arteries. They penetrate the brainstem, supplying it in a unilateral fashion. The posterior inferior cerebellar artery (PICA) is the major lateral branch of the vertebral artery. It has a proximal medullary segment that supplies a portion of medulla and then extends posteriorly to supply the lower cerebellum. The basilar artery provides the remaining supply to the posterior fossa. It lies anterior to the brainstem and courses superiorly within the prepontine cistern. The basilar artery has a number of brainstem perforating branches that directly feed the pons (Figs. 12.30 and 12.31). The basilar artery also gives rise to the anterior inferior cerebellar artery (AICA) and the superior cerebellar artery before terminating in the two posterior cerebral arteries. The AICA can be variable in size, often having a shared or balanced relationship with the PICA. It generally courses laterally to the cerebellopontine angle (Fig. 12.30). The superior cerebellar artery curves around the midbrain in the ambient cistern underneath the tentorium and extends posteriorly to supply the cerebellar hemisphere. The PICA supplies the inferior vermis and the posterior and inferior cerebellar hemispheres. The AICA in general has the smallest area of supply to the cerebellum and feeds the anterior portions. The superior cerebellar artery generally supplies the superior vermis and the upper surface of the cerebellar hemispheres (Fig. 12.34).

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FIGURE 12.27 Anterior cerebral artery (ACA) infarction in two patients. Acute infarction is demonstrated in the right superior frontal gyrus on diffusion-weighted imaging (DWI), apparent diffusion coefficient maps (ADC), and fluidattenuated inversion recovery (FLAIR) in a patient with thromboembolic occlusion of the right ACA (first column). Acute infarction is demonstrated in the bilateral superior frontal gyri on DWI, ADC, and FLAIR in a patient with severe cerebral vasospasm involving the bilateral ACAs (second column).

Thromboembolic events involving the anterior circulation (the circulation derived from the carotid artery) affect variable amounts of the supratentorial brain, depending on the site of occlusion and the adequacy of collateral circulation. In general, infarctions more commonly affect the MCA territory, with the anterior cerebral territory involved to a more variable degree. Thromboembolic events disturbing flow in the most proximal portion of the MCA (the M1 segment) cause infarction in the deep gray matter structures. The insula and frontal, parietal, and temporal lobes are involved to variable degrees, depending on the extent of occlusion and the amount of collateral supply from leptomeningeal vessels (transcortical vessels coming from the anterior and posterior artery circulations). Infarctions in these territories in general extend from the deep white matter through the cortex. The anterior cerebral artery circulation is variably affected because it may derive supply from the anterior communicating artery via the opposite carotid artery in many circumstances. Therefore, thromboembolic occlusions originating in the carotid artery circulation may not affect the anterior cerebral artery circulation to as great a degree because of adequate collateral supply from the contralateral carotid artery. 855

FIGURE 12.28 Middle cerebral artery (MCA) infarctions involving the lenticulostriate artery territories. Diffusionweighted imaging in the top row and matched apparent diffusion coefficient maps in the bottom row. Acute infarction within the medial lenticulostriate artery territory first and second rows (A,B,E,F) affecting the right caudate head and the medial lentiform nuclei. Acute infarction within the left lateral lenticulostriate artery territory (C,D,G,H) affecting the lateral lentiform nuclei, external capsule, and insula is also shown. An additional small area of infarction within the left anterior temporal lobe is present (C,D,G,H).

FIGURE 12.29 Middle cerebral artery (MCA) infarctions with DWI in the top row and matched FLAIR images in the bottom row involving the M1 segment (A,D), the M2 superior division segment (B,E), and the M2 inferior division segment (C,F) of the left MCA.

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FIGURE 12.30 Posterior circulation infarctions in four patients with DWI in the first row and matched FLAIR imaging in the second row. Cerebral infarction within the posterior inferior cerebellar artery (PICA) territory (A,E), the anterior inferior cerebellar artery (AICA) territory (B,F), basilar pontine perforator artery territory (C,G), and the superior cerebellar artery (SCA) territory (D,H).

FIGURE 12.31 Basilar artery thrombosis with acute infarction. Acute infarction within the pons and superior medulla is demonstrated as hyperintense signal abnormality on diffusion-weighted imaging (A,B) and hypointense signal abnormality on the apparent diffusion coefficient maps (C,D). A coronal MR angiogram maximum–intensity-pixel image (E) demonstrates no flow-related signal within the basilar artery, consistent with thrombosis of this vessel.

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FIGURE 12.32 Infarction in the distribution of the artery of Percheron. A,B: Axial T2-weighted magnetic resonance (MR), inferior to superior. C,D: Axial T1-weighted MR after gadolinium enhancement, inferior to superior. E: Coronal T1-weighted MR after gadolinium enhancement. Focal hyperintense lesions in both thalami are depicted (A,B). Typical involvement of the medial aspect of the thalamus is noted that abuts the third ventricular margins. After contrast administration (C–E), bilateral enhancement is seen, which on delayed image (E) is extensive in this subacute infarction. The absence of mass effect, correlation with clinical information, and knowledge of the expected vascular territory of Percheron permit the differentiation from other entities, such as lymphoma or glioma.

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FIGURE 12.33 Posterior cerebral artery (PCA) territory infarction. Acute infarction within the right PCA territory is demonstrated with hyperintense signal abnormality in the pulvinar of the right thalamus, right hippocampal gyrus, right parahippocampal gyrus, and medial aspect of the right occipital lobe on both diffusion-weighted imaging (A) and fluid-attenuated inversion recovery (B).

FIGURE 12.34 Superior cerebellar artery territory infarction. Consecutive axial images from the superior cerebellar hemisphere demonstrates scattered areas of acute infarction on diffusion-weighted imaging (A,B) and fluidattenuated inversion recovery (C,D).

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FIGURE 12.35 Embolic infarctions. Note innumerable lesions involving the cortex and white matter on both fluidattenuated inversion recovery (A) and diffusion-weighted (B) imaging from a shower of emboli.

Emboli can lodge proximally and produce a pattern that is similar to that of thrombotic occlusion in the larger proximal vessels (such as the internal carotid artery or the M1 segment of the MCA). Emboli, however, are often multiple and produce smaller cortical infarction. The pattern of emboli may involve a single vascular distribution or multiple vascular distributions. When more than one vascular distribution is involved, the diagnosis of emboli should be considered (Figs. 12.35 and 12.36). Vasculitis can also produce a pattern similar to that of embolic disease with involvement of multiple cortical regions. Infarctions with vasculitis can also involve the deep gray and deep white matter structures in concert or alone (Figs. 12.36 and 12.37). Note that MRA is not as valuable a diagnostic tool in the search for vasculitis. However, CT angiography has shown promise in this diagnosis.

FIGURE 12.36 Infarction accompanying vasculitis. Fluid-attenuated inversion recovery images (A) show multiple subcortical and cortical infarctions in varying vascular territories with restricted diffusion (B). Magnetic resonance angiography images (C,D) from the left carotid and the vertebral basilar system demonstrate arterial cutoffs and areas of non–branch point narrowing and irregularity (arrowheads) consistent with vasculitis.

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FIGURE 12.37 Granulomatous angiitis, pathologically proven. A–C: Axial T2-weighted images, inferior to superior. D–F: Axial T1-weighted images after gadolinium enhancement, inferior to superior. T2-weighted images (A–C) are nearly normal, with only a few scattered foci of hyperintensity in the white matter. After contrast, multiple tiny foci of enhancement are clearly seen throughout infratentorial and supratentorial brain parenchyma, mainly located in white matter, presumably due to inflammatory necrosis of the vascular endothelium.

Embolic Infarction from Septic Emboli An important subset of thromboembolic infarctions is infarction due to septic emboli. These patients often have a history of intravenous drug abuse and bacterial endocarditis, or are patients with congenital cardiac valve abnormalities. Often these patients present with seizure, a very uncommon clinical symptom in an uncomplicated infarction. Septic embolism can lead to one of three important cerebrovascular conditions: (a) cerebrovascular occlusions, (b) intracerebral abscesses, and (c) arterial mycotic aneurysms. In these patients, the diagnosis must be recognized rapidly, so that treatment can begin as quickly as possible. The most common MRI finding with septic emboli is simply ordinary embolic infarction. In cases with this single finding in isolation, the diagnosis of septic emboli–related infarction cannot be distinguished from that of bland infarction. In untreated cases, the infarction progresses and vasogenic edema becomes unusually prominent, and enhancement increases. Eventually, frank abscess develops. Another clue to the diagnosis is that the expected time course of imaging findings in an evolving infarction changes once it becomes infected. This is essential to understand because “typical” embolic infarction in the appropriate clinical setting may herald septic emboli, and its significance should not be minimized. The diagnosis should be obvious when a patient is imaged demonstrating both microabscesses and largevessel infarction (Fig. 12.38). Hemorrhagic Infarction An infarction can undergo hemorrhagic transformation with extravasation of small amounts of red cells, resulting in petechial hemorrhage, or a larger amount of blood, resulting in frank hematoma within the area of infarction. It is generally accepted that the hemorrhage associated with ischemic insult occurs after the onset of infarction and represents a conversion or transformation of the bland ischemic territory into an area of hemorrhage. Anticoagulant therapy and more recently the use of thrombolytic agents increase the incidence of hemorrhagic transformation. Hemorrhagic transformation occurs more commonly in cardioembolic stroke than in atherothrombotic stroke (230,231). In addition, larger cardioembolic strokes are more likely to exhibit hemorrhagic transformation than smaller strokes 861

(232–235). These observations led to the most commonly proposed explanation for hemorrhagic transformation. It has been suggested that after an embolic infarction the embolus may partially lyse and fragment. This event then exposes a vascular bed that has been ischemically injured to reperfusion, and the weakened capillary bed may undergo extravasation with petechial hemorrhage or the development of frank hematoma.

FIGURE 12.38 Septic emboli with acute embolic infarction and enhancing microabscesses. A–C: Fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging, apparent diffusion coefficient. D: T1 after gadolinium. E: Perfusion maps (Tmax, cerebral blood flow, cerebral blood volume). FLAIR is only questionably abnormal in the left occipital region (A), whereas clear acute left occipital infarction is shown on diffusion images (B,C). After gadolinium (D), scattered small enhancing microabscesses are shown. Note abnormal perfusion on Tmax and cerebral blood flow maps (E1,E2) and slightly smaller cerebral blood volume abnormality (E3).

Revascularization does not always need to take place for hemorrhagic transformation to occur. It has been observed that hemorrhage can occur distally to an area of permanent vessel occlusion in experimental models of stroke (236,237). A similar finding has also been seen in patients studied with angiography (204,238). Horowitz et al. (238) performed a prospective study using serial CT to evaluate 50 consecutive patients presenting within 5 hours of stroke onset. Thirteen of these patients (26%) had hemorrhagic transformation. Nine of them had angiography, and in eight (89%) continued occlusion of the artery was seen. This study suggests that reopening of the artery is not necessary for development of hemorrhage. Ogata et al. (204) studied 14 patients who died after brain herniation resulting from cardioembolic stroke. Seven of these patients demonstrated hemorrhagic conversion. In all of these patients the distal MCA responsible for the infarction was shown on premortem angiography and again on postmortem dissection to be occluded. In five of the seven patients who had hemorrhaged, the distal internal carotid artery was patent. This suggested to the authors that hemorrhage was more likely to occur when collateral flow to the ischemic region was preserved. Nevertheless, revascularization therapy does increase the rate of hemorrhagic transformation after ischemic stroke. A pooled analysis of the major intravenous tPA studies evaluating treatment in the first 6 hours after stroke found that hemorrhage occurred in 5.9% of patients receiving tPA versus 1.1% of 862

patients receiving placebo, and this difference was statistically significant (239). Biochemical markers have been identified that appear to promote hemorrhagic transformation. Damage to the integrity of basal lamina and endothelial tight junctions appears to result in hemorrhagic transformation. Matrix metalloproteinases (MMPs) are a group of proteolytic enzymes that have been shown to be increased in stroke and are capable of degrading the basal lamina (211,240,241). High levels of MMPs have been shown to be predictive of the risk of hemorrhagic transformation (242–244). In addition, MMPs appear to be increased with the use of tPA (245).

FIGURE 12.39 Petechial hemorrhage in subacute infarction identified on gradient-echo (GRE) imaging but not computed tomography (CT). Hypodensity in the left occipital lobe on CT (A) corresponds to a small subacute infarction. No hyperdense foci are present on CT to suggest the presence of superimposed petechial hemorrhage. GRE (B) identifies a small area of petechial hemorrhage (arrow) within the area of infarction that was not identified on CT.

In general, when serial imaging is performed after a stroke it is clear that the ischemic lesion has undergone hemorrhagic transformation. The infarcted region is first seen in a nonhemorrhagic state that later undergoes hemorrhagic transformation. If hemorrhage is appreciated with the first imaging obtained (i.e., if the preliminary infarction was not imaged before hemorrhagic transformation), then the area of hemorrhage is generally a small region within the area of edema caused by the infarction. In rarer cases, however, imaging of the brain is only performed at a much later point after symptom onset, and the hemorrhage may be a large hematoma. It may not be clear whether this larger hematoma is a hemorrhagic transformation or the primary bleed under these circumstances. In cases such as this, consideration should be given to another etiology for the hemorrhage such as an underlying anatomic lesion. This situation, in which an intracerebral hemorrhage is already identified, is an additional important role for DWI, that is, the search for the etiology of a hemorrhage by examining adjacent nonhemorrhagic tissue can yield the underlying diagnosis of infarction. It also appears that greater degrees of ischemia are related to hemorrhagic transformation. MRI has been shown to have some value predicting the risk of hemorrhagic transformation in ischemic stroke. Large regions of restricted diffusion or larger volumes of markedly decreased perfusion are more likely to develop hemorrhagic conversion (167,244,246–251). PWI source data may also be used to determine blood vessel permeability, which has also been found to predict subsequent development of a parenchymal hemorrhage with a sensitivity of 83% (252). Furthermore, the presence of leukoariosis has been correlated with an increased risk of intracranial hemorrhage following ischemic stroke (251). One of the primary reasons for imaging the acute stroke patient is to differentiate bland infarction from a primary hemorrhagic event or from an infarction that has already undergone hemorrhagic transformation. This has implications in the use of imaging for early infarction evaluation and early treatment decisions with anticoagulation and thrombolytic therapies. These treatments may be withheld in the face of pre-existing hemorrhage. Experimental and clinical studies have shown that MR can be effectively used to differentiate bland from hemorrhagic infarction even in the hyperacute phases of intracranial hemorrhage (205,253,254). These areas of acute hemorrhagic transformation can be appreciated as regions of signal loss due to magnetic susceptibility differences. When hemorrhage is suspected within the first few hours to days after an infarction, it is essential that MR is performed with a T2*-sensitive gradient-echo or susceptibility-weighted imaging (SWI) technique, the most sensitive method of detecting acute hemorrhage. When echo planar imaging is used in conjunction with DWI 863

studies, the T2-weighted “b = 0” image is also very useful to depict acute hemorrhage as areas of hypointensity or signal loss (205,254). MR is more sensitive to hemorrhage in infarction than CT, particularly if SWI is performed (187,195,255). MR may also detect more scattered “petechial” hemorrhage than CT (Figs. 12.7 and 12.39) (255). A complete discussion of the use of MR in the evaluation of hemorrhage is beyond the scope of this chapter; the reader is referred to Chapter 10. Watershed Infarction Watershed or boundary zone infarctions occur at the junctions between larger arterial territories (256). A number of pathogenetic mechanisms have been ascribed to their development, including internal carotid stenosis or occlusion, systemic hypotension, and embolic events (256–259). Earlier CT-based studies identified two types of hemispheric watershed or border zone infarction (260). These territories are demonstrated in Figure 12.40. One of these is a superficial border zone infarction seen in the cortical regions of the brain. These areas represent the boundary zone between leptomeningeal collaterals from adjacent arterial territories (258). Cortical infarctions may occur between the middle cerebral and anterior cerebral territories or between the middle cerebral and posterior cerebral artery territories (Figs. 12.41 and 12.42) (256). These superficial cortical border zone infarctions are usually secondary to a thromboembolic event and may occur in the absence of systemic hypoperfusion (256,261). Another group of border zone infarctions comprise the deep or medullary infarctions seen in the deep white matter of the hemisphere, in the corona radiata and centrum semiovale (Figs. 12.41 and 12.42) (256,260,262). These watershed areas occur between medullary arteries arising from the cortical branches of the MCA and lenticulostriate arteries from the proximal portions of the MCA trunk. Many patients with deep or medullary border zone infarction have carotid occlusion or high-grade stenosis associated with atherosclerotic disease or with other etiologies such as carotid dissection (256,261,263–265). These infarctions are also seen when the circle of Willis is incomplete (266). Watershed infarctions are often precipitated by an episode of systemic arterial hypotension that may occur as a result of shock, cardiac arrest, or an iatrogenically induced event such as with cardiopulmonary bypass surgery. Global hypoperfusion in the adult may also result in a different pattern of injury, specifically bilateral globus pallidus and other scattered areas of infarction. This pattern of infarction has classically been associated with carbon monoxide poisoning, but it can be seen with any cause of asphyxia (Fig. 12.43).

FIGURE 12.40 Diagrams of the arterial border zones.

Although not as commonly discussed, watershed infarctions have also been described in the posterior fossa (267). These infarctions generally involve small regions (less than 2 cm) usually seen in the cortical region between the superior cerebellar artery and the PICA but are occasionally seen more laterally in the cerebellum in the watershed areas between the PICA, superior cerebellar artery, and AICA territories (256). In one report of 115 patients with cerebellar infarctions largely diagnosed with MR, 31% were described as having small border zone infarctions (268). A study of posterior border 864

zone infarctions involving the MCA and posterior cerebral artery border zone territory suggested that when the infarction is unilateral, it is more likely to be due to an embolic event from either a cardiac source or the carotid artery, whereas when patients experience bilateral posterior border zone lesions these are more likely to be due to a hypotensive episode (269). Aside from the recognition of the pattern of the lesion by virtue of its location at boundaries of vascular territories, these infarctions have other characteristic features. Generally, watershed infarctions are more commonly hemorrhagic, and they commonly enhance earlier than thromboembolic infarctions. This appearance can be understood when one considers that global hypoperfusion in an otherwise patent vessel is the cause of the infarction. Once cerebral perfusion pressure is restored, the vessel is widely patent (because it was never occluded) but its endothelium is damaged. Hence, the restored perfusion pressure frequently results in hemorrhage. Similarly, the integrity of the blood–brain barrier is interrupted, but the widely patent vessel delivers a normal perfusion pressure, and so contrast agent readily crosses to the interstitial space.

FIGURE 12.41 Watershed infarctions. Fluid-attenuated inversion recovery images demonstrate characteristic neuroanatomic distribution of watershed, or boundary zone distribution, infarctions. Note that this case shows infarctions involving the boundary between posterior and middle cerebral territories (left) and between anterior and middle cerebral territories (right).

PWI using ASL has been used to define border zone territories based upon a prolonged arterial transit time, decreased CBF, and decreased CBV in normal volunteer patients (270). DWI and PWI have also been used to evaluate patients with border zone infarctions (271). Analysis of the pattern of perfusion deficit may be helpful in identifying the etiologies of the border zone infarction. Three patterns have been identified (271). Patients were seen with normal perfusion, and most of these had a history of preor peri-infarction hypotension as a presumed stroke mechanism. A pattern in which the perfusion deficit was equivalent to the diffusion deficit suggested a cardiac or aortic embolic source. The third pattern of perfusion deficit was more extensive, and all patients with this pattern had severe stenosis or occlusion of a large artery, suggesting this as a predisposing etiology to their border zone infarction. Another study followed progression of watershed infarct volumes with DWI and PWI (272). Higher rates of severe progression in volume appeared to occur in patients with perfusion–diffusion mismatch. Small-Vessel Infarction Lacunar infarctions are defined as small-vessel infarctions up to 1.5 cm in diameter, typically appearing in the deep gray matter, brainstem, and deep white matter of the hemispheres supplied by the perforating arteries (Fig. 12.44). Early work with conventional spin-echo MR showed that it was far more sensitive than CT for detecting these small (less than 1.5 cm) lacunar infarctions (62,273). With the development of MR it also became apparent that lacunar infarctions were often multiple (274). Many of these multiple lesions are in fact clinically silent and may be seen in elderly patients, particularly those at risk for the development of cerebral vascular disease (Figs. 12.45 and 12.46) (275–277). Because MR is a more sensitive imaging modality for the detection of focal areas of gliosis or abnormal water accumulation, other etiologies need to be considered in the differential diagnosis of lacunar infarctions. These include the demyelinating plaques of multiple sclerosis, areas of decreased myelination in the parietal pontine tracks or posterior internal capsules, and dilated perivascular spaces surrounding the penetrating vessels in the base of the brain (278–280). These dilated perivascular spaces are also known as Virchow–Robin spaces and when prominent are called état-criblé (Fig. 12.47). Virchow–Robin spaces tend to be smaller (2 × 2 mm or less by MR) (280), but size is probably the least useful finding to distinguish these from lacunar infarctions. Most important is that the signal intensity of lacunes virtually always differ somewhat from that of CSF (Fig. 12.47); in addition, Virchow–Robin 865

spaces are classically situated at the anterior commissure or radiating out from the ventricles or less commonly in the midbrain. Occasionally, Virchow–Robin spaces are difficult to clearly differentiate from lacunar infarctions, particularly because chronic lacunes can cavitate and in their end stages can be filled with CSF.

FIGURE 12.42 Watershed infarctions in a patient with a severe right internal carotid artery stenosis. Diffusionweighted imaging (A,B) demonstrates small foci of acute infarction in the watershed territory between the right anterior cerebral and middle cerebral arteries, (A, arrow) and a more confluent area of acute infarction in the watershed territory between the right middle cerebral and posterior cerebral arteries (B, arrow). Digital subtraction angiography (C,D) demonstrates a severe stenosis with an associated ulcerated atherosclerotic plaque in the cervical right internal carotid artery (C, arrow). Following endovascular placement of a carotid stent, the degree of narrowing in the right internal carotid artery is improved (D, arrow).

Diffusion-weighted MR has been found to improve the diagnostic detection of the acute lesions responsible for a patient’s clinical symptoms, particularly because it has long been recognized that conventional MR cannot readily age lacunar infarctions (Figs. 12.16 and 12.45) (281,282). In addition, in a subset of patients with lacunar infarctions, diffusion-weighted MR identifies multiple small acute infarctions that may be clinically silent, suggesting another etiology such as an embolic process or vasculopathy rather than a single infarction due to intrinsic vascular disease (283–285). This is often a key finding because the clinical workup and patient management can change dramatically once multiple vascular territory infarctions are identified.

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FIGURE 12.43 Acute diffuse anoxic brain injury in a patient who asphyxiated secondary to a hot dog that became lodged in the trachea during a hot dog–eating contest. A,B: Noncontrast head computed tomography (CT) images. C,D: Diffusion-weighted images (DWI). E,F: Apparent diffusion coefficient (ADC) maps. G,H: Fluid-attenuated inversion recovery (FLAIR) images. Head CT shows diffuse hypodensity with effacement of the cerebral sulci and gyri in the bilateral cerebral hemisphere (A,B). On MRI, there is diffuse hyperintense signal abnormality within the bilateral caudate heads, lentiform nuclei, and cerebral cortices on DWI (C,D) and FLAIR (G,H) sequences. Corresponding hypointense signal abnormality in these areas on the ADC maps (E,F) is consistent with restricted diffusion and acute infarction.

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FIGURE 12.44 Perforating artery territories. Top, left: Level of the caudate bodies. Top, right: Level of the lentiform nuclei. Middle, left: Level of the midbrain. Middle, right: Level of the pons. Bottom, left: Level of the medulla. A, artery; AICA, anterior inferior cerebellar artery; ICA, internal carotid artery; MCA, middle cerebral artery; mesencheph, mesencephalic; PICA, posterior inferior cerebellar artery; Posteromed, posteromedial; SCA, superior cerebellar artery. (continued)

It is well known that senescent changes in the periventricular white matter, which has been termed leukoariosis, are commonly seen in the elderly without any significant cognitive impairment or clinical correlate (Fig. 12.48). In contrast, Binswanger disease or subcortical atherosclerotic encephalopathy is a clinically used term to describe a disease involving small vessels of the brain that progresses in a stepwise fashion and usually begins in the sixth or seventh decade of life (286–288). The disorder is characterized by dementia and memory deficits, language disorders, and psychiatric symptoms. In addition, patients can develop focal neurologic symptoms. Hypertension has been identified as the key risk factor for the development of subcortical atherosclerotic encephalopathy (286,289). MR demonstrates bilateral diffuse areas of periventricular and subcortical high signal in the white matter and gray matter (290–293). Gradient-echo imaging frequently shows extensive focal hypointensities within the deep gray and white matter, indicative of old hemorrhage and characteristic of longstanding hypertension (Fig. 12.46). However, these findings, even when quite extensive, are not necessarily correlated with clinically apparent neurologic deficits or hemorrhagic episodes.

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FIGURE 12.45 Multiple lacunar infarctions. Axial images demonstrate an acute infarction (arrows) in the anterior thalamus on diffusion-weighted imaging (A), apparent-diffusion coefficient (B), T2-weighted imaging (C), and fluidattenuated inversion recovery (FLAIR) imaging (D). A second chronic lacunar infarction is present in the posterior limb of the left internal capsule (arrowheads) on T2 (C) and FLAIR (D) imaging.

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FIGURE 12.46 Multiple microhemorrhages in patients with hypertension. Gradient-echo (GRE) images demonstrate hypointense signal abnormality that correspond to prior microhemorrhage in the pons (A,B), lentiform nuclei (C,D), thalamus (E), the caudate head (F), and the subcortical white matter (F), which are characteristic locations for hypertension-related petechial hemorrhage.

Venous Infarction MR in combination with MR venography is often the best imaging modality for the diagnosis and follow-up of venous sinus thrombosis, although with newer CT technology, CT with CT venography is comparable (294,295). Frequently, the radiologist makes the diagnosis without a specific clinical suspicion because patients do not demonstrate specific symptoms or signs. Moreover, imaging findings can be rather subtle and confusing, particularly because imaging findings in venous infarction are completely different from those in arterial infarction. In fact, these two entities should virtually never be listed in the same differential diagnosis if one understands the imaging findings. The importance of MR in venous infarction cannot be overstated; even catheter angiography can fail to demonstrate the diagnosis, particularly because the workup focuses on excluding arteriovenous malformation in a patient with a hematoma, and thus late venous phase images are often not examined. The MR findings relate directly to the imaging of thrombus within the dural sinuses and the secondary parenchymal changes that occur as a result of the venous outflow obstruction (Table 12.5). It appears that these signal changes can resolve completely independent of whether the venous system recanalizes (296). Lesions may show heterogeneous signal intensity on DWI or be predominately high signal, similar to the cytotoxic edema pattern with arterial stroke (297). The MR signal intensity of the venous thrombus is affected by the degree of residual flow and the age of the thrombus and can have a wide variety of appearances (298–303). In the early or acute stages of venous thrombosis (the first 3 to 5 days), the hemoglobin moiety is the deoxyhemoglobin state, so the occluded vein will appear isointense on T1-weighted images and hypointense on T2-weighted images. The hypointensity of T2-weighted images can often be mistaken for a normal flow void, and the suspected occluded vein must be carefully evaluated. SWI appears to be particularly useful during this acute time period (255,304). In the subacute phase the thrombus becomes hyperintense on T1- and T2weighted images as deoxyhemoglobin is converted to methemoglobin. This pattern of signal change can be seen 5 to 30 days after the start of thrombosis (78,298). Later changes (beyond 2 to 4 weeks) generally depend on the degree of flow and recanalization that has been established. A flow void may return with recanalization; however, a high percentage of patients continue to have abnormal signal 870

within the venous sinus for months to years after the event (298,305). Because there is a variable spectrum of signal change that can occur within the thrombus over time and because slow-flowing blood within the venous sinuses exhibits a signal that confuses the interpretation, MR venography may be helpful (Fig. 12.49) and should also be done along with the MRI study (306–309). It should also be remembered that if the hyperintensity within a venous sinus on unenhanced T1-weighted images is ascribed to slow flow with “flow-related enhancement,” then that same region must be shown to enhance with contrast. If this does not occur on postcontrast scans, then the hyperintensity cannot be due to slow flow and therefore must be due to clot. TABLE 12.5 Venous Infarction: Magnetic Resonance Findings

FIGURE 12.47 Enlarged Virchow–Robin (VR) spaces, not lacunar infarctions. T2-weighted images (top row) and fluid-attenuated inversion recovery (FLAIR) images (bottom row) demonstrate prominent VR spaces (arrows) in characteristic locations. Similar to cerebrospinal fluid, VR spaces are hypointense on the FLAIR sequence, which may be used to distinguish these spaces from lacunar infarctions. Prominent superimposed microangiopathic changes with associated T2 and FLAIR hyperintense signal abnormality in the corona radiata are present in one patient (B,E).

A spectrum of parenchymal changes is seen with MR in the setting of venous thrombosis, and this can vary greatly depending on whether venous sinuses, superficial cortical veins, or the deep venous system is thrombosed (Figs. 12.49 and 12.50) (105,112,306). The parenchyma may not show any abnormality (112). This generally occurs early in the course of the disease or when the venous occlusive disease is not severe. In general, MR findings correlate with the degree of occlusion and rise in venous pressure (105). Parenchymal changes include edematous lesions and hemorrhagic lesions. Hematomas are present in an estimated 30% to 40% of cases and are characteristically in the white matter or sometimes at gray–white junctions (310,311).

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FIGURE 12.48 Patient with chronic hypertension and diffuse increased signal intensity in the subcortical white matter (fluid-attenuated inversion recovery images).

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FIGURE 12.49 Venous infarction presenting as temporal lobe hematoma in a 16-year-old patient with leukemia. A right temporal lobe hematoma (arrows) is demonstrated on axial computed tomography (A), T2-weighted (B), gradient-echo (C), and diffusion-weighted images (D). Cortical swelling with associated hyperintense signal abnormality is also evident on T2 weighted images (B, dashed arrow). Sagittal (E) and coronal (F) maximum-intensity projection images from a magnetic resonance venogram demonstrate extensive venous sinus thrombosis with absence of flow-related signal in the major dural venous sinuses; only the left transverse and sigmoid sinuses are patent (E,F, arrows). Sagittal digital subtraction angiography (DSA) also demonstrates occlusion of the major dural venous sinuses (G); the location of the occluded superior sagittal sinus is indicated by the arrow. Following endovascular thrombolysis, a sagittal DSA image (H) demonstrates recanalization of the superior sagittal sinus (arrow) and other major dural venous sinuses.

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FIGURE 12.50 Venous sinus thrombosis in a 62-year-old with headaches in the setting of dehydration following a long bike ride. Sagittal T1 (A) and postcontrast BRAVO (B) images demonstrate thrombus within the superior sagittal sinus (arrows). An axial T2-weighted image (C) demonstrates thrombus extending into the right transverse sinus (arrow). An axial fluid-attenuated inversion recovery image (D) demonstrates hyperintense signal abnormality within the vessels overlying the left (arrow) and right temporal lobes, consistent with venous congestion with associated slow blood flow. Two axial postcontrast BRAVO images (E,F) demonstrate thrombus within the bilateral transverse sinuses (E, arrowheads) and the superior sagittal sinus (F, arrow). Note the excellent anatomic delineation of the degree of thrombus on these images. Sagittal (G) and coronal (H) maximum-intensity projection images from a magnetic resonance venogram demonstrate extensive venous sinus thrombosis with absence of flow-related signal in the major dural venous sinuses; the occluded superior sagittal sinus is indicated on the sagittal image (G, arrow).

It is often assumed and even taught that the parenchymal abnormalities associated with venous thrombosis are never in recognizable distributions, due to the variability of venous drainage anatomy and territories. Although often confusing, it should be recognized by trained neuroradiologists that there are several very consistent neuroanatomic patterns of parenchymal abnormalities associated with venous sinus occlusion that should prompt consideration of that diagnosis, particularly in the appropriate clinical context (e.g., when the patient is a young adult) (Figs. 12.49–12.51). First, parasagittal hematomas in the high frontal white matter that spare the cortex, either unilateral or bilateral, should prompt consideration of superior sagittal sinus occlusion. Second, a unilateral temporal lobe hematoma in the absence of trauma should immediately instigate the search for transverse sinus occlusion (along with arteriovenous malformation). Third, bilateral deep gray matter lesions, usually but not always with hemorrhage, should motivate the consideration of internal cerebral vein thrombosis or thrombosis of the straight sinus (Fig. 12.51). Diffusion-weighted MR is also heterogeneous in the presence of venous infarction, that is, restriction of diffusion is not as constant a feature as it is in acute arterial infarction (312). Although the edema pattern observed with venous thrombosis shows evidence of cytoxic edema (i.e., restricted diffusion), much of the edema is vasogenic edema, which displays as elevated ADC. This has been postulated to occur from a combination of development of interstitial edema, increase in CSF production, and decrease in CSF resorption (112). A recent retrospective evaluation of MRI findings found that venous infarction and hyperintensity on DWI did correlate with clinical deterioration (313). In addition, hydrocephalus can be seen and is believed to be caused by elevated dural sinus pressure (105,112,314,315). Even when the specific patterns described here are not found, any young adult with a white matter hematoma in the absence of trauma, particularly in the temporal lobe, or with multiple 874

regions of hyperintensity on T2-weighted images not in a large-artery territory should be suspected of harboring venous thrombosis. Tsai et al. (103) evaluated the MR findings accompanying venous sinus thrombosis and correlated these with pressure measurement changes made in the venous sinuses. They described five stages to the MR findings. In stage 1, no parenchymal changes were seen. In stage 2, brain swelling was manifest as sulcal effacement, and mass effect was seen; however, there was no signal change observed in the parenchyma. Patients in stage 2 who underwent pressure measurements showed moderate elevation (20 to 25 mm Hg). In stage 3, some increase in signal intensity was seen within the parenchyma described as mild to moderate edema, and patients had greater elevations (32 to 38 mm Hg). In stage 4, more severe edema was present, and pressure measurements showed severe increases (42 to 51 mm Hg). In stage 5, there was massive edema and/or hemorrhage. Pressure measurements were not obtained in this group.

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FIGURE 12.51 Deep venous sinus thrombosis in a pregnant patient. Sequential axial (A,B) and coronal (C,D) fluidattenuated inversion recovery (FLAIR) images demonstrate prominent hyperintense signal abnormality within the bilateral basal ganglia and periventricular white matter. Note prominence of the anterior temporal lobes on the coronal image, which is consistent with hydrocephalus in the setting of impaired CSF resorption and increased intracranial hypertension due to the deep venous sinus thrombosis. Axial gradient-echo (GRE) images (E,F) demonstrate hypointense thrombus within the inferior sagittal sinus, internal cerebral veins, and other prominent intraventricular veins. Sagittal (G) and axial (H) maximum intensity projection images from a magnetic resonance venogram demonstrate occlusion of the deep venous system, including the straight sinus. Note that the superior sagittal sinus and the right transverse and sigmoid sinuses are patent.

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FIGURE 12.52 Periventricular hemorrhage in a 7-day-old infant born prematurely at 30 weeks gestational age. Neonatal ultrasound (A,B) demonstrates hyperechogenicity in the periventricular white matter (arrows) that corresponds to hemorrhage. (Courtesy of K. Yoem, Stanford, CA.)

The treatment for dural sinus thrombosis usually consists of anticoagulation (100). A multicenter study suggested the prognosis with dural sinus thrombosis treated with anticoagulants is good (100). In this study of more than 600 patients, approximately 80% had no symptoms or only mild residual symptoms. Use of thrombolytics by direct infusion into the dural sinuses has been advocated to treat patients when they show signs of deterioration or development of coma (104,105,316). It has been noted that much of the edema resolves with the reopening of the venous sinuses, suggesting that this represents interstitial edema in the earlier stages of development and not true infarction (105).

ISCHEMIC INJURY IN CHILDREN Stroke in children, particularly ischemic stroke, is an unusual event (317,318). Even when ischemic injury is suspected, neurologic histories can be hard to obtain and the neurologic examination can be confusing, particularly in the infant or neonate. Imaging, therefore, plays an important role in the diagnostic workup of these patients. Ultrasound, CT, and MR have been used to diagnose ischemic injury in the pediatric population. Ultrasound has the advantage of being portable and has been widely used in the neonatal period, particularly to evaluate the unstable infant. However, neurosonography is often normal in the face of hypoxic–ischemic injury and is very operator dependent, with a poor rate of interobserver agreement (317,318). Because there is a significant amount of unmyelinated tissue in the infant brain, CT may also be difficult to interpret. MR, particularly with DWI, provides greater sensitivity for the detection of infarction in this setting (319–321) and also will more sensitively evaluate early myelination (322). In addition, venous infarction must always be considered in neonates and infants as a possible cause of parenchymal lesion, particularly with intracranial hemorrhage. Ischemic Injury in the Preterm Infant Hypoxic–ischemic encephalopathy results when there is a global rather than a focal reduction in blood flow, oxygen, or glucose supply. The pattern of tissue damage depends on the duration of the insult and individual variables such as patient age and collateral circulation. The most common area to undergo ischemic injury in the premature infant is the periventricular white matter, which in the developing fetus is the vascular watershed zone and has a relatively high metabolic demand (323,324). Long-term sequelae result from injury to corticospinal motor tracks and the geniculocalcarine tracts with the optic radiations. Symptoms can include visual impairment and problems with visual spatial perception and spastic diplegia with motor function affected more to the leg (325–327). Periventricular hemorrhage in the region of the germinal matrix also occurs commonly in the premature infant (Fig. 12.52). The bleeding often breaks through the ependymal lining, resulting in intraventricular hemorrhage as well (Fig. 12.53). Periventricular hemorrhagic infarction is commonly associated with intraventricular hemorrhage, occurring in approximately 15% of infants with intraventricular hemorrhage (328). This change is thought to be due to a venous infarction which occurs in the adjacent white matter (329).

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FIGURE 12.53 Intraventricular hemorrhage and periventricular hemorrhagic infarctions. Axial slices shown with T1weighted and T2-weighted imaging, respectively, demonstrate bilateral intraventricular blood more pronounced in the right lateral ventricle. A focus of hemorrhage in the periventricular region adjacent to the right frontal horn of the lateral ventricle is also seen. This is a region of periventricular hemorrhagic infarction.

FIGURE 12.54 Periventricular leukomalacia in two 6-week-old infants born at 30 weeks gestational age. An axial T2weighted image (A) demonstrates multiple small cysts in the centrum semiovale (arrows). An axial T2-weighted image (B) in the second infant demonstrates a large right periventricular cyst (arrow) that represents cystic transformation of a hemorrhagic infarction that occurred in the perinatal period. An axial gradient-echo image (C) demonstrates hypointense signal abnormality in the bilateral periventricular white matter (arrows) that reflects prior hemorrhagic infarction. (Courtesy of K. Yoem, Stanford, CA.)

Periventricular infarction, which may or may not be hemorrhagic, is itself a common occurrence in the preterm infant, with an incidence of 25% to 40% (330). This is usually described as periventricular leukomalacia because it is often marked by areas of necrosis with later development of cystic cavitation and focal dilation of the lateral ventricles (Fig. 12.54). The most common sites of involvement are the posterior periventricular white matter adjacent to the trigones of the lateral ventricles and the white matter adjacent to the foramina of Monro (331). In some cases, the loss of white matter is so dramatic that the ventricular margins are wavy and follow the contour of the cortical gray matter (Fig. 12.55). In these cases the sulci are deep and in close proximity to the ventricles. The loss of white matter also is evident on sagittal images, which reveal a markedly thinned corpus callosum. MR is not as commonly used to evaluate the sick premature infant in the acute states of ischemia. Conventional MR has been reported to show T1 and T2 shortening in the affected ischemic areas (332). DWI may show these periventricular areas of ischemia with a good deal of sensitivity (319,320,333). MR has been used extensively to evaluate chronic changes (334–336). These chronic findings include gliosis or increased T2 signal in the periventricular white matter, thinning of the periventricular white matter volume, thinning of the corpus callosum, and the development of porencephalic cysts and ventriculomegaly (Figs. 12.55 and 12.56). These regions that undergo cystic cavitation with extensive white matter loss manifest as increased T2 signal (332,337).

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FIGURE 12.55 Chronic periventricular leukomalacia in a 3-year-old child born at 32 weeks gestational age. Fluidattenuated inversion recovery (FLAIR) image demonstrates abnormal periventricular hyperintense signal abnormality in association with an irregular ventricular margin (arrow). (Courtesy of K. Yoem, Stanford, CA.)

The premature infant with profound asphyxia resulting from hypotension or circulatory arrest demonstrates a different distribution of injury. In this setting, infarction involves the thalami, basal ganglia, and brainstem (Fig. 12.57) (338). These regions may be more sensitive to global anoxic injury because they have the highest metabolic rates and the greatest degree of maturity in the premature infant (339). Ischemic Injury in the Term Infant Asphyxia in the perinatal period with resulting neurologic sequelae is becoming increasingly less common. However, it is causally linked with the development of cerebral palsy (335,340). Two basic patterns of ischemic injury have been described in the term infant depending on the degree of asphyxia (341–344). Those infants with less profound asphyxia show cortical and subcortical injuries in a watershed distribution that are similar to the pattern of injury seen in adults and demonstrate relative sparing of periventricular white matter (Fig. 12.58). Profound episodes of hypotension and/or circulatory arrest cause injury in the thalami and basal ganglia with relative sparing of the cortex (Figs. 12.59 and 12.60) (343,344). Conventional spin-echo MR imaging often can be normal initially after the insult and develop subtle changes later (333). DWI in the term infant has been shown to demonstrate these deep gray matter infarctions and perirolandic lesions in this acute imaging time period (Figs. 12.58–12.60) (321). When hypoxia is severe or prolonged in full-term neonates or infants, there may be dramatic loss of supratentorial brain tissue resulting in cystic encephalomalacia of the cerebral hemispheres but relative preservation of cerebellum, brainstem, and diencephalic structures. Cystic encephalomalacia can be seen on imaging studies as multiseptated fluid collections replacing brain parenchyma. In addition to these ischemic lesions, hemorrhagic lesions, particularly in the basal ganglia, commonly occur in full-term infants.

FIGURE 12.56 Chronic periventricular leukomalacia. Two successive T1-weighted axial slices through the upper ventricular system demonstrate areas of extensive encephalomalacia in the periventricular region with accompanying cerebral atrophy.

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FIGURE 12.57 Neonatal hypoxic–ischemic encephalopathy. T1-weighted image through basal ganglia demonstrates bilateral abnormal high signal in deep gray and occipital lobes, whereas posterior limbs of internal capsules are abnormally hypointense. This distribution differs from the expected normal signal intensity pattern of deep structures in neonatal brain related to normal myelination.

Neonatal stroke may manifest as an arterial stroke or be secondary to venous sinus thrombosis in the perinatal period. Arterial stroke is thought to be due to emboli originating in the placenta and entering the patent foramen ovale (345). Hypoglycemia is associated with perinatal ischemic stroke and appears to be an independent risk factor for the development of stroke in this time period (346). Bilateral occipital lobe infarction has been noted in the neonate with severe symptomatic hypoglycemia (Fig. 12.61) (347–349). Adults may also exhibit MRI lesions, some of which appear to revert to normal following reversal of a hypoglycemic coma (350). Arterial Infarction in Older Children and Young Adults The lesion of arterial ischemic infarction in older children follows a similar imaging pattern to that seen in adults. In addition to the primary changes with infarct, secondary changes of Wallerian degeneration have also been demonstrated in children (351). Etiologies for infarct differ, however, from those seen in the adult patient. Unusual causes must be considered immediately whenever patients too young for atherosclerosis present with infarction. Although these entities are all relatively uncommon, many have specific associated findings that lead to their immediate diagnosis. Perhaps the primary diagnosis to be entertained in young patients with cerebral infarction should be arterial dissection, that is, arterial injury from significant or even very minor trauma, particularly when infarctions are found in the posterior circulation (Fig. 12.62) (352–354). Although dissections involving the vertebral artery are the most common, other sites, including the internal carotid artery and the intracranial MCA, are not uncommon. This diagnosis should be high on the list when large-vessel narrowing occurs in the face of normal vessel bifurcations in young adults and children. Underlying vasculopathic conditions affecting large vessels, such as moyamoya disease, and syndromes including neurofibromatosis should also be considered as possible etiologies of arterial infarction in this age group. Contrast enhancement can be useful in demonstrating the characteristic network of slow-flow collaterals in such disorders. Infection due to bacterial, viral, or fungal organisms can also lead to an occlusive intracranial arteritis and has been commonly implicated as a cause of infarction (also see Chapter 14) (355–357). Primary cardiac disease with valvular heart disease, cardiomyopathies, and cyanotic congenital heart disease all have higher incidences of ischemic injury in the brain (358,359). Hematologic disorders that predispose to ischemic injury in children include hemoglobinopathies and hypercoagulable states such as antithrombin III deficiency, protein C deficiency, protein S deficiency, and elevated antiphospholipid antibodies (360–364). In addition, a host of metabolic disorders, including mitochondrial disorders, lysosomal disorders, and organic acidurias, may be associated with infarctions.

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FIGURE 12.58 Hypoxic–ischemic injury in a 4-day-old-term infant that demonstrated decreased fetal movement in utero prior to birth. Diffusion-weighted images (A,B) demonstrate hyperintense signal abnormality with the cerebral cortex and subcortical white matter that represents ischemic injury (arrows). (Courtesy of K. Yoem, Stanford, CA.)

FIGURE 12.59 Severe hypoxic–ischemic injury in a 2-day-old-term infant with placental abruption. Diffusion-weighted imaging (A) and apparent diffusion coefficient maps (B) demonstrate restricted diffusion in the bilateral thalami, consistent with profound ischemic injury. (Courtesy of K. Yoem, Stanford, CA.)

FIGURE 12.60 Severe anoxic brain injury in a 9-month-old-term infant with asphyxiation. Diffusion-weighted imaging (A) and apparent diffusion coefficient maps (B) demonstrate restricted diffusion in the bilateral caudate heads (arrowheads) and the lentiform nuclei (arrows), consistent with severe ischemic injury. (Courtesy of K. Yoem, Stanford, CA.)

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FIGURE 12.61 A 5-day-old child with seizures and profound hypoglycemia. T2-weighted images (left column) show minimal high signal in the occipital lobes bilaterally. This is clearly seen on the apparent diffusion coefficient maps (middle and right columns) consistent with acute hypoglycemic infarction. (Courtesy of N. Fischbein, Stanford, CA.)

CONCLUSION Imaging has had an increasingly important role in the management of stroke patients. In the past catheter angiography was used to document indirect changes from mass effects from intraparenchymal and extra-axial hematomas. In the more modern era of stroke diagnosis and treatment, the role of imaging in the acute setting has expanded from primarily excluding surgically treatable lesions to focusing more on the earliest detection of ischemia and identifying potentially recoverable brain tissue. In the acute setting, MR has been shown to provide accurate and rapid diagnostic and prognostic information. CT technology has also continued to evolve, and now CT looks to be promising for having a similar role in triaging patients for immediate treatment. CT has other more practical advantages, including availability, lack of contraindications, and possibly lower costs, which ultimately may greatly affect the direction of medical imaging in the acute stroke patient. In the long term, however, the exact role of advanced CT or MR techniques will depend on clinical trial evaluation that couple imaging data with therapeutic results.

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FIGURE 12.62 Posterior circulation infarction in a patient with a cervical vertebral artery dissection and basilar thrombosis. Diffusion-weighted images (A,B) demonstrate scattered areas of acute infarction with the brain stem and cerebellum (A,B, arrow). Maximum intensity projection MR angiography images in the axial (C) and coronal (D) demonstrate occlusion of the basilar artery, accounting for the patient’s acute stroke presentation. Digital subtraction angiography in the anteroposterior (E) and lateral (F) projections also demonstrate basilar artery thrombosis just distal to the level of the bilateral anterior inferior cerebellar arteries.

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Arch Neurol 1988;45(5):567–572. 83. Levine SR, Twyman RE, Gilman S. The role of anticoagulation in cavernous sinus thrombosis. Neurology 1988;38(4):517–522. 84. van den Bergh WM, van der Schaaf I, van Gijn J. The spectrum of presentations of venous infarction caused by deep cerebral vein thrombosis. Neurology 2005;65(2): 192–196. 85. Adams H Jr., Brott TG, Furlan AJ, et al. Guidelines for thrombolytic therapy for acute stroke: a supplement to guidelines for the management of patients with ischemic stroke. Circulation 1996;94:1167–1174. 86. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359(13):1317–1329. 87. Jauch EC, Saver JL, Adams HP, Jr., et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44(3): 870–947. 88. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581–1587. 89. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999;282(21):2003– 2011. 90. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallel-group, non-inferiority trial. Lancet 2012;380(9849):1241–1249. 91. Nogueira RG, Lutsep HL, Gupta R, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet 2012;380(9849):1231–1240. 92. Smith W, Sung G, Starkman S. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2006;36:1432–1438. 93. Penumbra Pivotal Stroke Trial Investigators. The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke 2009;40(8):2761–2768. 94. Smith WS. Safety of mechanical thrombectomy and intravenous tissue plasminogen activator in acute ischemic stroke. Results of the multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, part I. AJNR Am J Neuroradiol 2006;27(6):1177–1182. 95. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368(10):893–903. 96. Kidwell CS, Jahan R, Gornbein J, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368(10):914–923. 97. Einhaupl KM, Masuhr F. Cerebral venous and sinus thrombosis. An update. Eur J Neurol 1994:109–126. 98. Villringer A, Mehraein S, Einhäupl K. Pathophysiological aspects of cerebral sinus venous thrombosis (SVT). J Neuroradiol 1994;21(2):72–80. 99. Preter M, Tzourio C, Ameri A, et al. Long-term prognosis in cerebral venous thrombosis. Follow-up of 77 patients. Stroke 1996;27(2):243–246. 100. Ferro JM, Canhão P, Stam J, et al. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004;35(3):664–670. 101. Barinagarrementeria F, Cantu C, Arredondo H. Aseptic cerebral venous thrombosis: proposed prognostic scale. J Stroke Cerebrovasc Dis 1992;2(1):34–39. 102. Lansberg MG, Fields JD, Albers GW, et al. Mechanical thrombectomy following intravenous thrombolysis in the treatment of acute stroke. Arch Neurol 2005;62(11):1763–1765. 103. Tsai FY, Higashida RT, Matovich V, et al. Acute thrombosis of the intracranial dural sinus: direct thrombolytic treatment. AJNR Am J Neuroradiol 1992;13(4):1137–1141. 104. Smith TP, Higashida RT, Barnwell SL, et al. Treatment of dural sinus thrombosis by urokinase infusion. AJNR Am J Neuroradiol 1994;15(5):801–807. 105. Tsai FY, Wang AM, Matovich VB, et al. MR staging of acute dural sinus thrombosis: correlation with venous pressure measurements and implications for treatment and prognosis. AJNR Am J Neuroradiol 1995;16(5):1021– 1029. 106. Siddiqui FM, Banerjee C, Zuurbier SM, et al. Mechanical thrombectomy versus intrasinus thrombolysis for cerebral venous sinus thrombosis: a non-randomized comparison. Interv Neuroradiol 2014;20(3):336–344. 107. Coutinho JM, Ferro JM, Zuurbier SM, et al. Thrombolysis or anticoagulation for cerebral venous thrombosis:

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rationale and design of the TO-ACT trial. Int J Stroke 2013;8(2):135–140. 108. Unger E, Littlefield J, Gado M. Water content and water structure in CT and MR signal changes: possible influence in detection of early stroke. AJNR Am J Neuroradiol 1988;9(4):687–691. 109. Unger EC, Gado MH, Fulling KF, et al. Acute cerebral infarction in monkeys: an experimental study using MR imaging. Radiology 1987;162(3):789–795. 110. Naruse S, Horikawa Y, Tanaka C, et al. Proton nuclear magnetic resonance studies on brain edema. J Neurosurg 1982;56(6):747–752. 111. Moseley ME, Kucharczyk J, Mintorovitch J, et al. Diffusion-weighted MR imaging of acute stroke: correlation with T2-weighted and magnetic susceptibility-enhanced MR imaging in cats. AJNR Am J Neuroradiol 1990;11(3):423– 429. 112. Yuh WT, Simonson TM, Wang AM, et al. Venous sinus occlusive disease: MR findings. AJNR Am J Neuroradiol 1994;15(2):309–316. 113. Yuh WT, Crain MR, Loes DJ, et al. MR imaging of cerebral ischemia: findings in the first 24 hours. AJNR Am J Neuroradiol 1991;12(4):621–629. 114. Bryan R, Levy LM, Whitlow W, et al. Diagnosis of acute cerebral infarction: comparison of CT and MR imaging. AJNR Am J Neuroradiol 1991;12:611–620. 115. Ida M, Mizunuma K, Hata Y, et al. Subcortical low intensity in early cortical ischemia. AJNR Am J Neuroradiol 1994;15(7):1387–1393. 116. Tamura H, Hatazawa J, Toyoshima H, et al. Detection of deoxygenation-related signal change in acute ischemic stroke patients by T2*-weighted magnetic resonance imaging. Stroke 2002;33(4):967–971. 117. Rovira A, Orellana P, Alvarez-Sabín J, et al. Hyperacute ischemic stroke: middle cerebral artery susceptibility sign at echo-planar gradient-echo MR imaging. Radiology 2004;232(2):466–473. 118. Kim HS, Lee DH, Choi CG, et al. Progression of middle cerebral artery susceptibility sign on T2*-weighted images: its effect on recanalization and clinical outcome after thrombolysis. AJR Am J Roentgenol 2006;187(6):W650– W657. 119. Crain MR, Yuh WT, Greene GM, et al. Cerebral ischemia: evaluation with contrast-enhanced MR imaging. AJNR Am J Neuroradiol 1991;12(4):631–639. 120. Elster AD, Moody DM. Early cerebral infarction: gadopentetate dimeglumine enhancement. Radiology 1990;177(3):627–632. 121. Kuhn MJ, Mikulis DJ, Ayoub DM. Wallerian degeneration after cerebral infraction evaluation with sequential MR imaging. Radiology 1989;172:179–182. 122. Sawlani V, Gupta RK, Singh MK, et al. MRI demonstration of Wallerian degeneration in various intracranial lesions and its clinical implications. J Neurol Sci 1997;146(2):103–108. 123. Buffon F, Molko N, Hervé D, et al. Longitudinal diffusion changes in cerebral hemispheres after MCA infarcts. J Cereb Blood Flow Metab 2005;25(5):641–650. 124. Gupta RK, Saksena S, Hasan KM, et al. Focal Wallerian degeneration of the corpus callosum in large middle cerebral artery stroke: serial diffusion tensor imaging. J Magn Reson Imaging 2006;24(3):549–555. 125. Brant-Zawadzki M, Atkinson D, Detrick M, et al. Fluid-attenuated inversion recovery (FLAIR) for assessment of cerebral infarction. Initial clinical experience in 50 patients. Stroke 1996;27(7):1187–1191. 126. Noguchi K, Ogawa T, Inugami A, et al. MRI of acute cerebral infarction: a comparison of FLAIR and T2-weighted fast spin-echo imaging. Neuroradiology 1997;39(6):406–410. 127. Alexander JA, Sheppard S, Davis PC, et al. Adult cerebrovascular disease: role of modified rapid fluid-attenuated inversion-recovery sequences. AJNR Am J Neuroradiol 1996;17(8):1507–1513. 128. Beaulieu C, de Crespigny A, Tong DC, et al. Longitudinal magnetic resonance imaging study of perfusion and diffusion in stroke: evolution of lesion volume and correlation with clinical outcome. Ann Neurol 1999;46(4):568– 578. 129. Ricci P, Burdette JH, Elster AD, et al. A comparison of fast spin-echo, fluid attenuated inversionrecovery, and diffusion-weighted MR imaging in the first 10 days after cerebral infarction. AJNR Am J Neuroradiol 1990;20:1535– 1542. 130. Cosnard G, Duprez T, Grandin C, et al. Fast FLAIR sequence for detecting major vascular abnormalities during the hyperacute phase of stroke: a comparison with MR angiography. Neuroradiology 1999;41:342–346. 131. Petkova M, Rodrigo S, Lamy C, et al. MR imaging helps predict time from symptom onset in patients with acute stroke: implications for patients with unknown onset time. Radiology 2010;257(3):782–792. 132. Thomalla G, Rossbach P, Rosenkranz M, et al. Negative fluid-attenuated inversion recovery imaging identifies acute ischemic stroke at 3 hours or less. Ann Neurol 2009;65(6):724–732. 133. Emeriau S, Serre I, Toubas O, et al. Can diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch (positive diffusion-weighted imaging/negative fluid-attenuated inversion recovery) at 3 Tesla identify patients with stroke at $60 billion annually (1). By the year 2020, injuries including TBI are estimated to account for 20% of worldwide burden of death and disability. As a result, considerable effort has focused on improving the prevention, accurate diagnosis, prognosis, and management of TBI patients. Effective diagnosis, treatment, rehabilitation, and prognostication for TBI are dependent upon the accurate characterization of initial injury severity. To complement standard clinical outcome measures, neuroimaging has played an increasingly integral role in injury characterization. Clinical history, exam findings, and demographic data remain the cornerstone of initial TBI patient assessment. Since 1974, the most widely used clinical indicator of head injury has been the Glasgow Coma Scale (GCS) score. The GCS score may range from 3 to 15 based upon three components of neurologic function: (1) eye opening to external stimuli, (2) motor response to stimuli, and (3) verbal response (Table 13.1). One of the important limitations of this scale is that different varieties of traumatic lesions can produce similarly low GCS scores at admission. For example, initial low GCS scores may be seen with subdural hematomas (SDHs), epidural hematomas (EDHs), cortical contusions, intracerebral hematomas (ICHs), and traumatic axonal injury (TAI). As a result, confident predictions of outcome are difficult to establish within the first 24 hours of admission using the GCS. TABLE 13.1 Glasgow Coma Scale

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Valid prognostic models at the time of admission are essential for early clinical decision-making and for research purposes. More recently, a prediction model based on admission characteristics leveraging data from several large patient series (more than 8,500 patients) available as part of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) project has been developed and externally validated (2). As part of this study, the authors found that head computed tomography (CT) characteristics were an important component of the core prognostic data for predicting patient outcomes at 6 months after injury. Contemporaneously, admission data for TBI patients from the Corticosteroid Randomization After Significant Head injury (CRASH) trial (including more than 6,600 patients) similarly identified the importance of admission CT findings for TBI prognostication (3). While the role of noncontrast head CT has been well-established in triage evaluation of TBI, value added by emerging magnetic resonance imaging (MRI) technologies are being increasingly realized (4). Rapid advancement in MRI speed, coupled with development of MRI sequences ever more sensitive to TBI pathology, is providing insight into brain injury previously unidentified, particularly in the setting of mild injury (4), which accounts for the vast majority of TBI cases. In this chapter, we briefly review the epidemiology and pathophysiologic mechanisms of TBI. We will then focus on the role of MRI in evaluating patients with head injury, highlighting the application of both conventional and advanced MRI techniques. The capabilities and limitations of MRI for imaging these patients are addressed. The classification, mechanisms, and pertinent clinical features of different types of traumatic lesions are also reviewed. Important imaging signs that can assist in predicting outcome from head injury are emphasized.

EPIDEMIOLOGY OF HEAD INJURY The most common cause of death and permanent disability in the first few decades of life is trauma, and the neurologic components of trauma are responsible for most of these deaths and disabilities. In the United States, the annual incidence of TBI has been estimated at 180 to 250 per 100,000 population. As the leading cause of disability in people under 40, there are 15 to 20 per 100,000 TBI-related disabilities every year. The incidence of head injury peaks at 550 per 100,000 population for ages 15 to 24 years. The incidence then declines slightly until the age of 50 years, when it again starts to increase. About 500.000 cases of head injury can be expected to occur in the United States each year. However, these estimates almost certainly underrepresent the true incidence of TBI when accounting for all cases of mild TBI, which accounts for the vast majority of head injuries (5). For example, with sports-related concussion, a lack of systematic reporting and tendency to underreport when there has been no loss of consciousness (LOC) leads to a discrepancy in estimates and actual incidence (4,6). The yearly incidence 896

of sports-related TBI alone in the United States has ranged from 300,000 to 3.8 million (4). Within the severe spectrum of TBI, up to 10% of the new cases will be fatal. As many as 5% to 10% of those that survive the initial trauma will experience some degree of residual neurologic deficit (7). Head injury mortality rates are estimated at 25 per 100,000 population each year (7). Fatal head injuries are four times more common in males than females (7). Traffic-related injuries account for between 20% and 50% of head injury deaths (7). Gunshot wounds to the head are responsible for 20% to 40% of deaths. Falls and nonfirearm assaults account for most of the remaining deaths (7). Falls typically account for a higher percentage of injuries at both extremes of life. Seventy-five percent of head injuries in preschool children are secondary to falls (7). Falls are also responsible for the vast majority of head injuries in the elderly population. Two-thirds of all head injury deaths occur before hospitalization (7). Measures designed to reduce mortality from head injury, therefore, will be unproductive unless preventative actions are also incorporated (7).

PATHOPHYSIOLOGY OF TBI Neurotrauma is unique among brain disorders with respect to the critical role that biomechanics contributes to the understanding of injury type and severity (8). Holbourn’s early pioneering work concerning the mechanisms of head injury in adults has served as the fundamental basis for understanding the means by which traumatic stresses produce cerebral injury (Fig. 13.1) (9,10). Using a gelatin model of the brain, Holbourn concluded that injury to the brain occurred through two major mechanisms: direct injuries due to skull distortion (contact phenomenon) and indirect or inertial injuries that arise irrespective of skull deformation. The former is produced by localized fracture or inbending of the skull with direct injury to adjacent brain parenchyma. Neural damage of this type is typically superficial and localized to the immediate vicinity of the calvarial injury and almost always isolated to moderate and severe injuries. Examples of lesions caused by this mechanism are cortical lacerations and contusions due to depressed fracture fragments, and EDHs secondary to lacerations of meningeal arteries. The second mechanism of injury relates to inertial forces which operate irrespective of skull deformation and may produce extensive neural damage, even in the absence of a direct blow to the head. Two related strain metrics applied to model brain deformation after traumatic injury include (1) pressure-induced volumetric strain and (2) shear strain. Largely composed of water, the brain tissue is highly resistant to pressure-induced volumetric deformation and thus volumetric strain does not significantly contribute to TBI pathology and will not be considered further (8). In contrast, shear-strain deformation is characterized by a change in shape without a change in volume and is responsible for most mechanically induced TBI lesions. Because of their inherently low rigidity, neurons are extremely susceptible to shear-strain deformations. These shear strains develop because of differential movements of one portion of the brain with respect to another. Shear–strain forces are greatest at the junction of tissues that differ in density and rigidity (e.g., CSF–brain, gray–white matter, brain–pia-arachnoid, piaarachnoid–dura, skull–dura).

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FIGURE 13.1 Theoretical distribution of shear–strain forces during rotational acceleration of the head. Holbourn experimentally mapped the locations of maximum shear–strain force during rotational acceleration of the head in the (A) sagittal, (B) coronal, and (C) axial planes. A greater frequency of rotationally induced traumatic lesions is anticipated in the more highly susceptible darkly shaded regions. (Adapted from Holbourn AHS. Mechanics of head injuries. Lancet 1943;2:438–441, with permission.)

Early investigations on shear strain focused on linear accelerations measured during impact in animal models of TBI and correlations with pressure recordings within brain surrogates (11). A strong correlation between peak pressure, peak acceleration, and neurologic dysfunction was established (12). Similar studies examining embalmed human cadavers identified injury thresholds for skull fracture and intracranial pressure thresholds, resulting in a human injury tolerance curve, commonly referred to as the Wayne State Tolerance Curve (WSTC). The WSTC, which is based on linear acceleration thresholds, ultimately formed the basis for testing standards for protective equipment design and automotive safety systems (8). Rotational acceleration is the second form of inertial loading contributing to shear-strain injury experienced by the brain at the moment of impact. Animal studies, largely performed subsequent to the development of the WSTC, have validated the early pioneering work of Holbourn and led to the now commonly accepted wisdom that shear strain secondary to rotational acceleration is largely responsible for the majority of traumatic cerebral injury (13). In these studies, primates subjected to highmagnitude angular inertial forces developed widespread axonal injury and prolonged unconsciousness. The complex, interconnected, oblique, and orthogonal orientations of many organized fiber bundles in the brain make its structure highly susceptible to diffuse injury as a result of shear forces resulting from rotational acceleration. This phenomenon can explain the often diffuse distribution of TAI, even in the absence of direct contact injury. Although traumatic coma is very difficult to produce when the head is constrained to exclude rotational motion, allowing rotational acceleration markedly increases the risk of TAI and an unconscious episode (14). However, the precise relative contributions of linear and rotational accelerations as well as other impact factors to neurologic dysfunction remain under active debate. Unlike traumatic lesions from contact phenomenon, rotationally induced shear-strain lesions are typically multiple, bilateral, and widespread. They can occur remote from the site of impact, and may be either superficially or deeply situated (Figs. 13.2–13.5) (9,10). The location of lesions produced by this mechanism, as would be expected, closely corresponds to the locations of maximum shear strains 898

that develop during rotational acceleration of the head. The expected anatomic distribution was experimentally mapped by Holbourn (9,10) for the three orthogonal planes of rotation using a gelatin brain model (Fig. 13.1). Despite the limitations of this model, the distribution of traumatic lesions in fatal head injuries and animal trauma models has generally followed Holbourn’s theoretical predictions. Figure 13.1 illustrates the location of maximum shear strain for all three orthogonal planes of rotation (9,10). Rotationally induced shear-strain injury typically produces lesions at one of the four topographic levels: cortical surface of brain (contusions), TAI, brainstem, and penetrating blood vessels (arteries or veins). The predominate types of lesions observed in a particular patient are determined by the specific mechanical circumstances present during trauma. Although neurons are the most susceptible tissue to rotationally induced shear-strain deformations, non-neuronal tissues (glia, penetrating blood vessels, bridging veins, pia-arachnoid) may also be injured by this mechanism (9,10). In addition to biomechanical mechanisms, an understanding of the molecular and cellular changes underlying TBI can inform our radiologic evaluation of underlying pathology. The biomechanical forces outlined above produce a primary injury which directly disrupts the normal structure and function of neurons, glia, and blood vessels. Subsequent to this primary insult, a vast array of secondary injury processes are initiated resulting in complex molecular and cellular alterations which may persist for days, weeks, and months after injury (15). Mechanical disruption of both neurons and glial cells results in distortions of membrane-bound ion channels with loss of normal electrochemical gradients necessary for maintenance of cell function. Associated mitochondrial failure depletes ATP supply and prohibits energy-dependent restoration of ionic gradients. Simultaneously, disruption of the vasculature results in opening of the blood–brain barrier and vasogenic edema. Loss of vascular autoregulatory mechanisms contributes to hypoxic conditions with resultant ischemia and cytotoxic injury (7,15–18). Widespread neuronal depolarizations are also implicated in expression of immediate early genes including those for excitotoxic neurotransmission and neuroinflammatory genes which further exacerbate tissue damage (19). At the axonal level, varying degrees of shear strain influence the extent of TAI (15). With less than 5% strain, transient axonal depolarizations occur with full membrane and functional recovery. Greater than 20% strain leads to membrane fragmentation, cytoskeletal breakdown, and primary axotomy. Intermediate strain levels (5% to 20%) activate a complex cascade of ionic fluxes, cytoskeletal disruptions, and myelin breakdown precipitated by axolemmal damage (15). These processes can occur over hours to weeks. As Bigler and Maxwell point out in their recent review, a broad appreciation of TBI pathophysiology is important for interpretation of neuroimaging studies (15). For example, alterations in blood-oxygen level–dependent (BOLD) contrast are noted after TBI in a growing body of functional MRI (fMRI) literature. Such findings may reflect, in part, primary neural damage, but consideration of microvascular pathology and autoregulatory dysfunction must be integrated into the interpretation of these results (15). We are entering an exciting era in neuroimaging where advanced imaging tools are beginning to noninvasively tease out these molecular and cellular underpinnings of TBI.

FIGURE 13.2 Acute hemorrhagic contusion and SAH. Magnetic resonance with fluid-attenuated inversion recovery (FLAIR) imaging versus computed tomography (CT). T1-weighted (A,B) and T2-weighted (C,D) MR images show an

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acute hematoma with surrounding mild edema in the left temporal lobe. Note the extracranial scalp soft-tissue swelling posteriorly along the right side. Axial FLAIR (E,F) imaging demonstrates the hemorrhagic contusion along with a bilateral acute subarachnoid hemorrhage. CT (G,H) performed on the same day also shows the acute left temporal hemorrhage, but only vague hyperdensity suggestive of acute subarachnoid hemorrhage.

FIGURE 13.3 Enhancement of subacute TAI lesions. Axial GRE (A), axial T1-weighted noncontrast (B) and postcontrast (C) images show abnormal susceptibility artifact with associated enhancement (arrows in C) related to breakdown of the blood–brain barrier in the right anterior temporal lobe and pons.

RELATIVE ROLES OF IMAGING STUDIES FOR HEAD TRAUMA IMAGING In the setting of acute head trauma, CT remains the imaging standard of care for evaluation of lesions requiring immediate neurosurgical intervention (i.e., acute EDH) (20). Advantages of noncontrast CT imaging for acute head trauma include rapid acquisition, widespread availability, and lack of any significant contraindications. As a diagnostic exam, CT provides excellent sensitivity for demonstrating mass effect, acute hemorrhage, bone injury, and ventricular size/displacement (21,22). For these reasons, CT remains the diagnostic study of choice for the initial evaluation of TBI patients (Table 13.2) (20). This is likely to be true for the immediate future, especially for the patient with multiple-organ trauma. While CT imaging for acute moderate and severe TBI is clearly indicated, guidelines for screening CT in mild TBI (mTBI) are less well defined. Indications for head CT in patients with mTBI (defined as GCS 13 to 15) according to most major guidelines include LOC >30 seconds to 1 minute, prolonged altered or deteriorating level of consciousness, severe headache, focal neurologic deficit or seizure, or worsening symptoms (4).

FIGURE 13.4 TAI, anoxic brain injury, anterior cerebral artery infarction. Axial fast spin-echo (FSE) scans in a 25year-old man obtained 3 days after severe head injury that was accompanied by a period of anoxia. A: Proton density–weighted and (B) T2-weighted fast spin-echo (FSE) imaging reveal areas of TAI in the corpus callosum (curved arrows) and frontal white matter (large arrows). Also present are widespread areas of anoxic injury (arrowheads) in the deep gray matter nuclei (caudate, putamen, thalami) and bilateral anterior cerebral artery distribution infarctions (small arrows).

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FIGURE 13.5 Acute TAI with hemorrhage. Comparison of MR techniques at 1.5 T using FSE (A) versus GRE imaging (B). Scattered focal lesions of TAI are subtle but identifiable on FSE images (A) in the dorsal rostral midbrain, corpus callosum, and supratentorial white matter. Note the demonstration of hypointense hemorrhages in most of these sites and in other subcortical (gray–white junction) locations on the GRE images (B). The extensive involvement of brain damage is unexpected from FSE images alone.

TABLE 13.2 Diagnostic Flow Chart for Evaluation of Acute Head Injury Patients

The role of MRI in head trauma evaluation is evolving. Factors that limit the widespread use of MR as the primary diagnostic study for evaluation of trauma patients include its limited availability in the acute trauma setting, long imaging times relative to CT, sensitivity to patient motion, greater cost, greater difficulty of patient monitoring, lower sensitivity for detecting fractures, and physician unfamiliarity with the MR appearance of traumatic lesions (23–26). An additional major drawback to the use of MR in head trauma has been the logistic difficulty of safely imaging severely injured patients in the MR environment (27). These limitations have been greatly reduced, or eliminated, during the last few years and now offer little impediment to the use of MR for evaluating acute TBI patients (16,17). 901

Notable advances include the development of self-shielded magnets, wider and more accessible scanning gantries, and a wide range of nonferromagnetic life-support and monitoring devices that are compatible with the MR environment. These developments have greatly facilitated the evaluation of these critically ill patients. Every physiologic parameter that might need to be monitored in these patients can be safely monitored (7). Sensors for monitoring respiratory rate and effort, invasive or noninvasive blood pressure, arterial oxygen saturation (pulse oximetry), heart rate and rhythm, end-expiratory CO2 levels, electrocardiographic activity, temperature, and intracranial pressure are available. Multiple types of respirators, ventilators, and full anesthesia machines that are MR compatible are also available. The radiologist should be familiar with the many important concerns, principles, and techniques regarding patient monitoring in the MR environment. With these considerations in mind, the decision to use MRI for diagnostic evaluation of TBI patients largely relies on the clinical scenario. While the most appropriate imaging test must be tailored to each individual patient, several general guidelines can be provided (Table 13.2). A significant factor to consider is the severity of injury as assessed by the GCS. As mentioned above, neurotrauma patients are routinely categorized into three clinical subgroups, depending on the degree of impairment of the admission GCS score: mild (GCS = 13 to 15), moderate (GCS = 9 to 12), and severe (GCS 30 seconds to 1 minute, prolonged altered consciousness, severe headache, seizure or other focal neurologic deficit, or worsening symptoms (4) (Table 13.2). This subgroup of patients has a 5% to 30% incidence of intracranial hemorrhage on initial head CT (22). Mild TBI patients are less likely than those with more severe degrees of injury, however, to have significant intraparenchymal lesions. For patients meeting clinical criteria for mTBI, CT is the most efficacious method for evaluating the lesions for many reasons including availability, speed, and high sensitivity and specificity for both fracture and intracranial hemorrhage (7). Conventional MRI sequences have been shown in numerous studies to have superior sensitivity compared with CT for detecting many types of traumatic injury in these patients, including TAI, small contusions, and small extra-axial hematomas (7,28). As a result, MRI is appropriate in the acute setting of mTBI when the clinical symptomology does not match the CT imaging findings (Table 13.2) (20). Moreover, due to its superiority for detection and characterization of nonsurgical injuries, MRI is recommended for evaluation of mTBI patients with persistent symptoms in the subacute and/or chronic stages of injury (20) (Table 13.2). Whereas these findings may not be known to alter the clinical management or outcome of mild head injury patients (22), there is increasing evidence that valuable prognostic information may be derived from subacute MRI (28–30). Although advanced MRI neuroimaging techniques, including diffusion tensor imaging (DTI), fMRI, susceptibility-weighted imaging (SWI), MR spectroscopic imaging (MRSI), and perfusion-weighted MRI (PW-MRI) may have utility in identifying and characterizing otherwise occult injury of brain trauma (discussed later in this chapter), these techniques are not yet recommended for guiding routine clinical management of mTBI patients (20). The moderate and severe head injury categories share many clinical features and management concerns (7). These two groups, therefore, will be considered together. Neurologically unstable patients in these two categories should be initially studied with CT (7,20). These patients, by definition, already have significant impairment of consciousness and focal neurologic deficits that are deteriorating. The most critical issue in this situation is to rapidly detect potentially treatable hematomas or other surgically correctable lesions. Although CT may miss several important types of injuries, it is still the most efficient means of rapidly excluding surgical lesions (7). Moderate and severe head injury patients who are initially stable can be primarily evaluated by MR (7,16,17,27). It is advantageous to use MR in these patients, if possible, because it is considerably more sensitive for detecting most traumatic parenchymal and extraparenchymal lesions (7,17,27). 902

It is reasonable to suggest that all moderate to severe head injury patients should be evaluated with MR at some point in time during the first 2 weeks after injury (Table 13.2). The full extent of TBI will not be fully determined if only CT is used to evaluate this group of patient as MR is more valuable than CT for assessing the full magnitude of injury (7,17). It also provides more accurate information regarding the expected degree of final neurologic recovery (28,29). The MR exam can be done as the initial examination in stable patients (7,17,18,27). In unstable patients, however, it is probably the best to initially study the patients with CT and postpone the MR examination until they can be safely imaged. It is advisable to obtain the MR study within the first 2 weeks after injury, if possible, because most parenchymal lesions are more visible during this time period. Edema and axoplasmic leakage around areas of neuronal disruption are maximal during the first 2 weeks, rendering lesions more conspicuous. Smaller lesions are more difficult to detect over the ensuing weeks as intra- and extracellular edema gradually subsides (7). After the edema resolves, many traumatic intra-axial lesions may be quite indistinct on CT and standard T2-weighted MR scans (7). CT remains the study of choice for the acute evaluation of neurologically or hemodynamically unstable patients who have significant impairment of consciousness (Table 13.2) (7). The most critical issue in this situation is rapid detection of potentially treatable hematomas or other surgically correctable lesions. In unstable patients, it is unwise to spend even a few extra minutes to obtain an MR exam when CT can more quickly and safely answer the urgent questions. Similarly, CT can be used for evaluation of patients with rapid changes of neurologic status at any point in time after acute head injury, although emergency MR is increasingly common in this setting when available (Table 13.2).

MAGNETIC RESONANCE IMAGING STRATEGIES AND TECHNIQUES Conventional Imaging Protocols The optimal MR protocol for a specific acute head injury patient varies, depending on the individual circumstances. The patient’s clinical condition must always be of principal concern. It may be necessary to delay the MR exam or substitute a CT in some patients if they are neurologically unstable (Table 13.2). When the MR study is performed, it is best to obtain the MR images as rapidly as possible. A judgment must often be made as to how much time can be safely permitted for answering all critical questions. An abbreviated MR examination, tailored to address the most crucial questions in the shortest time possible, may be necessary in some cases. With the aforementioned considerations in mind, the MR exam should be structured so that it can detect all intracranial hematomas, identify nonhemorrhagic forms of injury, provide sufficient anatomic information to classify lesions, guide surgical treatment, and provide an estimation of long-term prognosis (7,17,18,31). The primary emphasis should be directed at maximizing the sensitivity of the examination because these objectives can only be met if all traumatic lesions are accurately identified. Recently, experts in TBI convened as part of the “Advanced Integrated Research on Psychological Health and Traumatic Brain Injury: Common Data Elements (CDE)” joint workshop (31). One task of this expert panel was to define a standardized MRI protocol for studying TBI. MRI protocols including conventional (tier 1) and advanced (tiers 2 to 4) MRI sequences were developed for 1.5 and 3 Tesla (T) (31). Tier 1 protocols are designed for routine clinical applications whereas tiers 2 to 4 are designed for research applications (31). A recommended clinical protocol tailored for TBI evaluation at 1.5 T (tier 1) incorporates multiplanar T1-weighted (3D T1 if available), T2-weighted, T2 FLAIR–weighted, and T2*weighted gradient-recalled echo (GRE) or SWI sequences, in addition to standard DWI. At 3 T, the use of 3D T2-weighted imaging is recommended in addition to the above for high-resolution multiplanar localization of traumatic lesions. Multiple imaging planes are very beneficial for detection and characterization of traumatic lesions (7,31). For example, superficial lesions are most reliably detected when the imaging plane is perpendicular to the cortical base of the lesion (16). Multiplanar imaging is also helpful for the detection of small lesions (e.g., traumatic brainstem lesions) because they may be missed due to partial volume effects or an interslice gap (18). Multiple planes are also essential for determining the exact location of traumatic lesions. Precise localization is necessary for accurate classification of lesions, which in turn has great impact on defining the long-term prognosis. For example, it can be quite difficult with only one plane of imaging to determine whether a small lesion close to the cortical surface of the brain is a cortical contusion or a peripheral TAI lesion. Only when the imaging plane is perpendicular to the adjacent calvarium can this be reliably established. It is desirable to have both T1and T2-weighted scans in at least two perpendicular planes for precisely localizing and classifying 903

traumatic lesions, another advantage to 3D acquisitions. The visibility of a lesion on a particular pulse sequence is influenced by a number of factors: lesion size and location, presence and age of hemorrhage, presence of edema, and MR acquisition parameters (16). The most important factor that affects lesion visibility is the MR pulse sequence used (16). T1weighted imaging is commonly employed to map brain anatomy. Usually limited to research applications, 3D T1 sequences may also be utilized for quantitative volumetric analysis of the brain. Increased water content in the brain evidenced by T2 prolongation generally has an inverse effect on T1 signal with decrease in T1 intensity. T1 imaging can be very helpful for identification of subacute blood products secondary to the T1-shortening effect of methemoglobin. Contrast-enhanced T1-weighted imaging may identify areas of trauma-induced increase in blood–brain barrier permeability beginning 5to 6 days after injury (Fig. 13.3). Moreover, pachymeningeal hyperenhancement following TBI has been described as a sensitive indicator of TBI. However, T1-weighted postcontrast imaging does not improve sensitivity for TBI lesions compared with conventional sequences and is not recommended as part of routine TBI MRI protocol (31). Nevertheless, postcontrast imaging may have value as an optional sequence for helping establish chronicity of injury and for following evolution of TBI lesions when other nontraumatic intracranial pathologies are under consideration. In general, T2-weighted imaging is sensitive to pathology, but it can be nonspecific with respect to etiology. An increase in water content, as seen with vasogenic edema, manifests as T2 prolongation and increased T2 signal intensity. T2 imaging is also sensitive to the paramagnetic effects of iron in the form of hemosiderin. Phase dispersion results in T2 shortening and hypointense signal. Importantly, T2 imaging is superior in its sensitivity to TAI lesions compared with CT (31). Fast spin-echo (FSE) T2weighted images, rather than conventional SE images, allow images with T2-weighting to be obtained in a fraction of the time required for conventional SE techniques and can be implemented on conventional scanners (Figs. 13.4 and 13.5) (7). Because FSE uses radiofrequency refocusing pulses to generate echoes, true T2 contrast is maintained. The FSE sequence, however, is less prone to magnetic susceptibility–induced artifacts than T2*-weighted GRE sequences that use gradient refocusing to generate echoes (7). Clearly, this is disadvantageous in the case of TBI, where it is desirable to identify hematomas by their distinctive areas of susceptibility-induced hypointensity arising from paramagnetic iron (Fig. 13.5). Therefore, it is recommended that all patients be imaged with GRE or SWI scanning as a supplement to an FSE T2-weighted sequence. FLAIR T2-weighted imaging highlights both parenchymal lesions that abut the ventricles, subarachnoid space and extra-axial hemorrhage by virtue of suppression of normal cerebrospinal fluid (CSF) signal (Fig. 13.2). The intrinsic T2 weighting with FLAIR is highly sensitive for evaluation of edema, both vasogenic and cytotoxic in nature. FLAIR and standard T2-weighted imaging are also useful for identifying iron content in the form of hemosiderin, when hypointense signal is present. FLAIR and T2 images may also identify foci of TAI that are beyond sensitivity of CT (28,32). Recently, Kim and colleagues demonstrated high sensitivity for contrast-enhanced FLAIR imaging for identification of posttraumatic pachymeningeal hyperenhancement (33). This conspicuous finding alerts the physician to the detection of additional, more subtle, traumatic intracranial lesions, including trace subarachnoid and subdural hemorrhage. DWI is sensitive to microscopic motion of water molecules in tissue and has demonstrated utility for identifying foci of TAI (34). In the acute setting, DWI has been shown to have superior sensitivity for detection of traumatic white matter injury compared with FLAIR and T2* GRE sequences (Figs. 13.6–13.8). Moreover, apparent diffusion coefficient (ADC) values can readily distinguish cytotoxic from vasogenic edema in the acute and subacute phases and allows for highly sensitive detection of secondary acute ischemic infarction in the setting of TBI.

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FIGURE 13.6 Acute TAI (hemorrhagic and non-hemorrhagic) imaged with DWI. A,B: Axial T2-weighted FSE images show focal lesions in the splenium and centrum semiovale without evidence of hemorrhage. C,D: T2*-weighted GRE images show smaller hemorrhagic foci in part of the splenial lesion and in different white matter lesions. E,F: Note restricted diffusion on DWI in the splenium and bilaterally in the nonhemorrhagic TAI foci. G: Photomicrograph demonstrating axonal swellings and numerous axonal retraction balls (large, rounded, dark-staining structures), typical of severe axonal damage (Palmgren, ×225). The implication of restricted diffusion in TAI was uncertain at the time of publication. (G: Courtesy of David I. Graham, Glasgow, Scotland; and Mark J. Kotapka, Philadelphia, PA.)

Accurate detection of hemorrhage also constitutes an important aspect of trauma imaging. MR was initially believed to be insensitive for detection of some hematomas. However, it is apparent that MR is extremely sensitive to hemorrhage throughout all stages of its evolution (16,35). The sensitivity of different MR pulse sequences to hemorrhage varies with the age of the hematoma and the specific biochemical nature of the hemoglobin (35), as well as with a variety of intrinsic and operator-dependent factors. Briefly, hyperacute hematomas less than 4 to 6 hours old will, for simplicity’s sake, be considered to be primarily composed of hemoglobin that is in a fully oxygenated state (oxyhemoglobin) (35). Oxyhemoglobin is diamagnetic and therefore (unlike deoxyhemoglobin, methemoglobin, and chronic iron storage forms such as hemosiderin) does not produce significant shortening of the T1, T2, or T2* relaxation time. Hyperacute hematomas, therefore, may have signal intensities that are quite similar to that of adjacent brain parenchyma or any nonparamagnetic lesion on all MR pulse sequences (35). It was initially believed that MR might not detect these relatively isointense lesions. It is now clear that few significant hyperacute hematomas will be overlooked if MR images are acquired with T1, T2-, and T2*-weighted sequences (7,16). Invariably there is enough anatomic distortion, perifocal 905

edema, and MR signal intensity difference between hyperacute hematomas and brain parenchyma to allow their recognition.

FIGURE 13.7 DWI and FLAIR for evaluation of TAI. This 18-year-old female patient after TBI secondary to a motor vehicle crash. DWI (first column) shows a larger volume and higher number of TAI (arrows) than do the FLAIR images (second column), T2-weighted images (third column), and GRE images (fourth column). (From Schaefer PW, Huisman TAGM, Sorensen AG, et al. Diffusion-weighted MR imaging in closed head injury: high correlation with initial Glasgow Coma Scale score and score on Modified Rankin Scale at discharge. Radiology 2004;233:58–66, with permission.)

MR angiography (MRA) has become another important diagnostic tool for the evaluation of vascular pathologies of the central nervous system. In the last decade, there has been dramatic improvement of CT angiography (CTA) with multidetector scanners, and that has proceeded so rapidly that many trauma centers have shifted emergency evaluation of the neck and head vessels to CTA rather than MRA. The current role of MRA for evaluation of traumatic vascular injury, however, is noted later in this chapter.

FIGURE 13.8 DWI lesion volume correlates with outcome. This 17-year-old male patient after TBI secondary to a motor vehicle crash. Total lesion extent, with abnormality involving the bilateral corona radiata, bilateral centrum semiovale, and corpus callosum, is better depicted on DWI (first row) than on T2-weighted images (second row) or GRE images (third row). Hemorrhagic foci (arrows) are best seen on the GRE images. This example demonstrates why lesion volume on DWI may have a higher correlation with clinical scores than does lesion number. This patient had fewer lesions than the patient in Figure 12.7, but he also had a much larger lesion volume on DWI and a higher score on the Modified Rankin Scale. (From Schaefer PW, Huisman TAGM, Sorensen AG, et al. Diffusion-weighted MR imaging in closed head injury: high correlation with initial Glasgow Coma Scale score and score on Modified Rankin Scale at discharge. Radiology 2004;233:58–66, with permission.)

Advanced MRI Techniques The last decade has witnessed rapid advancement in MRI sequence development and analysis techniques which are enabling the interrogation of microstructural, metabolic, and functional connections within the brain. While a complete review of the literature related to these advanced MRI techniques is beyond the scope of this chapter, notable advances in DTI, SWI, functional MRI (fMRI), magnetic resonance spectroscopy (MRS), and PW-MRI will be highlighted. It should be stated that presently, none of these advanced MR techniques are recommended by the American College of Radiology (ACR) 906

appropriateness guidelines for routine evaluation of the TBI patient (20). Diffusion Tensor Imaging (DTI) With DTI, the 3D directionality of water motion can be modeled in tissues. The highly organized structure of white matter bundles in the brain strongly favors free diffusion of water along the orientation parallel to white matter bundles with relative reduction in diffusion perpendicular to axon bundles. Diffusion imaging with acquisition of at least six noncollinear diffusion gradient directions (usually many more) allows for tensor modeling with derivation of quantitative scalar metrics which reflect diffusion properties averaged over a voxel of tissue at the smallest scale (36). The most commonly utilized DTI parameters include fractional anisotropy (FA), a unitless scalar metric quantifying the degree of anisotropy within a voxel, and mean diffusivity (MD), the overall magnitude of diffusivity averaged over all sampled directions. Other parameters such as axial diffusivity (AD) (a measurement of diffusivity along the primary eigenvector of the tensor), and radial diffusivity (RD) (the averaged diffusivity along the two minor axes of the tensor ellipse) have been shown to correlate with microstructural white matter pathologies including axonal injury and demyelination, respectively (37,38). Analysis techniques for DTI datasets include histogram analysis, voxelwise analysis, region-ofinterest analysis, and tractography. The reader is referred to excellent reviews on this topic for further detail (4). Extensive investigation has focused on utilizing DTI as a biomarker for investigating white matter microstructural alterations in TBI, specifically damage related to TAI (39). A thorough review of the DTI literature related to TBI is beyond the scope of this chapter and the reader is referred to excellent reviews recently published on this topic (39–41). The heterogeneity with respect to patient populations, imaging parameters, analysis techniques, and imaging time points complicates the interpretation of TBI–DTI literature (39). For example, during the acute/semiacute stages of TBI, FA values within affected white matter regions have been shown to be normal (42), decreased (29), and increased (43) relative to normal controls. Such discrepancy may, to some degree, reflect underlying heterogeneity of the TBI syndrome, but also highlights the need for larger longitudinal studies incorporating standardized acquisition and analysis protocols and outcome measures (39). Despite these limitations, DTI has been validated as a robust measure of TAI at a group level, implicating TBI-related injury to frontal and temporal lobe association areas including the anterior corona radiata, uncinate fasciculus, superior longitudinal fasciculus, and anterior corpus callosum (Figs. 13.9 and 13.10) (40). Importantly, abnormal MD and FA measures in these regions have been shown to correlate with behavioral and cognitive outcome measures at follow-up (29,44). Yuh and colleagues have recently demonstrated the prognostic utility of DTI in individual mTBI patients (Fig. 13.9). As part of a prospective multicenter study entitled Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) pilot, the authors used both whole-brain voxelwise and selective region of interest (ROI) DTI analysis techniques in a heterogeneous mTBI patient population. DTI parameters surpassed CT, clinical, demographic, and socioeconomic variables as predictors of 3- and 6-month outcomes at both group and individual patient levels (29). Such studies will certainly soon lead to consensus guidelines for utilization of DTI parameters for diagnostic and prognostic purposes in individual TBI patients.

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FIGURE 13.9 Voxelwise nonparametric statistical comparison between mTBI patients and controls (with corrections for multiple voxelwise comparisons using threshold-free cluster enhancement). This analysis was used to compare (A) 76 mTBI patients to 50 controls, (B) the subgroup of 32 CT/MRI-positive mTBI patients to the 50 controls, and (C) the subgroup of 44 CT/MRI-negative patients to the 50 controls. Voxel clusters with statistically significant differences in FA between mTBI and control groups at p < 0.05 are shown in red/orange/yellow, with yellow denoting greater statistical significance. A: The 76 mTBI patients demonstrated significantly lower FA in the genu of the corpus callosum, uncinated fasciculi, and anterior corona radiate bilaterally, as well as right internal and external capsules, compared to the 50 control subjects. B: In a comparison of a much smaller subgroup of 32 CT/MRI-positive mTBI patients to the 50 controls, areas of reduced FA were even more extensive and attained much higher levels of statistical significance (yellow regions, corresponding to p < 0.01) than in the comparison of 76 mTBI patients to the control group (mostly red/orange areas, corresponding to p < 0.05, in [A]). C: This method demonstrated no evidence for white matter injury in 44 CT/MRI-negative mTBI patients, compared to the 50 controls.

Future directions in diffusion imaging research for TBI include improved standardization of DTI techniques and commencement of larger, longitudinal prospective studies utilizing standardized outcome measures. In addition, application of more advanced diffusion acquisitions and modeling algorithms, including multishell diffusion techniques like neurite orientation dispersion and density imaging (NODDI) and diffusion kurtosis imaging are under active investigation (45,46). Diffusion modeling algorithms utilizing these techniques are not constrained by the Gaussian tensor model and may add to the limited specificity currently provided with standard DTI metrics. Although in their infancy, such techniques may add additional information to conventional DTI parameters (47). Susceptibility-Weighted Imaging (SWI) SWI takes advantage of susceptibility differences between tissues to provide contrast. Filtered phase image data from a high-resolution, 3D velocity–compensated gradient-echo sequence is combined with the magnitude image to produce the final SW image. The resulting SW image is exquisitely sensitive to blood products in hemorrhage, a property that has been exploited for evaluating TBI lesions (Fig. 13.11) (48,49). Compared with conventional GRE T2* sequences, SWI has been shown to be three to six times more sensitive for detection of hemorrhagic lesions (50). However, mixed results have been reported with respect to correlations between SWI findings and clinical outcomes. Compared with T2 and FLAIR images, Chastain and colleagues (51) showed that SWI is highly sensitive for hemorrhagic lesions, but does not discriminate between good and poor outcomes as measured by Glasgow Outcome Scores (GOS). In contrast, Spitz and colleagues more recently showed significantly increased sensitivity for 908

hemorrhagic brain lesions compared with FLAIR and better correlation with some clinical measures of injury severity (52).

FIGURE 13.10 DTI reveals white matter abnormalities in mTBI. FLAIR (A), fractional anisotropy (FA) map (B), and fiber tracking (C,D) in a 49-year-old patient imaged 16 months after the initial trauma. The FLAIR image shows no abnormalities. From the color-coded FA map (B), a region with reduced FA was identified in the white matter of the left frontal lobe. This region of interest (ROI), illustrated in the top right T2-weighted image, included forceps minor and frontotemporo-occipital fibers (C, superior oblique view). At the level of the ROI, the respective fibers are discontinuous (D, arrow). (From Rutgers DR, Toulgoat F, Cazejust J, et al. White matter abnormalities in mild traumatic brain injury: a diffusion tensor imaging study. Am J Neuroradiol 2008;29:514–519, with permission.)

Interestingly, Li and colleagues (53) recently reported artifactual mimics of traumatic microhemorrhage related to specific phase filtering methods with SWI. As the authors assert, recognition of this artifact is important to avoid overestimation of pathology, particularly in the setting of TBI. The added diagnostic and prognostic value of SWI compared with conventional sequences, including GRE T2* imaging at 3 T, remains to be determined. Functional MRI (fMRI) While advanced structural techniques, including DTI, have significantly improved our ability to anatomically probe microstructural alterations in the brain, fMRI promises to directly visualize resultant functional deficits underlying complex cognitive impairment often associated with TBI. A full discussion of fMRI literature related to TBI is beyond the scope of this chapter and the reader is referred to excellent recent reviews on this topic (54,55). Briefly, brain regions that are activated by performance of a specific task (task-based fMRI) or regions which show temporally correlated activity during rest (resting-state fMRI or rsfMRI) are identified based on coherent BOLD effect. The associated elevations in oxygen-rich blood in these regions can be detected with specialized MRI sequences. Most of the fMRI literature to date for TBI has focused on task-based techniques in mTBI populations (4). McAllister et al. (56) performed the first such study utilizing working memory tasks. The authors demonstrated hyperactivation of bilateral frontal and parietal regions in mTBI patients compared with controls while performing increasingly loaded memory tasks. This finding was despite no appreciable performance difference of the tasks between mTBI patients and normal controls. Interestingly, in a subsequent study by the same authors, mTBI patients challenged with the highest working memory load showed decreased activation in typical working memory circuitry (57). Findings from numerous subsequent task-based fMRI studies in TBI patients have converged on the supposition that TBI impairs 909

the brains ability to activate, modulate, and/or allocate resources for neural circuitry implicated in cognitive activities (55).

FIGURE 13.11 Susceptibility-weighted imaging (SWI) reveals hemorrhagic TAI. A 33-year-old male status-postvehicle rollover. (A) Noncontrast CT scan on admission demonstrates multifocal subarachnoid hemorrhage (arrows) and several small intra-axial hemorrhages within the left frontal subcortical white matter (circle), consistent with hemorrhagic TAI. (B) Axial T2-weighted image obtained 4 days after injury shows hypointensity within the lesions, consistent with acute deoxyhemoglobin (circle). (C) SWI at a slightly higher level more conspicuously demonstrates the extent of TAI (circle). Note additional foci (arrows) not evident on the T2-weighted sequence shown in (B). (From Gean AD. Brain Injury: Applications from War and Terrorism. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2014, with permission.)

rsfMRI evaluation for TBI is in its infancy. Complementary to structural DTI techniques, rsfMRI provides in vivo functional connectivity data for large-scale brain networks (54). Several recent studies have demonstrated abnormal connectivity within thalamocortical (58), default mode (59), cognitive control, motor, and primary visual-processing networks (Fig. 13.12). To date, literature for rsfMRI in TBI is limited by relatively small patient populations and heterogeneity with respect to injury severity and injury chronicity. Future longitudinal prospective studies with larger patient populations will be needed to translate previously described group differences to useful diagnostic and prognostic information for precision medicine applicable to individual patients.

FIGURE 13.12 Reduced connectivity of the default mode network (DMN) in mTBI. The top row shows three orthogonal views (axial, coronal, and sagittal) of the connectivity pattern of the DMN in 96 subjects (51 mTBI patients and 45 control subjects). The copper regions are areas that demonstrated statistically significant resting-state functional connectivity with a “seed” region selected within the posterior cingulate cortex (PCC). The bottom row is a 3D depiction of the group difference regions between mTBI patients and controls, rendered on the MNI152 brain template (excluding the copper-colored group level connectivity for clarity). (Yuh EL, Hawryluk GWJ, Manley GT. Imaging concussion: a review. Neurosurgery 2014;75:550–563;Figure 5.)

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FIGURE 13.13 Magnetic Resonance Spectroscopy in TBI. A: Normal MR spectrum. The metabolites displayed from right to left are N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and myo-inositol (mI). A line drawn to connect the peaks of the metabolites is called Hunter’s angle (blue line). Note how Hunter’s angle has a 45-degree slope. This aids in the evaluation of normal versus abnormal MRS, although it is not specific for a pathologic diagnosis. B: Abnormal MRS in a TBI patient. Note the abnormal decrease in NAA and the abnormal increase in lactate (Lac), glutamate (Glx), Cho, and mI. In addition, Hunter’s angle has lost its normal 45-degree slope (blue line). (From Gean AD. Brain Injury: Applications from War and Terrorism. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2014, with permission.)

Magnetic Resonance Spectroscopic Imaging (MRSI) MRSI is a quantitative technique that enables in vivo evaluation of tissue metabolism with standard clinical MR hardware. The reader is also referred to excellent reviews on this topic (60,61). Briefly, most clinical MRSI applications evaluate signal from the hydrogen proton (1H) because of its shear abundance within biologic molecules of interest. Specific metabolites within an ROI or voxel can then be identified based upon the location of their peak along a spectrum of sampled frequencies (chemical shift) (Fig. 13.13). Tissues can be interrogated with single voxel technique which involves selection of a 3D cubic volume of interest. Alternatively, large regions can be subdivided into grids of smaller voxels using a technique called chemical shift imaging (CSI). Commonly examined metabolites in the brain include N-acetylaspartate (NAA), a marker of neuronal viability; lactate, a marker of anaerobic glycolysis; choline (Cho), a marker of cellular membrane turnover; creatine (Cr), a standard reference for measuring other peaks; myo-inositol (mI), a marker of membrane turnover and possibly reactive gliosis; and glutamate and glutamine (Glx), a marker of excitatory neurotransmission. In the acute and subacute periods of TBI across all injury severity levels, consistent metabolic alterations have been described including decreased NAA and increased Cho in regions of the brain most susceptible to shear injury such as the splenium of the corpus callosum and centrum semiovale (Fig. 13.13) (62,63). While metabolic alterations in regions of visibly injured parenchyma on conventional sequences may simply reflect primary tissue injury, when present in areas of otherwise normalappearing white matter, such changes have been interpreted to reflect TAI (64–66). Longitudinal studies following patients with mTBI have highlighted the transient and dynamic nature of these metabolic changes with mTBI patients often showing normalization of NAA, Cho, and Glx peaks in the chronic time periods (63). Persistent elevation of Cho and mI in the chronic phases of injury has been attributed to proliferative astrogliosis. For severe TBI, MRSI has shown prognostic value with respect to clinical outcomes (61,67). Data correlating MRSI with outcomes for mTBI are more limited. A recent longitudinal study by George and colleagues (68) used MRSI at multiple time points after mTBI with a demonstrated correlation between centrum semiovale Cr levels and performance on neuropsychiatric metrics assessed 6 months after injury. Such studies correlating MRSI findings with clinical outcomes in mTBI are scarce. Translation of current MRSI data for TBI also suffers from the limited specificity of findings, which may also be seen in a wide variety of nontraumatic brain injuries. Magnetic Resonance Perfusion Ischemia is an important secondary pathologic process contributing to significant tissue damage 911

following the initial primary injury of TBI. As discussed previously, increased metabolic demands on the acutely injured brain tissue relate to excitotoxic state, neuroinflammation, and massive electrochemical gradient shifts resulting from membrane disruption (15). These metabolic alterations are in the setting of concomitant impairment or complete loss of vascular autoregulatory control and compromised cerebral blood flow (CBF) (15). Much of the existing data related to brain perfusion after TBI is derived from single-photon emission computed tomography (SPECT) imaging studies utilizing the perfusion radiopharmaceutical agent technetium-99m hexamethylpropylenamine oxime (99mTc-HMPAO) (69–71). Xenon-enhanced computed tomography (Xe-CT) and CT perfusion techniques have also been applied (72). These studies have demonstrated regions of hypoperfusion in the brain that can be associated with injury severity (72). A favorable outcome is seen in TBI patients with hyperemia on baseline imaging, while oligemia portends a poor outcome (72). To date, few studies have evaluated the utility of perfusion-weighted MR (PW-MRI) techniques in TBI. The most common utilized MR perfusion technique is dynamic susceptibility contrast (DSC). Using this technique, Garnett and colleagues (73) measured reductions in cerebral blood volume (CBV) in regions of brain demonstrating evidence for contusion on conventional sequences. Furthermore, a subset of patients showed reduced CBV in areas of normal-appearing parenchyma on conventional sequences. Although the number of patient’s was small, reduced CBV on PW-MRI in all regions was correlated with poorer clinical outcomes. Using an alternative PW-MRI technique that does not require intravenous contrast known as arterial spin labeling (ASL), reductions in regional CBF in the thalami were observed in mTBI patients, a finding that correlated strongly with neurocognitive impairment (46,74). These studies were underpowered to evaluate prognostic capacity of ASL perfusion measurements for mTBI patients. As with other advanced imaging techniques, more prospective and longitudinal studies are needed to determine the role of MR perfusion imaging for TBI evaluation. Given the complex and dynamic pathophysiologic mechanisms underlying TBI, it is reasonable to anticipate that imaging characterization of brain injury for diagnostic and prognostic purposes will require multiparametric analysis with a combination of MRI techniques that probe detailed structural, functional, and metabolic derangements across multiple time points.

INJURY CLASSIFICATION Various classification systems for head injury have been proposed (Tables 13.3 and 13.4) (7,13,31,75,76). In order to standardize definitions and imaging protocols for TBI classification, the Interagency Common Data Elements Project was established in 2008. Pathoanatomic terms and definitions for injury classification have thus been established and recently updated (31,76). Throughout the following descriptions of TBI injury classification we attempt to adhere to the common data element pathoanatomic terminologies. We will begin with a discussion of primary intra-axial lesions, followed by a review of primary hemorrhage (both extra-axial and intra-axial). Finally, MR evaluation and imaging characterization of traumatic vascular insults will be discussed.

PRIMARY INTRA-AXIAL LESIONS Primary intra-axial lesions can be categorized into three anatomically well-defined categories: TAI, contusion, and brainstem injury (BSI). This method of classification is applicable to both radiologic imaging and pathologic analysis and avoids imprecise nomenclature. Intracerebral hemorrhage independent of contusion and TAI will be considered separately as part of the following section on primary hemorrhage. Traumatic Axonal Injury TAI is one of the most common and important types of primary injury found in patients with mild, moderate, and severe head trauma. A radiologic definition for TAI was described in the CDE-TBI working group as: “A radiologic entity which demonstrates a pattern consistent with scattered, small hemorrhagic and/or non-hemorrhagic lesions which have been shown historically to correlate with pathologic findings of relatively widespread injury to white matter axons, typically due to mechanical strain related to rotational acceleration/deceleration forces” (31). Autopsy and histopathologic studies have shown that the extent of axonal injury exceeds that 912

visualized macroscopically (13,75,77). Current imaging modalities, including MR, likely underestimate the true extent of TAI. TABLE 13.3 Traumatic Intracranial Pathoanatomic Entitiesa

Although commonly used interchangeably, the terms TAI and diffuse axonal injury (DAI) have been separately defined radiologically (31). Specifically, when there is imaging evidence for axonal disruption involving three or less foci, the term TAI is applied. DAI refers to imaging evidence for multifocal TAI (greater than three foci of radiographically evident TAI) which are present within at least two separate lobes of the brain and the corpus callosum. TAIs in the brainstem and cerebellum are usually seen in the setting of DAI (Fig. 13.5). Most TAI lesions spare the overlying cortex, frequently being located at the gray–white matter interface. Occasionally, the cortex may be secondarily involved by larger lesions. Lesions range in size from 2 to 15 mm, with peripheral lesions tending to be smaller than more central ones. Lesions are usually ovoid to elliptical in shape, with the long axis parallel to the direction of the axonal tracts that are involved. When present, TAI lesions tend to be multiple. TABLE 13.4 Classification of Traumatic Brainstem Injury

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TAI tends to occur in three fundamental anatomic areas: lobar white matter, corpus callosum, and the dorsolateral aspect of the upper brainstem (Figs. 13.4, 13.5, 13.14, 13.15). Adams and coworkers (75) emphasized that TAI tends to occur in these three areas in successive grades, with the involvement becoming sequentially deeper with increasing severity of trauma. In patients with mild head trauma, TAI lesions may be confined to the white matter of the frontal and temporal lobes (grade 1) (Fig. 13.16). Most of these are found at the gray–white matter junction, with a smaller number in the deep central white matter (corona radiata) (Figs. 13.1 and 13.5). Grade 1 TAI typically involves the parasagittal regions of the frontal lobes and the periventricular regions of the temporal lobes. Occasionally, TAI lesions occur in the parietal and occipital lobes (Figs. 13.17 and 13.18). About 8% of TAI lesions involve the internal and external capsules, whereas only 4% of lesions are found in the cerebellum (17).

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FIGURE 13.14 Primary BSI as part of grade 3 TAI with hemorrhagic contusions. Sagittal T1-weighted (A) image demonstrates hemorrhagic contusions along the vertex. Axial T2-weighted, FSE (B–D) images and FLAIR (E–G) images demonstrate focal lesions in the right lateral aspect of the brainstem, splenium of the corpus callosum, and a hemorrhagic lesion in the body of the corpus callosum. Smaller TAI lesions were present in the supratentorial white matter as well. Note that FLAIR imaging shows these lesions with apparently greater conspicuity, as is seen in many other entities. Primary brainstem TAI is invariably accompanied by similar lesions in the corpus callosum and deep lobar white matter (grade 3 DAI). Gross specimen (H) shows primary hemorrhagic lesion in the dorsolateral quadrant of the rostral brainstem typical of TAI involving the midbrain. (H: Courtesy of David I. Graham, Glasgow, Scotland; and Mark J. Kotapka, Philadelphia, PA.)

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FIGURE 13.15 Grade 3 TAI. Axial GRE T2*-weighted (A–D) images show multiple juxtacortical lobar (A), callosal (B), and brainstem (C,D) foci of susceptibility artifact consistent with stage 3 TAI. Coronal T1-weighted (E), and FLAIR (F) images in the same patient show areas of T1 prolongation (E) and T2 shortening (F) in regions of callosal and brainstem TAI. Hemorrhagic contusions are also present within the bilateral temporal lobes (C–E). G: Coronal gross section at the level of the internal capsule and basal ganglia in a different patient with similar pathology demonstrates hemorrhage in the body of the corpus callosum, small contusions, and deep ganglionic hemorrhage. (G: Courtesy of David I. Graham, Glasgow, Scotland and Mark J. Kotapka, Philadelphia, PA.)

MRI has increased sensitivity for TAI compared with CT (27,28). On MRI, hemorrhagic axonal injury is commonly identified as foci of parenchymal susceptibility artifact in characteristic locations, best seen on GRE or SWI sequences. FLAIR imaging demonstrates foci of hyperintense signal at characteristic locations for both hemorrhagic and nonhemorrhagic TAI. In the acute stage, DWI reveals reduced ADC values in areas of TAI, a finding equally sensitive with FLAIR imaging. Even mTBI patients can show diffuse neuronal and axonal injuries with widespread fiber disruption by DTI (Figs. 13.9 and 13.19), a finding that has been corroborated by a reduction in whole-brain NAA and regional reductions in white matter FA (29,78). Patients with more severe rotational acceleration may develop lesions in the lobar white matter and the posterior half of the corpus callosum (grade 2) (Figs. 13.4 and 13.5). If the trauma is of even greater severity, TAI lesions also will be found in the dorsolateral aspect of the midbrain and upper pons (grade 3) (Figs. 13.14 and 13.15). The corpus callosum is the second most common area involved with TAI (21% of TAI lesions) (17). TAI of the corpus callosum invariably occurs in conjunction with TAI of the lobar white matter (grade 2 TAI). Most callosal lesions (72%) occur in the posterior body and splenium (Figs. 13.4, 13.5, 13.15, and 13.20) (17,75,79). When TAI lesions are found in more rostral areas of the corpus callosum, they are usually, but not always (Fig. 13.15), found in conjunction with lesions of the splenium. Callosal TAI 916

lesions may be quite large and occasionally may involve the entire corpus callosum. These lesions are usually unilateral and slightly eccentric to the midline but may also be bilateral and symmetric. The mechanism for production of traumatic corpus callosum injury was originally believed to be due to traumatic laceration of the corpus callosum by the free edge of the falx (79). It is now generally accepted that this mechanism is implausible and that corpus callosum injury is mediated by rotationally induced shear–strain forces (13). Gennarelli et al. (13) showed in primate experiments that nonimpact rotational acceleration of the head in the lateral or oblique–lateral direction will uniformly produce shearing injury of the corpus callosum. TAI of the brainstem is the third area that is frequently involved with TAI (grade 3 TAI), but this is discussed as a separate topic.

FIGURE 13.16 Grade 1 TAI. Axial T2 FSE (A) and axial T2*-weighted GRE (C) images through the level of the centrum semiovale show the characteristic location and imaging appearance of grade 1 TAI involving frontal lobe juxtacortical white matter. B: High magnification view of boxed region in A demonstrates subtle T2 signal hyperintensity related to TAI which correlates with areas of focal susceptibility artifact seen in C.

Classically, patients with high-grade TAI present with prolonged LOC starting at the moment of impact (75). Patients with TAI usually have significantly greater impairment of consciousness than do patients with many other primary lesions, such as contusions, ICHs, and extra-axial hematomas. Moreover, studies on patients with MR-documented TAI show that diffusion-weighted sequences showed the strongest correlation between lesion volume and subacute Modified Rankin Score at discharge (Figs. 13.7 and 13.8) (80). In a recent prospective study evaluating 128 patients with moderate and severe TBI, Moen and colleagues (32) showed that TAI lesion load in the corpus callosum, brainstem, and thalami on DWI and FLAIR were independent prognostic factors. However, TAI is not limited to severe TBI. In a prospective study limited to mTBI patients, Yuh and colleagues (28) recently showed that the presence of four or more foci of hemorrhagic axonal injury was independently associated with poorer 3month outcomes.

FIGURE 13.17 Grade TAI. A 3-T MRI performed 14 days after a boating accident resulting in loss of consciousness and posttraumatic amnesia. FA, fractional anisotropy; FLAIR, fluid-attenuated inversion recovery; MPGR, multiplanar gradient echo. (Courtesy of Pratik Mukherjee, University of California, San Francisco, CA.)

Contusions Contusions are the second most frequently encountered group of primary intra-axial lesions. They comprise about 44% of intra-axial lesions (16,17,81). Contusions primarily involve the superficial gray matter of the brain (Figs. 13.21–13.25) (17,81). Because gray matter is much more vascular than white 917

matter, contusions are frequently hemorrhagic (Fig. 13.22) (16,17). The hemorrhagic foci may vary in size from small petechiae scattered throughout a much larger nonhemorrhagic zone of injury to multiple large confluent regions of hemorrhage occupying most of an entire lobe (Figs. 13.23 and 13.24). Contusions, when present, tend to be multiple and bilateral (Figs. 13.21 and 13.22).

FIGURE 13.18 Grade 1 TAI. Arrows show the characteristic finding of axonal shearing injury of the right parietooccipital subcortical white matter. FA, fractional anisotropy. (Courtesy of Pratik Mukherjee, University of California, San Francisco, CA.)

FIGURE 13.19 Grade 1 TAI. Axial FLAIR image (A), fractional anisotropy (FA) map (B), and fiber tracking (C,D) in a 38-year-old patient imaged 2 weeks after the initial trauma. The FLAIR image shows no abnormality. The color-coded FA map (B) shows a region of reduced FA identified in the right centrum semiovale. This region of interest (ROI) included projection fibers (C, posterolaterosuperior view). At the level of the ROI, projection fibers are discontinuous (D, arrow). (From Rutgers DR, Toulgoat F, Casejust J, et al. White matter abnormalities in mild traumatic brain injury: a diffusion tensor imaging study. Am J Neuroradiol 2008;29:514–519, with permission.)

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FIGURE 13.20 Grade 2 TAI involving the corpus callosum. Axial FLAIR (A) and T2-weighted (B) MR images show abnormal hyperintense signal within the splenium of the corpus callosum. Axial DWI (C) and ADC map (D) show associated reduced diffusion.

FIGURE 13.21 Frontotemporal hemorrhagic contusions and SDH. T1-weighted (A,B) and T2-weighted (C,D) images clearly demonstrate subacute hemorrhagic contusions in their classic locations. Note the accompanying small SDH. Patients with contusions usually have a good neurologic outcome or are only mildly disabled unless the lesions are very large or are accompanied by other more ominous lesions, severe mass effect, or secondary brainstem injury.

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FIGURE 13.22 Cortical contusions. Lateral (A) and inferior (B) views of the brain of a patient who died from head trauma demonstrate the characteristic appearance and distribution of traumatic cortical contusions. Contusions are often hemorrhagic, superficially located, and typically involve the inferior, lateral, and anterior surfaces of the frontal and temporal lobes.

FIGURE 13.23 Secondary BSI due to transtentorial uncal herniation. Axial (A) and coronal (B) FLAIR images of a patient with new signs of secondary BSI were imaged 10 days after the initial trauma. Despite the left decompressive hemicraniectomy, there is persistent mass effect related to the large bifrontal and anterior temporal hemorrhagic contusions that contribute to uncal herniation (white arrows in B) and brainstem compression. Axial T2-weighted image (C) demonstrates a compressed and deformed midbrain with T2 hyperintense tegmental edema (white arrows in C outline the compressed midbrain). Mass effect obliterates the ambient and interpeduncular cisterns. Coronal DWI (D) shows asymmetric hyperintensity in the left cerebral peduncle (black arrow) related to TAI and/or secondary Wallerian degeneration of the corticospinal tract. Additional gyriform DWI hyperintensity involving the left insular and frontal opercular cortex (white arrow) relates to secondary ischemic injury in this patient.

Contusions most commonly involve the temporal (46%) and frontal (31%) lobes (17,31,81). Particularly prone to injury are the inferior, anterior, and lateral aspects of these lobes (Figs. 13.17, 13.22, and 13.26). Temporal lobe lesions are most likely to occur just above the petrous bone or posterior to the greater sphenoid wing. Frontal lobe lesions tend to lie just above the cribriform plate, orbit roof, planum sphenoidale, and lesser sphenoid wing (Figs. 13.21, 13.22, and 13.26). The parietal and occipital lobes are implicated much less frequently (13%). Cerebellar contusions constitute approximately 10% of contusions and are typically found in the superior vermis, tonsils, and inferior hemispheres (17). 920

In a series of trauma patients, contusions were much less likely to be associated with severe initial impairment of consciousness than with TAI (7,16–18). Severe impairment of consciousness typically only occurred when the contusions were very large, multiple, bilateral, or associated with TAI or secondary BSI (Figs. 13.23 and 13.24). Cervicomedullary Junction and Brainstem Injury As with supratentorial traumatic lesions, BSI can be separated into primary and secondary forms, depending on when the injury occurs (Table 13.4) (18,82). Primary lesions are those that result from the initial traumatic force, whereas secondary ones are those that develop subsequent to initial trauma. Much of the knowledge regarding the imaging appearance of primary and secondary BSI has arisen from autopsy studies because CT has never been sensitive enough to allow detection and characterization of most types of BSI. MRI makes it possible to effectively evaluate and characterize BSI in nonfatally injured patients (18). In support of early work done by Gennarelli et al. (13) and Gennarelli and Ommaya (14), recent MRI studies have correlated the presence of BSI with poor outcome (83). Hemorrhagic lesions involving the dorsal brainstem and the presence of bilateral BSI were particularly associated with poor outcomes (83). Importantly, one-third of patients with MRI evidence for BSI did have good clinical outcomes, with nonhemorrhagic lesions yielding the highest positive predictive value for good outcome (83). Primary BSI can be classified into four major types (Table 13.4). One type is due to direct forces (18), whereas the other three are due to indirect forces (18,75). The first type of primary BSI is believed to be quite rare. With severe displacement of the brain, the dorsolateral aspect of the upper brainstem may strike the free edge of the tentorium, producing a superficial contusion or laceration (Fig. 13.23). The colliculi, superior cerebellar peduncles, and lateral aspect of the cerebral peduncles are most susceptible to this uncommon form of injury. Individual susceptibility to BSI by this mechanism is highly influenced by considerable variation in size and shape of the tentorial incisura. Unlike brainstem TAI, this type of injury is not necessarily associated with involvement of the cerebral white matter and corpus callosum. Indirect forces are responsible for most cases of primary BSI (13,18,75). The most common type, by far, is that associated with widespread TAI (Fig. 13.15) (13). Brainstem TAI, according to Adams and colleagues (75), rarely occurs without the presence of histologically similar lesions in the corpus callosum and deep cerebral white matter (Fig. 13.15). TAI in these three locations form a frequently associated triad described by Adams et al. (75). Brainstem TAI is characteristically located in the dorsolateral quadrants of the rostral brainstem (midbrain and upper pons) (18,75,83). The ventral aspect of the pons and midbrain and the entire medulla are typically spared. There is a strong predilection for injury to specific fiber tracts, such as the superior cerebellar peduncles and medial lemnisci (75). Less commonly, lesions may involve the lateral aspect of the midbrain and cerebral peduncle (18). Because the lesions are usually nonhemorrhagic, they may be difficult to visualize with CT (17,18). Unless the brainstem lesions are accompanied by lesions in other portions of the brain, the diagnosis of primary brainstem TAI should be made with extreme caution (75). In addition, the diagnosis cannot be confidently made in the presence of transtentorial herniation, cisternal compression, or posterior fossa mass effect, which may produce secondary BSI (75).

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FIGURE 13.24 Secondary BSI due to herniation from extensive contusions. Axial T2-weighted images from inferior to superior (A–C) demonstrate extensive bilateral temporal lobe contusions. The brainstem is secondarily deformed from descending tentorial herniation, and subsequent ischemic necrosis of the ventral brainstem is seen. Also, note on higher slices (C) the posterior cerebral artery infarctions due to herniation-related posterior cerebral occlusions. Serial sections through the supratentorial brain (D) show extensive cortical contusions. In sections through the posterior fossa (E), note the “coning” deformity of the brainstem due to descending transtentorial herniation with secondary brainstem Duret hemorrhages. (C,D: Courtesy of Nicholas Gonatas, Philadelphia, PA.)

A third type of primary BSI was described by Adams and colleagues (75). This type consists of multiple petechial hemorrhages that are scattered throughout the brain but are particularly prominent in the deep central white matter, hypothalamus, thalamus, and periaqueductal regions of the rostral brainstem. Although the location is similar to that of brainstem TAI, there is no specific association with lesions of the lobar white matter, corpus callosum, or superior cerebellar peduncles (75). The distribution of these petechial hemorrhages is also quite different from secondary (Duret) hemorrhages that are described later in this chapter. Histologically, these lesions are characterized by multiple, primarily microscopic, perivascular collections of blood (75). This type of injury is usually associated with a grim prognosis (75), and may represent shear–strain injury to numerous small penetrating blood vessels in the brainstem. The fourth type of primary BSI is the pontomedullary separation or rent (75). Unlike brainstem TAI, this lesion may occur in the absence of more widespread cerebral damage (75). It is characterized by a hyperextension-induced tear of the ventral surface of the brainstem at the junction of the pons with the medulla (75). This may range from an incomplete tear to complete brainstem avulsion. This type of injury is typically, but not invariably, fatal. Secondary BSI can arise from two general mechanisms: systemic factors (anoxia, hypotension, ischemia) and severe mechanical compression or displacement of the upper brainstem (Table 13.4) (18,75,84–86). Diffuse hypoxic or ischemic BSI usually occurs in conjunction with supratentorial ischemic injury. Brainstem involvement with diffuse hypoxia is usually a late or terminal event. The brainstem is usually spared until just before death (18). Mechanical compression is invariably secondary to transtentorial herniation caused by increased intracranial pressure, intracranial hematomas, multiple contusions, or diffuse edema (Figs. 13.23, 13.24, 13.27, and 13.28) (18,75,85,86). Mechanical compression may initially cause only distortion and displacement of the brainstem (18). Clinical signs and symptoms of brainstem dysfunction may be potentially reversible (82,86), especially if the only radiographic findings of BSI are displacement or compression of the brainstem. If mechanical compression is prolonged, however, there is often development of focal intrinsic secondary lesions within the brainstem that are unlikely to be completely 922

reversible (Figs. 13.23, 13.24, 13.27, and 13.28).

FIGURE 13.25 Acute hemorrhagic contusions with acute SAH. A heterogeneous right inferior frontal and anteriorinferior temporal lesion on T1-weighted (A,B) and T2-weighted (C,D) images is in the characteristic location for a traumatic contusion and/or hematoma. Acute hemorrhage is admixed with a nonhemorrhagic component. Also note the small extra-axial hematoma along the temporal pole (A–D). Hyperintensity within sulci on FLAIR (E,F) indicates the presence of associated acute SAH.

Several types of intrinsic secondary lesions may be seen within the brainstem (Table 13.4). Secondary Duret hemorrhages consist of centrally placed, generally midline collections of blood in the tegmentum of the rostral pons and midbrain (18,75,84,85). These hemorrhages may vary from numerous petechiae to massive central tegmental hemorrhages involving the entire upper brainstem. They are usually located in the ventral and paramedian aspects of the midbrain and upper pons (Fig. 13.24), with relative sparing of the dorsolateral aspects of the brainstem (18,75). Duret hemorrhages are not limited to head injury patients but also occur after transtentorial herniation from other causes. As is the case with grade 3 TAI, the Duret hemorrhage is usually, but not always, associated with a grim prognosis (87). Most authors believe that secondary brainstem hemorrhages result from stretching or tearing of the penetrating arteries as the upper brainstem is caudally displaced during transtentorial herniation (18,85). Focal brainstem infarcts may also occur via the same mechanism (18). Although differentiation of brainstem infarcts from TAI lesions can be difficult, the location of infarcts is typically in the central tegmentum of the pons and midbrain, whereas TAI usually involves the dorsolateral midbrain (18). Severe pressure necrosis involving the entire upper brainstem is commonly seen in individuals who eventually die from prolonged brainstem compression due to transtentorial herniation (Figs. 13.23 and 13.28) (18,84). Primary Hemorrhages Traumatic hemorrhage can result from injury to any of the cerebral vessels (meningeal, pial, artery, vein, capillary). The site, shape, and anatomic pattern of the resulting hemorrhage are determined by the exact location and type of vessels that are injured (Table 13.3). The anatomic features of different types of primary hemorrhages on MR scans are identical to those seen on CT studies. The MR 923

appearance varies with the age of the lesion and the specific parameters that are used to acquire the MR images (35). EDHs are commonly of arterial origin. They usually arise from direct laceration or tearing of meningeal arteries (typically the middle meningeal artery) by a skull fracture. A fracture is present in 85% to 95% of cases. Occasionally (9%) they may occur from stretching and tearing of meningeal arteries in the absence of a fracture. The latter is particularly common in children and is usually due to transient deformation and depression of the calvarial vault. Arterial EDH typically occurs in the temporal or temporoparietal region (Figs. 13.23, 13.29, and 13.30). A fracture can often be seen on the MR scan due to hemorrhage or fluid that often extends between the fracture margins. The dura can often be seen to be displaced away from the inner table of the skull (Figs. 13.29 and 13.30) (16,18). It is visualized as a thin line of low signal intensity between the brain and the lenticular-shaped hematoma. Visualization of the dura on MR scans allows one to be certain of the diagnosis of an EDH. With CT, one cannot always differentiate small EDHs from SDHs because the former may not have the classic lenticular shape, may not be associated with a fracture, and the dura is not visualized.

FIGURE 13.26 Posttraumatic encephalomalacia due to prior frontal lobe contusions. Axial (A) and coronal (B) fluidattenuated inversion recovery (FLAIR) images show characteristic cystic encephalomalacia with surrounding FLAIRhyperintense gliosis related to remote inferior bifrontal lobe intraparenchymal injury.

FIGURE 13.27 Tonsillar, subfalcine, and transtentorial herniation secondary to a SDH. (A) Sagittal T1-weighted and (B) coronal inversion recovery images demonstrate a large, crescent-shaped subacute SDH (S), which comprises hemoglobin in the methemoglobin state. There is anatomic evidence of tonsillar (large arrow) and subfalcine (curved arrow) herniation. Also present are specific signs of transtentorial herniation, including the fourth ventricular compression (small arrow), midbrain deformity (large arrowhead), and compression of the interpeduncular cistern (small arrowhead). Multiplanar MR imaging is very helpful for revealing the size and shape of SDHs and for demonstrating associated displacement, compression, and anatomic distortion of the brainstem.

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FIGURE 13.28 Bilateral SDHs, transtentorial herniation, and secondary brainstem injury. The gross specimen reveals the typical autopsy changes of secondary brainstem injury resulting from transtentorial herniation. Marked craniocaudal shortening, kinking, and deformity of the brainstem with severe compression of the fourth ventricle are present. Pressure necrosis and hemorrhagic infarction are noted within the midbrain. An additional abnormality is extensive hemorrhagic infarction involving the posterior thalamus and medial parieto-occipital lobes from PCA occlusion. The latter is due to compression of the PCA between the herniated medial temporal lobe and the edge of the tentorium. (From Gentry LR, Godersky JC, Thompson B. MR imaging of head trauma: review of the distribution and radiopathologic features of traumatic lesions. AJNR Am J Neuroradiol 1988;9:101–110; AJR Am J Roentgenol 1988;150:663–672, with permission.)

Venous EDHs are less common than those of arterial origin and are usually due to laceration of a dural sinus by occipital, parietal, or sphenoid bone fractures (88). The most common locations of venous EDHs are the posterior fossa from laceration of the transverse or sigmoid sinus (Fig. 13.31), the middle cranial fossa from injury to the sphenoparietal sinus (Fig. 13.30) (88), and the parasagittal area from a tear of the superior sagittal sinus. Differentiation of arterial and venous EDHs is often possible with MR and may have some therapeutic and prognostic significance. Venous EDHs are more variable in shape than those of arterial origin. All, however, are invariably separated from adjacent brain by displaced dura matter that is easily seen on T2-weighted scans. Another characteristic feature of venous EDHs is that they invariably lie adjacent to a dural sinus that is transgressed by a fracture line (89). Frequently, the injured dural sinus is stripped away from the adjacent calvarium by the expanding hematoma (Fig. 13.31), and occasionally the sinus is occluded by the fracture-induced intimal tear. MR can often be quite helpful for differentiating arterial and venous epidurals and determining whether the dural sinus is occluded. Patency of the sinus can usually be established by MR or MRA without the necessity of performing a conventional arteriogram. A venous EDH, unlike a SDH, will often lie both above and below the tentorium. The lower pressure of the injured vein also means that these lesions may expand more slowly than arterial lesions and therefore may be delayed in onset (89). Posterior fossa EDHs are much less frequent (2% to 29%) than supratentorial lesions (89), more likely (85%) to be of venous origin (89), and more likely to be associated with a poor outcome (89). SDHs are typically caused by stretching and tearing of bridging veins (Fig. 13.32) that traverse the subdural space as they leave the cortical surface of the brain to drain into the dural sinuses (75). These veins are quite susceptible to shear–strain injury when the relatively mobile brain moves in relationship to the fixed dural sinuses (9,10). SDHs may be produced by either rotational or linear acceleration (9,10). Symptoms of isolated SDH are quite variable (asymptomatic, headache, unconsciousness) (14). Generally, patients with SDH do not have as severe impairment of consciousness as those who have primary neuronal injuries unless there is severe mass effect or other associated lesions. Survival is significantly better if large SDHs with mass effect are evacuated within 4 hours of injury.

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FIGURE 13.29 Acute EDH. (A) Sagittal T1-weighted and (B) axial T2-weighted images reveal a hyperacute (6-hourold) right parietal EDH (H). The EDH is isointense to gray matter on the T1-weighted image (A), recognizable only by displacement of adjacent cortical veins (arrow). A thin low-intensity line, representing displaced dura (arrowheads), aids in recognition of the nearly isointense hematoma (B). Although the majority of the hematoma has a signal intensity that is consistent with oxyhemoglobin, a small area of low-intensity deoxyhemoglobin is noted on the T2weighted image (curved arrow).

FIGURE 13.30 Acute EDH. (A) Sagittal T1-weighted and (B) axial T2-weighted sequences reveal a 3-day-old middle cranial fossa EDH (curved arrows). Despite its small size, the hematoma is clearly seen to lie within the epidural space, displacing the dura mater (arrowheads) away from the calvarium. Note how the acute EDH is hypointense to gray matter on the T2-weighted scan due to the presence of deoxyhemoglobin and intracellular methemoglobin. Hyperintensity from methemoglobin (m) is noted in a portion of the EDH on the T1-weighted image. A skull fracture (arrow) is faintly seen. Both the indolent behavior and the location (i.e., posterior to the sphenoid wing), of the EDH are consistent with a sphenoparietal venous EDH.

FIGURE 13.31 Posterior fossa venous EDH and cerebellar contusion. (A) Axial inversion recovery and (B) T2weighted MR scans reveal a large subacute posterior fossa venous EDH (H). The EDH displaces the venous confluence (curved arrows), transverse sinus, and dura mater away from the occipital bone. It extends across the midline, posterior to the venous confluence, clearly differentiating it from a SDH. The patent venous confluence and transverse sinus are identified by their high-velocity flow void. A left cerebellar contusion (c) is also present.

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FIGURE 13.32 Subacute SDH secondary to abusive head trauma (AHT). A: Sagittal T1-weighted, (B) coronal T1weighted, and (C) axial T2-weighted MR images reveal a large subacute convexity SDH in this 3-year-old child subjected to violent shaking. Note stretching of numerous “bridging” subdural veins (arrows). Displacement of cortical veins (arrowheads) on the surface brain away from the skull, crescentic shape, and extensive spread of the lesion over the whole hemisphere, indicate the subdural location of the hematoma.

Although most SDHs are usually found along the supratentorial convexity (Figs. 13.27, 13.32, and 13.33), some are located in the posterior fossa (Fig. 13.34), along the falx, and adjacent to the tentorium (Fig. 13.34) (90). The latter two locations are especially common in children (91). Interhemispheric and tentorial leaf SDHs are commonly found in children who are victims of nonaccidental injury (91), due to violent shaking (shaken-baby syndrome) (Fig. 13.34). Although these hematomas are not completely specific for child abuse, their presence should always alert one to the possibility of this syndrome. MR images in patients with an SDH reveal the typical crescentic collection of blood between the brain and the falx, tentorium, or inner table of the skull (91). The MR signal appearance of the SDH varies with the age of the lesion. SDHs are visualized on all MR pulse sequences as crescentic areas that have a signal intensity that is always higher than that of the adjacent cortical bone (7,16,17). There are many advantages of MR over CT (Figs. 13.32–13.34) when evaluating patients with SDH. First, MR has been shown to be considerably more sensitive than CT for detection of SDH (16). In a series of acute to subacute SDHs, CT detected only 53% of lesions, as compared with T1- and T2-weighted MRI, which detected 70% and 95% of lesions, respectively (16). The wide difference in the imaging contrast between the hematoma and signal void of cortical bone is responsible for the exquisite sensitivity of MRI to these lesions. SDHs that are missed with CT are almost always only 1 to 2 mm in thickness and of doubtful clinical significance (16). Second, MR can be quite helpful for evaluation of patients with CT-suspected isodense SDHs (16,18). Unlike CT, these lesions are quite conspicuous on MRI. On CT, an isodense SDH has increased signal intensity on all MR pulse sequences because they are typically composed of free methemoglobin in solution (16). Contrast-enhanced CT is no longer necessary for confirmation of these lesions. MR also more clearly reveals the multicompartmental nature of subacute to chronic SDHs (Figs. 13.32 and 13.33). This information may be helpful for the aging and surgical drainage of these complex lesions (7).

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FIGURE 13.33 Subacute SDH. (A) T1- weighted and (B) T2-weighted MR images reveal a large, 12-day-old, subacute, convexity SDH. The cortical veins (arrow) on the surface brain are separated from the skull by the crescentic-shaped SDH. There is compression and displacement of the left lateral ventricle and septum pellucidum. The SDH is primarily composed of hemoglobin in the methemoglobin state, as demonstrated by the short T1 of the lesion on the T1-weighted image. A faint secondary subdural membrane (arrowheads) suggests multiple episodes of hemorrhage. MR imaging is usually more helpful than CT for identifying the multicompartmental nature of the SDH and for guiding surgical drainage.

FIGURE 13.34 Ischemic infarction, AHT and SDH. (A) Sagittal T1-weighted, (B) axial proton density–weighted, and (C) coronal T2-weighted images in a child who sustained multiple episodes of AHT with possible strangulation. Multiple SDHs of different ages are present, including chronic convexity (white arrow), subacute peritentorial (arrow), and subacute convexity (arrowhead) lesions (A). Extensive hyperintensity from diffuse cerebral swelling and ischemic infarction are present in both hemispheres, but most severe in the right middle, right posterior, and bilateral anterior cerebral artery distributions (B). Note the loss of normal gray–white matter differentiation on this strongly T2weighted scan (C). Normal signal intensity and improved gray–white differentiation are noted in the less involved portions (arrows) of the cerebellum and inferior temporal lobes.

Traumatic ICHs are focal collections of relatively homogenous and confluent blood that most commonly arise from rotationally induced shear–strain injury to intraparenchymal arteries or veins (Fig. 13.35) (7,92). They may occasionally result from a penetrating injury to a vessel. ICHs may vary from a few millimeters to several centimeters in size and occur in 2% to 16% of trauma victims (92). 928

Differentiation from hemorrhagic contusions or TAI is often difficult (92). The distinction rests primarily with the fact that ICHs primarily expand between relatively intact parenchyma, whereas the hemorrhage within contusions is interspersed in areas of simultaneously injured and edematous brain (7). The published variability in outcome from these lesions is likely the result of a failure to make this distinction (92). Prognosis of an isolated ICH is often quite good unless it causes marked mass effect, is associated with TAI, or is associated with multiple shear–strain–related basal ganglia hemorrhages. ICHs are usually (80% to 90%) located in the frontotemporal white matter (Fig. 13.35) or basal ganglia (92). These lesions are frequently associated with other primary neuronal lesions and calvarial fractures. Unlike patients with TAI or primary BSI, however, these patients may not lose consciousness and often (30% to 50%) remain lucid throughout the duration of their injury. Signs, symptoms, and clinical course are variable but similar to those seen with extra-axial hematomas. Temporal lobe hematomas are especially unpredictable, however, in that even small lesions may produce secondary BSI due to focal medial temporal lobe herniation. Delayed ICH should always be considered in patients who have a deterioration of their level of consciousness because they may occur in 2% to 8% of all patients with severe head injury (90). Intraventricular hemorrhage (IVH) is quite common in patients with head injury, varying in incidence from 3% to 35% of cases, depending on the severity of trauma (7,17,18,90). Primary IVH may be caused by a variety of traumatic lesions (TAI, ICH, large contusions) (7,17,18,90). The etiology of IVH in most cases, however, appears to be due to rotationally induced tearing of subependymal veins on the ventral surface of the corpus callosum and along the fornix and septum pellucidum. These veins are often disrupted by the same force that causes TAI of the corpus callosum. In a published series of trauma victims, IVH occurred in 60% of patients with TAI of the corpus callosum but in only 12% of patients without callosal injury. IVH in patients without callosal injury was invariably due to dissection of large ICH into the ventricular system. More recently, IVH seen on admission CT was shown to be the only CT imaging finding predictive of grade II and III DAI on subsequent MRI (93). The MR appearance of IVH varies. The blood is invariably hyperintense to CSF on T1-weighted and especially FLAIR scans, however, easily allowing detection (17). IVH on delayed imaging often relates to recirculation of subarachnoid blood.

FIGURE 13.35 Late subacute ICH. A,B: Respective FLAIR and T1-weighted MR images reveal a “late subacute” ICH in the left temporal lobe (white arrows) imaged 15 days after injury. The predominant FLAIR and T1-hyperintense signal of blood products within the hematoma are consistent with extracellular methemoglobin. Coronal GRE T2*weighted MR image (C) shows a linear hypointense hemosiderin rim (white arrow) outlining the left temporal ICH. Foci of hemorrhagic TAI are also evident in the left frontal juxtacortical white matter and right temporal stem (yellow arrows in C). Note also a small left-sided frontal and parieto-occipital SDH (yellow arrows in A,B), which demonstrates signal characteristics similar to the temporal lobe ICH. Hemorrhagic contusion injury is evident in the

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right inferior frontal lobe (white arrowheads in A and B). D: Coronal pathologic section from a different patient with similar pathology.

Subarachnoid hemorrhage (SAH) in the past was considerably more difficult to detect with conventional MR than with CT. More recent studies have shown that MRI, particularly FLAIR imaging, is sensitive to increased CSF cellularity and protein levels related to SAH in both acute and subacute periods (Fig. 13.25) (94,95), whereas CT sensitivity falls sharply after the first few days. Hyperintense CSF signal on FLAIR imaging is indicative of increased cellularity and/or protein content within the CSF and highly suggestive of hemorrhage in the traumatic setting, although infection and carcinomatosis may have a similar appearance. The combination of FLAIR and SWI sequences has recently been shown to yield a higher detection rate for SAH than CT alone with SWI sensitive for central and FLAIR sensitive for peripheral SAH (96). The T1-shortening effect of methemoglobin increases sensitivity for SAH in the subacute periods as well (Fig. 13.36). Primary Vascular Injuries Traumatic vascular injuries are likely to be much more prevalent than were previously reported in the literature (7,97). Asymptomatic vascular lesions may escape detection in the initial stages because of a low index of suspicion (97). In many instances, there may be a significant delay between the time of trauma and the onset of symptoms (Figs. 13.37 and 13.38) (98). Many symptomatic lesions also go unrecognized in the acutely injured patient because they are masked by other intra- or extracranial injuries. Often the clinical symptoms and imaging findings arising from primary traumatic vascular injuries are attributed to other traumatic parenchymal injuries (e.g., contusion, SDH, ICH). CT is very helpful in some respects in identifying those patients who are at increased risk for traumatic vascular injuries (98). Patients who have basal skull fractures that extend across the carotid canal, sphenoid bone (especially body, greater/lesser wings), petrous pyramid, and occipital bones have a much higher incidence of symptomatic and asymptomatic vascular injuries. CTA is the most widely used vascular imaging modality for these patients, both for reasons of high accuracy in defining traumatic vascular injuries and for the practical aspects of being widely available and already being used in patients’ initial evaluations immediately after stabilization. Whereas MR can be considered an effective screening test for vascular injuries (98), CTA is now routinely implemented in the evaluation of all emergency patients suspected of harboring intracranial and/or neck vessel injury, whether arterial or venous. Findings from Vertinsky and colleagues (99) evaluating nontraumatic cervical dissections suggested that CT/CTA visualized more features of arterial dissection in the neck compared with MRI/MRA. Conventional arteriography may be necessary for definitive diagnosis of subtle lesions and clearly for the endovascular treatment of several types of traumatic vascular injuries (severe hemorrhage, epistaxis, carotid-cavernous fistulae [CCFs]).

FIGURE 13.36 Traumatic SAH. A: Axial non-contrast CT demonstrates increased density within the right sylvian

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fissure, consistent with acute SAH. A small pre-existing middle cranial fossa low-density arachnoid cyst is noted adjacent to the SAH. Right parieto-occipital scalp soft tissue swelling is present. Axial (B) and coronal (C) FLAIR imaging reveal abnormal linear T2-hyperintensity within the sylvian fissure, compatible with acute SAH. Axial DWI imaging (D) shows increased signal within the hemorrhage and decreased signal (facilitated diffusion) in the arachnoid cyst. The corresponding GRE image (E) demonstrates asymmetric hypointensity within the sylvian fissure, characteristic of acute hemorrhage. Note that SAH tends to evolve and disappear more rapidly than hemorrhage in other locations.

FIGURE 13.37 Traumatic vertebral artery dissection with intramural hematoma. This 36-year-old woman presented with diplopia and nystagmus after striking her head while skiing. A: Axial T1-weighted image reveals a normal flow void in the right vertebral artery (curved arrow), indicating patency of this vessel. There is marked reduction in the caliber of the left vertebral artery flow void (arrow), however, due to the presence of a dissecting intramural hematoma (arrowhead) containing high–signal intensity methemoglobin. B,C: Respective 3D time-of-flight (maximum intensity pixel projection) and 2D phase-contrast MRA images confirm patency of the right vertebral artery (arrowheads) but demonstrate irregularity and a reduction in the caliber of the vessel lumen. Note that the intramural hematoma (open arrows) is visible on the time-of-flight image due to the very short T1 of methemoglobin, but is not visible on the phase-contrast study because the later excludes stationary spins.

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FIGURE 13.38 Traumatic carotid artery laceration, dissection, pseudoaneurysm, and partially thrombosed carotidcavernous fistula (CCF). A: Axial T1-weighted image reveals a markedly dilated superior ophthalmic vein (arrow). A flow void was not identified on multiple MR pulse sequences, consistent with thrombosis. B,C: Respective coronal proton density-weighted and T2-weighted images through the cavernous sinus reveal fluid and hemorrhage (H) of different ages in the sphenoid sinus. The right cavernous sinus (arrowheads) is enlarged due to the fistula. The internal carotid artery lumen is markedly compressed by an intramural hematoma (arrow) secondary to traumatic carotid dissection. Also visualized is a small angiographically proven pseudoaneurysm (open arrows) that was responsible for an episode of severe epistaxis 1 day before the MR exam. (From Gentry LR. Facial trauma and associated damage. Radiol Clin N Am 1989;27: 435–466, with permission.)

The appearance of traumatic vascular injuries on MR/MRA scans varies depending on the severity, location, and exact nature of the lesion. Spasm may be the only finding with minimal arterial injury (97), and this may not be directly visible with MR. More extensive laceration of the vessel may produce an intimal flap or damage to the vasa vasorum with subsequent development of a dissection and intramural hematoma (Figs. 13.37 and 13.38) (7,97). These hematomas may significantly compromise the arterial lumen and impair flow (7). Slow arterial flow may be manifest on standard images by a diminution or disappearance of the normal “flow void” (Figs. 13.37 and 13.38) (7,98). A narrowed but patent vessel can be differentiated from an occluded one through the use of flow-sensitive pulse sequences or MRA (Figs. 13.37 and 13.39). Arterial dissection, laceration, and occlusion can occur through a variety of mechanisms: laceration by skull fractures, penetrating injuries, blunt trauma, and stretching of the artery (7,97). Fractures of the skull base are among the most common causes of arterial injury (97). These typically result from displaced fracture fragments that lacerate the vessel (97). The exact pathology depends on the precise location and severity of arterial injury (Table 13.4) (Figs. 13.36 and 13.37) (7,97). The internal carotid arteries are most vulnerable to fracture-related dissections and occlusions in the area near the anterior clinoid process and clinocarotid canal (Fig. 13.38) (97,98). Patients with fractures in this area should be carefully screened for the possibility of a vascular injury. Thin-section, fatsaturated, T1-weighted MRI can often provide a definitive diagnosis of vessel occlusion or dissection, obviating the necessity of arteriography (Fig. 13.38) (98). In fact, MR may provide even more information than angiography in some cases because the intramural hematoma is never directly visualized at angiography and secondary ischemic insults can be clearly defined with MRI (7,92,98). Carotid lacerations in this region are often accompanied by simultaneous optic nerve injuries, and conversely, there is a much higher incidence of traumatic vascular injuries in patients who present with 932

traumatic optic neuropathy (7,98). The combination of conventional MRI and MRA should be performed in any patient who presents with either of these two diagnoses (98). Occasionally, the adventitial layer of the vessel is left intact and a pseudoaneurysm (Fig. 13.40) develops (97,98). These false aneurysms can develop over a period of a few weeks to a few years. Symptoms are usually secondary to those of a suprasellar mass with progressive bitemporal hemianopia, palsies of cranial nerves III to VI, epistaxis, or intermittent ischemic events due to embolization from partially clotted pseudoaneurysms (97,98). The MR appearance of the pseudoaneurysm varies, depending on its size, age, and extent of thrombosis (98). Generally, there are concentric laminated rings of hemorrhage in various stages of evolution and a variably sized patent lumen that can be recognized by its flow void (98). Posttraumatic ICA pseudoaneurysms may in some cases slowly expand into the cavernous sinus or even the sinonasal cavity through a fracture defect and present in a delayed fashion with epistaxis and pulsatile sinonasal “mass” (Fig. 13.40) (100,101). Familiarity with this complication and the imaging appearance of pseudoaneurysm described above is important to facilitate rapid intervention and prevent potentially catastrophic biopsy of these pseudotumors (Fig. 13.40).

FIGURE 13.39 Vertebral artery dissection. 2D time-of-flight magnetic resonance angiography in 32-year-old man with posterior fossa infarctions demonstrates a long segment of irregular narrowing in the mid-vertebral artery (arrows) on anteroposterior (A) and oblique (B) views.

FIGURE 13.40 Chronic traumatic cavernous ICA pseudoaneurysm herniating into the sphenoid sinus mimicking a sinonasal mass. This 41-year-old female has a history of a motor vehicle collision 6 months prior to admission when she presented with massive epistaxis and right-sided monocular vision loss. Axial standard (A) and bone (B) algorithm CT images at the level of the orbit demonstrates a heterogeneously dense soft tissue “mass” eroding portions of the posterior walls of the sphenoid sinus, ethmoid septa, and medial orbital wall on the right (outlined by arrows in A). Brainlab MR exam performed in preparation for planned biopsy of this “mass” demonstrates internal hypointense flow voids (arrows in C and D) on axial T2-weighted (C) and T1-weighted post-contrast (D) images which appear contiguous with the flow void of the right cavernous internal carotid artery (ICA). The planned biopsy

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was aborted based on the MRI findings and the patient underwent emergent conventional angiography. Digitally subtracted angiographic image in the anterior–posterior (AP) projection (E) following injection of the right ICA shows a giant pseudoaneurysm (arrow) arising from the cavernous segment of the right ICA. F: 3D reconstructed image of the giant pseudoaneurysm from the AP ICA angiographic series.

When the full thickness of the arterial wall is torn, several other types of vascular lesions may develop (97). The precise nature of the lesion depends on which segment of the carotid artery is torn. A carotid sheath hematoma may be seen if rupture occurs in the neck (97). These patients usually present with neck pain, neck mass, Horner syndrome, and cerebral ischemic events (97). A CCF results if a fullthickness arterial tear occurs within the cavernous sinus (Figs. 13.38) (97,98,102). The MR appearance of the CCF depends on the size and type of arterial tear and on the pattern of venous drainage. The fistula may be “high flow” if a large tear is present (97), and there is marked enlargement of the superior ophthalmic vein, cavernous sinus, and petrosal sinuses (Fig. 13.38). There is MR evidence of rapid flow (flow void) in these venous structures. There may be moderate proptosis, enlargement of extraocular muscles, and swelling of the preseptal soft tissues of the orbit. There may be bilateral enlargement of the superior ophthalmic veins when there is free communication of the fistula through the cavernous plexus of veins (97). If the drainage of the fistula is predominately via the inferior petrosal sinus, the superior ophthalmic vein may not be significantly enlarged. Less commonly, only a small intracavernous branch of the internal carotid artery is avulsed and the fistula may be of a “lowflow” variety (97). The MRI findings may be much less obvious in these cases. Finally, massive SAH occurs if the carotid laceration is intradural and of full thickness (Fig. 13.36). Rarely, a skull fracture lacerates the middle meningeal artery and its associated vena comitantes. When this occurs, the patient may not develop the expected EDH because it may be “self-evacuating” through a dural (meningeal artery–meningeal vein) fistula. This injury may be completely asymptomatic, or it may produce tinnitus because of increased flow through the petrosal sinuses and internal jugular vein. The MR findings in these cases are usually limited to venous distention. Injuries of the vertebral arteries are also quite common, producing a wide spectrum of pathologies that closely correspond to those seen with injuries of the carotid arteries (97). The most common injuries of the vertebral arteries are traumatic laceration, dissection, and arteriovenous fistula (Fig. 13.37) (97).

ACKNOWLEDGMENT We would like to especially acknowledge Dr. Lindell Gentry and Dr. Edmond Knopp who authored the previous version of this chapter and supplied an excellent foundation for the current revised addition.

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2004;233(1):58–66. 81. Kim JJ, Gean AD. Imaging for the diagnosis and management of traumatic brain injury. Neurotherapeutics 2011;8(1):39–53. 82. Turazzi S, Alexandre A, Bricolo A. Incidence and significance of clinical signs of brainstem traumatic lesions. Study of 2600 head injured patients. J Neurosurg Sci 1975;19(4):215–222. 83. Hilario A, Ramos A, Lagares A. Traumatic brain stem injury: evaluation by MRI. Author reply. AJNR Am J Neuroradiol 2013;34(5):E57. 84. Rosenblum WI, Greenberg RP, Seelig JM, et al. Midbrain lesions: frequent and significant prognostic feature in closed head injury. Neurosurgery 1981;9(6):613–620. 85. Friede RL, Roessmann U. The pathogenesis of secondary midbrain hemorrhages. Neurology 1966;16(12):1210– 1216. 86. Seelig JM, Greenberg RP, Becker DP, et al. Reversible brain-stem dysfunction following acute traumatic subdural hematoma: a clinical and electrophysiological study. J Neurosurg 1981;55(4):516–523. 87. Stiver SI, Gean AD, Manley GT. Survival with good outcome after cerebral herniation and Duret hemorrhage caused by traumatic brain injury. J Neurosurg 2009;110(6):1242–1246. 88. Gean AD, Fischbein NJ, Purcell DD, et al. Benign anterior temporal epidural hematoma: indolent lesion with a characteristic CT imaging appearance after blunt head trauma. Radiology 2010;257(1):212–218. 89. Pozzati E, Tognetti F, Cavallo M, et al. Extradural hematomas of the posterior cranial fossa. Observations on a series of 32 consecutive cases treated after the introduction of computed tomography scanning. Surg Neurol 1989;32(4):300–303. 90. Cooper PR. Post-traumatic Intracranial Mass Lesions. 2nd ed. Baltimore, MD:Williams & Wilkins; 1987. 91. Cohen RA, Kaufman RA, Myers PA, et al. Cranial computed tomography in the abused child with head injury. AJR Am J Roentgenol 1986;146(1):97–102. 92. Katz DI, Alexander MP, Seliger GM, et al. Traumatic basal ganglia hemorrhage: clinicopathologic features and outcome. Neurology 1989;39(7):897–904. 93. Mata-Mbemba D, Mugikura S, Nakagawa A, et al. Intraventricular hemorrhage on initial computed tomography as marker of diffuse axonal injury after traumatic brain injury. J Neurotrauma 2014;32(5):359–365. 94. Maeda M, Yagishita A, Yamamoto T, et al. Abnormal hyperintensity within the subarachnoid space evaluated by fluid-attenuated inversion-recovery MR imaging: a spectrum of central nervous system diseases. Eur Radiol 2003;13(Suppl 4): L192–L201. 95. Mitchell P, Wilkinson ID, Hoggard N, et al. Detection of subarachnoid haemorrhage with magnetic resonance imaging. J Neurol Neurosurg Psychiatry 2001; 70(2):205–211. 96. Verma RK, Kottke R, Andereggen L, et al. Detecting subarachnoid hemorrhage: comparison of combined FLAIR/SWI versus CT. Eur J Radiol 2013;82(9):1539–1545. 97. Davis JM, Zimmerman RA. Injury of the carotid and vertebral arteries. Neuroradiology 1983;25(2):55–69. 98. Gentry LR. Facial trauma and associated brain damage. Radiol Clin N Am 1989;27(2):435–446. 99. Vertinsky AT, Schwartz NE, Fischbein NJ, et al. Comparison of multidetector CT angiography and MR imaging of cervical artery dissection. AJNR Am J Neuroradiol 2008;29(9):1753–1760. 100. Adeel M, Ikram M. Post-traumatic pseudoaneurysm of internal carotid artery: a cause of intractable epistaxis. BMJ Case Rep 2012:bcr02.2012.5927. 101. Saket RR, Hetts SW, Tatum JK, et al. CT and MRI findings of sphenoid sinus internal carotid artery pseudoaneurysm: an important and challenging differential diagnosis for a skull base mass. Clin Radiol 2012;67(8):815–820. 102. Komiyama M, Hakuba A, Yasui T, et al. Magnetic resonance imaging of intracavernous pathology. Neurol Med Chir 1989;29(7):573–578.

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14 Intracranial Infection L. Celso Hygino da Cruz, Jr

INTRODUCTION Despite advances in antibiotic therapy, infectious diseases continue to be a threat to life and livelihood. Central nervous system (CNS) infections lead to persistent health problems that affect a significant percentage of the population worldwide. In brain infection in particular, prognosis depends on the prompt etiologic diagnosis and the correct treatment at presentation. Both early detection and accurate diagnosis of CNS infection are especially critical because most of these disorders are readily treatable yet highly destructive if treatment is delayed. When the appropriate clinical information is communicated to radiologists they can be of great importance in helping clinicians to narrow the spectrum of possible diagnoses. Beyond ascribing an infectious etiology to a patient's abnormal scan, there are sometimes imaging clues that should suggest specific infectious agents. In this chapter, these findings are highlighted in the context of describing magnetic resonance imaging (MRI) appearances of intracranial infection. Whenever appropriate, we discuss the contribution of advanced neuroimaging techniques to the evaluation and diagnosis of specific pathologic entities.

VIRAL INFECTION Intracranial viral infection is usually a multifocal or diffuse inflammatory process, termed encephalitis. In many cases, viral infection involves the meninges as well; it is then known as a meningoencephalitis. The disease process may result from acute or latent infection of the CNS. In the general population, aseptic meningitis is most often due to enteroviruses (especially coxsackieviruses and echoviruses) and less frequently due to herpes simplex virus (HSV) or mumps virus. Viruses that may result in meningitis in AIDS patients include human immunodeficiency virus (HIV) and the herpes viruses, especially cytomegalovirus (CMV) and occasionally HSV types 1 and 2 (HSV-1 and HSV-2). Imaging is not highly sensitive to viral meningitides when the parenchyma is spared, even with postcontrast fluid-attenuated inversion recovery (FLAIR) imaging (the most sensitive MR sequence for meningitis, surpassing contrast-enhanced T1 images). Therefore, a normal MRI cannot totally exclude viral meningitis, and if confirmation of that diagnosis is sought beyond clinical examination and history, cerebrospinal fluid (CSF) analysis is indicated. Pathologically, the primary features of viral encephalitis include neuronal degeneration and inflammation. Gross histopathologic findings range from unremarkable to diffuse brain congestion and edema with hemorrhage and necrosis (as in HSV-1, HSV-2, and some arboviral encephalitides). There is often some degree of cerebral edema and congestion of meningeal vessels. On MR, the pathologic changes that result from viral encephalitis appear as scattered or confluent areas of hyperintensity on T2-weighted images and are isointense or hypointense on T1-weighted images, with variable mass effect. Foci of subacute hemorrhage (extracellular methemoglobin) demonstrate increased signal intensity on both T1- and T2-weighted images. Contrast enhancement may or may not be present. Diffusion-weighted imaging (DWI) characteristically shows patchy restricted diffusion and is key to the consideration of any acute encephalitis. On follow-up, localized or generalized atrophy resulting from chronic or prior infection with tissue destruction may appear. Although these general features apply to most of the viral encephalitides, certain infections demonstrate particular features that may be characteristic and are thus helpful in the differential diagnosis. These are described in the following subsections. 938

CNS Infections of Herpesvirus Family The herpesvirus family consists of a large group of DNA viruses, where humans are the sole reservoirs for them. This family include HSV-1 and HSV-2, varicella zoster virus (VZV), CMV, Epstein–Barr virus (EBV) and herpes virus type 6 (HHV-6) and type 7 (HHV-7). Herpes Simplex Virus Type 1 HSV-1 is the causative agent in more than 90% of herpetic encephalitis cases and it accounts for 10% to 20% of all viral encephalitis. Incidence is one to four cases per million people annually. HSV encephalitis (HSE) is the most common cause of fatal sporadic encephalitis and has a high mortality, ranging from 50% to 70% without treatment. Early diagnosis and initiation of appropriate treatment is of great importance. More than 70% of HSV-1 encephalitis cases result from reactivation of latent HSV-1 infection of the trigeminal ganglion in adult individuals previously exposed to the virus. The virus then spreads along branches of cranial nerve V that innervate the meninges of the anterior and middle cranial fossa (1). About one-third of herpes encephalitis cases are due to the primary HSV infection. A nonspecific alteration in mental status, including a lowered level of consciousness, together with focal neurologic deficit, seizures, and fever are the principal clinical symptoms in adults. The diagnosis of HSE should be considered in a patient with a progressively deteriorating level of consciousness, fever, focal neurologic findings, in the absence of other causes. CSF findings are nonspecific, and isolation of HSV from the CSF is rare. However, polymerase chain reaction (PCR) techniques are routinely employed in obtaining a more accessible and rapid diagnosis from the CSF, reducing the necessity of brain biopsy. A single negative PCR result does not exclude the diagnosis, especially if it was performed within the first 72 hours after onset of clinical symptoms (2). Early intervention with appropriate treatment is important because it can dramatically improve patient outcome. Therefore, the radiologist must be cognizant of the characteristic neuroanatomic pattern of involvement in HSE and specifically suggest the diagnosis when that pattern is identified. In such cases, treatment is instituted immediately (3). Herpes encephalitis is often but not always hemorrhagic, affecting primarily the medial temporal and inferior frontal lobes. In most cases, herpes encephalitis is initially unilateral, with asymmetric contralateral involvement seen in later stages. The most suggestive finding to be sought by the radiologist is unilateral or bilateral involvement of the insula in association with other frontal and temporal cortex (Fig. 14.1). Despite the fact that this is a limbic inflammation, commonly affecting cingulate and parahippocampal gyri, the diagnostic radiologist should note that it would be highly atypical for herpes encephalitis to involve the hippocampus alone, that is, without any insular and temporal cortex changes. This stands in contrast to other disease states affecting hippocampi (including limbic encephalitis, a paraneoplastic noninfectious process, and status epilepticus), which can be isolated to unilateral or bilateral hippocampus. In immunocompetent individuals, HSV-1 encephalitis may result in necrotizing encephalitis involving mostly the temporal lobes and orbital surfaces of the frontal lobes. Other locations are also involved. The limbic system, including the insular cortex, cerebral convexity, cingulate gyrus, and posterior occipital cortex, may become involved. The disease often spares the basal ganglia. As noted, lesions strictly limited to the hippocampus should prompt the consideration of other entities. Although disease is not found with higher prevalence in immunocompromised patients, the presentation and pattern of involvement are more variable in that setting.

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FIGURE 14.1 Acute herpes encephalitis, restricted diffusion and high cerebral blood volume (CBV). A: T2. B: Fluidattenuated inversion recovery. C: T1 postgadolinium. D: Diffusion-weighted imaging. E: Apparent diffusion coefficient map. F: CBV. The left frontotemporal lesion (A,B) involves the uncus and the hippocampus, with highly characteristic insular involvement with almost no enhancement (C). Heterogeneous restricted diffusion (D,E) is typical of encephalitis. Note the elevated CBV throughout the abnormal region (F), a finding opposite to what would be seen in other lesions with restricted diffusion, most notably acute infarction.

Although computed tomography (CT) may be negative in the early phase of disease, it can reveal hypodense lesions in the temporal lobes with or without involvement of the frontal lobes. Enhancement and gross hemorrhage are infrequent on CT. MRI techniques are far more sensitive than CT in demonstrating parenchymal involvement; however, some authors have noted negative MRI in almost 941

10% of patients with CSF PCR-positive (1). MR demonstrates the early edematous changes of herpes encephalitis, with increased signal and swelling seen in the temporal and inferior frontal lobes on T2weighted images. This hyperintense signal involves both cortex and white matter and may be seen within hours after the onset of signs and symptoms, compared with the reported delay of up to 3 to 5 days on CT. MR often demonstrates bitemporal involvement when CT shows only unilateral infection. As areas of involvement enlarge and coalesce, the early associated mass effect may increase. Extension from the temporal lobes across the Sylvian fissure to the isle of Reil is frequently seen, sparing the putamen. Enhancement is often absent or only minimal in the early stages (Figs. 14.1 and 14.2), but cortical enhancement can be seen immediately and often becomes more prominent with disease progression (Fig. 14.3). Magnetization transfer (MT)-suppressed T1-weighted images may be able to depict subtle areas of enhancement, but visualization of enhancement is not essential for making the correct diagnosis. Perfusion MRI, such as cerebral blood flow (CBF) or cerebral blood volume (CBV) mapping, can show high blood flow or blood volume even though no contrast enhancement is seen (Fig. 14.1). However, characteristically infection processes demonstrate decreased perfusion. Focal hemorrhage is consistently present at autopsy yet is often not detected on early imaging studies obtained in the acute phase of the disease. Atrophy and clear parenchymal destruction with old hemorrhage is a common late sequela well visualized on follow-up MR (Fig. 14.4). MR has been used to monitor response to treatment with acyclovir.

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FIGURE 14.2 Acute herpes encephalitis, cortical enhancement. A1,A2: T2. B1,B2: Diffusion-weighted imaging. C1,C2: T1 postgadolinium. T2 images (A) clearly show high signal with swelling in the left uncus, hippocampus, and inferior frontal lobe and extension into the left insula and left cingulate gyri. Patchy reduced diffusion in the uncus and cortex (B) is mixed with other regions of elevated diffusion. Note cortical enhancement in the left cingulate and left insula (C).

FIGURE 14.3 Herpes encephalitis. A: Axial fluid-attenuated inversion recovery image (6,000/128, inversion time 2,000) reveals hyperintense signal with minimal mass effect primarily involving the left temporal lobe but also affecting the right temporal lobe, although to a lesser degree. B: T1-weighted (600/14) axial magnetic resonance without contrast reveals hyperintense signal in the medial aspect of the left temporal lobe extending to the parahippocampal gyrus. This gyriform hyperintense signal denotes the presence of subacute hemorrhage (methemoglobin). C: Postcontrast T1-weighted (532/16) image demonstrates minimal patchy enhancement in the left temporal region. Compare with panel B.

FIGURE 14.4 End-stage herpes encephalitis. A1,A2: T2. B1,B2: Gradient-recalled echo. End-stage bilateral herpes encephalitis with extensive tissue destruction also shows an old hemorrhage on T2 (A) and gradient-recalled echo (B). Again note the highly characteristic insular involvement.

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FIGURE 14.5 Herpes simplex encephalitis. A: Coronal T1-weighted magnetic resonance image without contrast (600/20) reveals a focus of subacute hemorrhage in the right frontal lobe, which is not apparent on computed tomography performed earlier the same day. This patient was a 10-year-old boy presenting with confusion who rapidly progressed to become encephalopathic. B: T2-weighted axial image (2,433/80) in the same patient reveals bilateral hyperintense signal.

It has been suggested that the pattern of HSV-1 involvement in infants and young children differs from that of encephalitis in adults, older children, and neonates. In infants and young children particularly, extensive bilateral cortical areas of the hemispheres and the adjacent subcortical white matter may be involved at the beginning of the disease (Fig. 14.5). Distribution of involved areas sometimes corresponds to a vascular distribution, suggesting a hematogenous spread. Diffuse cortical swelling involving the occipitoparietal cortex and subcortical white matter, thalamus, and corpus callosum can also be demonstrated (3). As in all encephalitides, DWI shows characteristic findings of patchy restricted diffusion acutely. This is helpful in distinguishing encephalitis from other lesions. In HSE, this may be particularly important because the neuroanatomic pattern may be mimicked by noninfectious entities that also present with seizures in the same patient population, such as neoplasm. Herpes encephalitis typically shows heterogeneously restricted diffusion in early stages of disease, when the inflammatory reaction is greatest (Figs. 14.1, 14.2, and 14.6) (4). In some circumstances, DWI is able to depict parenchymal alterations characterized by restricted diffusion before abnormalities are noted on T2-weighted and FLAIR images. DWI may reveal a greater extent and number of lesions than T2-weighted images and may be a method for monitoring treatment response (5). Later, parallel to the development of vasogenic edema and encephalomalacia, elevated diffusion with high apparent diffusion coefficient values is seen. In the acute phase, MR spectroscopy (MRS) demonstrates a reduction of Nacetylaspartate (NAA) levels at the temporal lobes, reflecting a neuronal loss secondary to herpes encephalitis, associated to a mild increase in choline level and lactate. Glutamine–glutamate complex may also be increased in acute stage. Elevation in myo-inositol (mI) may represent gliosis (Fig. 14.7). Others areas of the CNS can be also involved concomitant without encephalitis. Cranial nerve involvement is not uncommon in herpes simplex infection (4). HSE associated with HIV infections is a rare complication, occurring in 2% of AIDS autopsy cases, in patients with neurologic symptoms. In AIDS patients, HSV often results in diffuse rather than localized temporal/frontal involvement (Fig. 14.8). Mild to severe forms of both HSV-1 and HSV-2 encephalitis have been reported and may coexist with other infections. Typical pathologic findings of necrotizing encephalitis may be absent in the AIDS patient, even when HSV-1 or HSV-2 is cultured from the brain tissue. In these immunocompromised patients, there appears to be an inverse relationship between the degree of immunodeficiency and the severity of the inflammation induced by the herpes viruses and the rapidity of disease progression.

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FIGURE 14.6 Herpes simplex encephalitis is a 68-year-old man. A: Axial fluid-attenuated inversion recovery (6,000/128, inversion time 2,000) image shows diffuse hyperintense signal involving mostly the gray matter of the anterior and mesial portions of the right temporal lobe and hippocampus with minimal mass effect. B: Axial diffusionweighted imaging reveals areas of restricted diffusion. A,C: Axial T1-weighted (600/30) MR demonstrates enhancement in the mesial aspect of the temporal lobe and the hippocampus. In the contralateral hippocampus there is also the same imaging abnormalities shown in both temporal lobes, involving both gray and white matter.

FIGURE 14.7 Herpes simplex encephalitis. A 47-year-old man presenting with seizures and right hemiparesis. A positive herpes simplex virus-1 polymerase chain reaction was detected in the cerebrospinal fluid. Magnetic resonance spectroscopy was performed with a point-resolved spectroscopy sequence using an echo time of 30 ms in the left temporal lobe. There is a reduction in the N-acetylaspartate relative to creatine and an increase in choline, and the presence of glutamine/glutamate and lactate/lipid is noted.

KEY POINTS Most common symptoms Altered mental status Focal neurologic deficit Seizures Fever CSF, HSV, PCR positive Imaging features FLAIR and DWI most sensitive sequences; T2WI and FLAIR: hyperintense insula/temporal cortex/subcortical white matter; T1WI: may show hemorrhage; DWI: patchy restricted diffusion (even with normal MRI); CBV elevated, even without parenchymal enhancement. Limbic system: temporal lobes, insula, inferior frontal lobes, Sylvian fissures, cingulated gyrus, and posterior occipital cortex.

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Herpes Simplex Virus Type 2 HSV-2 is a major cause of neonatal encephalitis along with other TORCH (toxoplasmosis, other, rubella, CMV, and herpes) agents. The primary route of infection is via the maternal birth canal, although infrequent hematogenous transplacental in utero infection can occur. In children, HSV-1 acquisition is usually postnatal, and in neonates, HSV-2 acquired via maternal genital herpes is much more frequent than HSV-1, accounting for 80% to 90% of neonatal herpes virus infections and almost all congenital herpes virus infections. The CNS is involved in approximately 30% of infected infants (6). HSV-2 encephalitis presents with fever, seizures, abnormal CSF HSV PCR, abnormal MRI brain imaging, ventriculomegaly, multicystic encephalomalacia, and death (7). Patients that survive have neurodevelopmental problems, with psychomotor retardation, learning disabilities, microcephaly, microphthalmia, and blindness (7). One in 2,000 to 5,000 neonates is infected per year. Approximately 35% of these develop encephalitis and 25% have the disseminated disease. Use of acyclovir may improve the outcome and has reduced mortality of HSV-2 encephalitis from 40% to 15% (7). Pathologic examination demonstrates acute and chronic parenchymal and leptomeningeal inflammation, with a diffuse pattern of involvement that may result in widespread brain destruction.

FIGURE 14.8 Herpes simplex encephalitis, late sequela. An HIV-positive 35-year-old man with previous herpes encephalitis. A: Axial T2-weighted magnetic resonance image reveals a diffuse hyperintense signal involving the gray and white matter of the temporal lobes bilaterally with enlargement of the adjacent sulci and compensatory ventricules dilatation. B: Coronal fluid-attenuated inversion recovery image shows not only involvement of the temporal lobes and highly characteristic insular involvement, but also extension into the corona radiata.

Neuroimaging reflects various degrees of parenchymal inflammation and leptomeningeal involvement, evolving to necrosis. HSV-2 encephalitis usually localizes in the frontal and temporal lobes like HSV-1. Immunocompromised patients are not usually infected by HSV-2. When infected, these patients develop a subacute encephalitis, with a more diffuse involvement. In immunocompetent adults, HSV-2 can cause aseptic meningitis. MRI may reveal a diffuse meningeal contrast enhancement (4). CT may reveal only subtle hypodensity of the periventricular white matter with relative sparing of the central gray matter, including basal ganglia and thalami, and the posterior fossa. This may progress to increased white matter lucency and a fingerlike increase in the density of the cortex. This augmented density is believed to result from an increase in cortical blood flow as a consequence of cortical infection. With disease progression, CT may show focal hemorrhagic necrosis, parenchymal calcification, and cystic encephalomalacia. MRI findings are similar to those of CT in early stages of disease, including a loss of distinction at the gray–white matter interface. DWI can demonstrate restricted diffusion in the involved area at the acute phase. Edema may be difficult to distinguish from the surrounding unmyelinated immature white matter because both have increased signals on T2-weighted images. Reduced signal intensity on T2-weighted images of the cortices may be related to hemorrhagic necrosis and parenchymal calcifications. KEY POINTS Major cause of neonatal encephalitis Most common symptoms 946

Fever Seizures May lead to death Psychomotor retardation Microcephaly Microphthalmia, blindness Imaging features T2WI and FLAIR: hyperintense cortex/subcortical white matter Leptomeningeal involvement Focal hemorrhagic necrosis Cystic encephalomalacia Spare central gray matter Varicella Zoster Virus VZV can cause two distinct clinical disorders, an acute febrile exanthematous illness (varicella or chicken pox) and herpes zoster (shingles) infection. Although CNS infection may be seen in both entities, it is rare in healthy populations. Varicella is a highly contagious generalized skin eruption that occurs primarily in children and usually produces no serious consequence in those who are healthy. In immunocompetent patients, encephalitis is seen in less than 1% of infected patients. Mortality is low, with complete or near-complete recovery as the usual outcome. In immunocompromised patients, however, encephalitis may result. Neurologic complications of VZV reactivation occur most frequently in the elderly and in immunocompromised individuals. Among AIDS patients, VZV infection is described in around 4% of infected people (8). The different patterns suggest that spread of VZV to the CNS can occur in different ways. Latent viruses residing in the ganglia of cranial nerves (especially cranial nerves V and VII) can reactivate and extend retrogradely to the brainstem by direct transneuronal spread, resulting in encephalitis. A hematogenous spread and CSF seeding, as opposed to the classically described “reactivation” of a dormant virus in the dorsal root ganglia that produces cutaneous shingles, have also been proposed. Varicella CNS infection may result in transverse myelitis, meningoencephalitis, cerebellar ataxia, and aseptic meningitis. Symptoms of cerebellar ataxia are usually self-limited and often concurrent with the skin eruptions. Neuroimaging findings, however, are often negative in these patients. Meningoencephalitis is a serious uncommon CNS complication of varicella presenting with fever, headache, vomiting, seizures, and altered mental status some days to several weeks after the onset of the rash. CSF reveals mild to moderate lymphocytic pleocytosis and elevated protein. EEG may also be diffusely abnormal. On MR, multifocal areas of increased signal in the cortex have been observed on T2weighted images. Zoster CNS infection may produce encephalitis, neuritis, myelitis, and/or herpes ophthalmicus. These rarely complicate the clinical course in healthy adults with shingles, but in immunodeficient patients, there is an increased risk of CNS involvement. In immunocompetent patients, cranial and peripheral nerve palsies are the most common neurologic disorders seen in zoster infections, whereas diffuse encephalitis is the most frequent manifestation seen in AIDS patients and other immunosuppressed patients. Five different patterns of CNS involvement in AIDS patients have been proposed: multifocal leukoencephalitis, ventriculitis, acute meningomyeloradiculitis, focal necrotizing myelitis, and necrotizing angiitis involving leptomeningeal arteries with cerebral infarction. Fever, meningismus, and altered mental status in a patient with shingles suggest the diagnosis. CSF is nonspecific, with mild lymphocytic pleocytosis, slightly elevated protein, and normal glucose. The characteristic MR features of this infection are clustered subcortical plaquelike lesions demonstrating rapid demyelination and active lesions enhanced with intravenous contrast medium administration. Edema and hemorrhage are not prominent early findings but develop as the infection evolves. MR may also reveal an increased signal in the brainstem and supratentorial gray matter on T2-weighted images and may reveal brainstem enlargement despite meningeal enhancement (Fig. 14.9). The multifocal leukoencephalopathy pattern of VZV necrotizing encephalitis has a unique MR appearance and distribution, with multiple 947

discrete target lesions coalescing into larger regions of extensive parenchymal involvement. Cranial and peripheral nerve palsies occur in dermatomes affected by the distinguishing skin lesions. Involvement of cranial nerve V results in pain in the distribution of the trigeminal nerve, associated with headache and sometimes a change in the corneal reflex. The first division of cranial nerve V is the branch most often affected (herpes zoster ophthalmicus) and presents with pain and a vesicular eruption in the distribution of the ophthalmic division of cranial nerve V. Fat-suppressed MRI with gadolinium may show enhancement of the intraorbital portion of the trigeminal nerve. Contralateral hemiplegia may develop and is usually preceded by herpes ophthalmicus several weeks to months before. The immunodeficient patient is at increased risk for this complication. Pathogenesis of the hemiplegia is believed to result from viral infection of the larger intracranial arteries, resulting in cerebral angiitis and formation of mycotic aneurysms. The Ramsay Hunt syndrome is characterized by the geniculate ganglion involvement, accompanied by seventh and eighth cranial nerve impairment, resulting in facial palsy, hearing loss with vertigo, and ipsilateral herpetic lesions of the external ear and canal. On MRI, this syndrome is represented by a contrast enhancement of the seventh and eighth cranial nerves. Bickerstaff encephalitis is a rare monophasic inflammatory condition that affects the brainstem, probably caused by an immune-mediated response to VZV or CMV infection. Clinically presents as ataxia, ocular paresis, and impaired reflexes.

FIGURE 14.9 Herpes zoster encephalitis in a patient with AIDS (autopsy proven). A: Axial T2-weighted (200/80) magnetic resonance (MR) image demonstrates abnormal signal in the right occipital lobe. A small focus of hyperintensity is seen in the left occipital lobe (arrow) as well, seen also on other images. B: T1-weighted (600/30) axial MR from the same patient reveals focal enhancement in the right occipital region, primarily involving gray matter. C: Midline sagittal T1-weighted (600/30) image demonstrates enhancement in the suprasellar and interpeduncular cisterns (arrows).

Reports associated VZV infection with arterial ischemic stroke and transient ischemic attack. A postvaricella arteriopathy is described, characterized by unilateral stenosing arteriopathy affecting the distal internal carotid artery and proximal segment of the anterior cerebral artery and middle cerebral artery. Thus, brain imaging almost always discloses infarcts within the vascular territory of their lenticulostriate branches, mostly involving basal ganglia and the vascular territory of the main cerebral arteries. CT may show hypodense lesions on basal ganglia, which are nonenhancing hypointense on T1weighted images and hyperintense on T2-weighted images, corresponding to infarcts (9). 948

Diffuse encephalitis associated with VZV infection is rare. It is usually seen in immunocompromised patients, and the white matter may be more involved than the gray matter. Affected areas appear hyperintense on T2-weighted images and may be a result of direct infection and/or an immunemediated reaction. Vasculitis may also occur. Epstein–Barr Virus EBV causes infectious mononucleosis that clinically presents with fever, lymphadenopathy, and eruption. EBV is associated with a number of CNS disorders, including acute encephalitis, meningitis, Guillain–Barré syndrome, meningoencephalitis or cerebellitis, cranial neuritis (mostly involving the second and seventh cranial nerves), transverse myelitis, and chronic fatigue syndrome. These may occur in the presence or absence of infectious mononucleosis. CNS complications are observed in approximately 5% of patients with infectious mononucleosis, including diffuse encephalitis—which has been seen in less than 1% of patients with infectious mononucleosis—demyelinating disease, acute cerebellar ataxia, myelitis, and meningitis (10). Diffuse encephalitis has a short but severe clinical course and a good prognosis for recovery. MRI findings related to EBV infection are not as common. Most acute cases do not reveal any abnormality. MR may reveal multifocal, diffuse, and reversible areas of hyperintensity on T2-weighted images in gray matter or at the gray–white junction. Basal ganglia, corpus callosum, and the brainstem may also be involved. Restricted diffusion has been noted in a lesion located in the splenium of the corpus callosum. This lesion showed reversible reduction in apparent diffusion coefficient after the patient's improvement of symptoms (11). An unusual fusiform arterial dilation may be secondary to direct virus infection of vessels. Cytomegalovirus In adults, CMV infection is typically seen in AIDS patients, accounting for 85% of patients, and is less common, corresponding to 12%, in other immunocompromised patients and only 3% in immunocompetent individuals. This virus exists in a latent form in most of the population, and nearly 90% of adults have antibodies to CMV. Reactivation usually results in a subclinical or mild infection, mimicking mononucleosis. In some immunodeficient patients, however, reactivation results in disseminated infection and/or severe necrotizing meningoencephalitis and ependymitis. CMV may involve the CNS and/or peripheral nervous system. CNS involvement is more common in the brain, but spinal cord lesions may also be noted. Neurologic manifestations of CMV include acute or chronic meningoencephalitis, cranial neuropathy, vasculitis, retinitis, myelitis, brachial plexus neuropathy, and peripheral neuropathy (4).

FIGURE 14.10 Cytomegalovirus. A: T2-weighted (2,400(80) axial magnetic resonance scan reveals a large patchy area of increased signal in the frontal white matter, without mass effect, in this renal transplant patient on immunosuppressive therapy. B: Subependymal neurons with intranuclear inclusions surrounded by clear halos or “owl's eyes” (arrows) and perivascular involvement is characteristic of cytomegalovirus infection. Hematoxylin–eosin, ×20. (From Whiteman MLH, Post MJD, Bowen BC, et al. AIDS-related white matter diseases. Neuroimaging Clin N Am 1993;3: 331–359, with permission.)

In AIDS patients, CMV frequently disseminates to CNS in the late stages with low CD4+ cell count. Usually, it may coexist with other lesions, including toxoplasmosis and cryptococcosis. This infection may be subclinical in immunocompetent and in immunocompromised patients. Approximately 70% of adult AIDS patients show CMV on neuropathologic examination (12). Neuropathologic changes in CMV include atrophy, periventricular necrosis, neuronal loss, 949

demyelination, and accumulations of enlarged cells with distended nuclei containing eosinophilic viral inclusions and surrounded by a halo, producing the characteristic “owl’s-eye” appearance (Fig. 14.10). Other typical histopathologic findings in the CNS include well-circumscribed microglial nodules. CMV intranuclear inclusions may also be found in the spinal cord, spinal nerves, and retina. CMV can spread to the meninges and adjacent cranial nerve roots within the brain causing meningoencephalitis and ventriculitis (Fig. 14.11). It is most often seen in HIV-seropositive patients and transplant patients, but it can also occur in otherwise healthy adults. Less often, subacute symptoms develop over days to months, with fever, confusion, altered mental status, memory loss, and progressive dementia. Brain involvement may be diffuse or limited to the subependymal regions. CSF findings and complement fixation blood titers are nonspecific, and thus the clinical diagnosis can be difficult. CT is virtually always less sensitive than MR in detecting CMV encephalitis abnormalities. CT grossly underestimates the degree of involvement by CMV and it is usually normal at the acute stage (12). Typically, CT may reveal atrophy, the most common finding, and, less commonly, white matter hypodensity and ring-enhancing lesions. In addition to atrophy and white matter hypodensity, periventricular and subependymal enhancement may be noted. MRI depicts patchy and, less often, confluent periventricular white matter lesions with hypointense signal on T1-weighted images, as well as a hyperintense signal on T2-weighted images (Fig. 14.12). In less than 50% of the cases a thin (A are known to be significantly associated with susceptibility to neural tube defects. Among these, homozygous AA carriers are more likely to suffer neural tube defects than are others with GA or GG genotypes (64). Neural tube defects are also known to be associated with disorders of maternal methionine metabolism and with elevated maternal levels of homocysteine. The greater availability of folate after folate supplementation may act to prevent methionine deficiency or homocysteine excess (32). Because folate supplementation appears to correct only 70% of neural tube defects, other etiologies and treatments must also be sought (61,65). These include agents that interfere with cell mobility and contraction by disrupting the intracellular protein actin; calcium channel antagonists that hinder calcium-mediated microfilament contraction; and agents that disrupt the cell surface glycoprotein interactions needed to fuse the dorsal edges of the neural tube (66). Neural tube defects have also been related to derangements in the paired box gene Pax3 that affects N-CAMs, complex basement membrane glycoproteins, and microfilaments in the apical region of the neuroepithelium (60). Pax3 mutations in the Splotch mouse and the corresponding human Pax3 mutation (Waardenburg syndrome I on chromosome 2q35-q37.3) are both associated with neural tube defects (Figs. 19.7C and 19.8) (62,67). Myelomeningocele may also be related to fragile X syndrome, a genetic disease caused by defects in the fragile X mental retardation gene (FMR-1) at Xq27.3 (68). Other chromosomal abnormalities such as full and partial aneuploidy are found in 4.4% to 17.3% of fetuses with spina bifida (69). Triploidy, trisomy 13, and trisomy 18 are among the most frequent of the full aneuploidal defects associated with spina bifida (69). Multiple diverse partial deletions and partial duplications of autosomes and sex chromosomes are also common (69).

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FIGURE 19.11 Rostrocaudal patterning of the axial spine. Compare with Figures 19.10 and 19.12. Homeotic transformation of the axial spine is induced by time-related and concentration-related gradients of retinoic acid. The vertebral levels are shown on the left. The transformation frequencies are indicated as percentages of the animals studied. The approximate boundaries of expression of parologous groups of Hox genes are shown on the right. (From Kessel M, Gruss P. Homeotic transformations of murine vertebrae and concomitant alterations of Hox codes induced by retinoic acid. Cell 1991;67:89–104, with permission.)

FIGURE 19.12 Homeotic transformation of rostrocaudal patterning. Newborn mouse specimens. The Alcian bluealizarin red preparation stains cartilage blue and ossified calcium-containing tissue red. The variations in the vertebral pattern produced by exposure of mouse embryos to retinoic acid on day 7 or day 8 after timed matings (tm) indicate that retinoic acid (RA) shifts the expression of the Hox code along a rostrocaudal axis. This shift respecifies segment identity, leading to transitional vertebrae and alterations in the number of costal elements. The normal mouse pattern is C7, T13, L6 (see also Figs. 19.10 and 19.11). A: Vertebral pattern C6, T13, L5 induced by RA at 7 days, 4 hours (tm). B: Vertebral pattern C6, T13, L6 induced by RA at 7 days, 4 hours (tm). C: Vertebral pattern C7, T14, L6 induced by RA at 8.5 days (tm). D: Vertebral pattern C7, T5, L5 induced by RA at 8.5 days (tm). E: Vertebral pattern C7, T13, L6 (wild-type, normal for mouse). (From Kessel M, Gruss P. Homeotic transformations of murine vertebrae and concomitant alterations of Hox codes induced by retinoic acid. Cell 1991;67:89–104, with permission.)

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FIGURE 19.13 Molecular factors driving body asymmetry. Diagrammatic representation. The earliest signal appears shortly after gastrulation and is mediated by activin receptor II (axtRII) positioned along the right side of the primitive streak. This inductive signal is relayed to the lateral plate mesodermal cells as they migrate anteriorly from the primitive streak. The zinc finger protein Snail related (cSnR) also becomes expressed in lateral plate mesoderm on the right. A few hours later nodal (a member of the transforming growth factor β family) becomes selectively expressed in a broad stripe of lateral plate mesoderm on the left side of the body, roughly mirroring the distribution of cSnR on the right. The primitive heart tube then begins its program of looping and bends to the right, followed closely by a rightward rotation of the entire body axis. Shh, sonic hedgehog. (From Robertson EJ. Left-right asymmetry. Science 1997;275:1280–1304, with permission.)

Myelomeningocele afflicts females slightly more commonly than males (57,70) and is evident at birth in all cases. The lesion involves the lower back predominantly: thoracic 2%, thoracolumbar 32%, lumbar 22%, and lumbosacral 44% (57). Because studies of embryos indicate that cervical and holocord myeloceles and myelomeningoceles actually occur more commonly than lumbosacral lesions, the predominance of caudal lesions evident at birth most likely reflects their lesser severity and greater survival to term (71). Patients with myelomeningocele manifest a number of neurologic signs, including sensorimotor deficits of the lower extremities, incontinence of bladder and bowel, hindbrain dysfunction, intellectual– perceptual impairments, and hydrocephalus (72–76). A component of the motor deficit appears to result from birth trauma and spinal shock. Infants delivered by cesarean section before onset of labor manifest less severe deficits than those delivered vaginally or those delivered by cesarean section after some period of labor (77). Motor strength typically improves one to two levels after the initial repair of the myelomeningocele and then stabilizes at a set motor level. Deterioration thereafter is regarded as evidence of a secondary complication. Recent decades have brought significant improvement in the care and prognosis of patients with myelomeningocele (78). In an older cohort born in 1975–1979, mortality at the 20- to 25-year follow-up was 24% and continued to increase into young adulthood. A majority of the deaths occurred during infancy and the preschool years. Most of the children died of hindbrain dysfunction. Shunt diversion of CSF was required in 86%; 95% of those with shunts required at least one revision (78). In a younger cohort born in 2000–2004, none of the children died during infancy or in the preschool years (78). Four children underwent posterior fossa decompression. One child required a tracheostomy with long-term ventilator support (since weaned successfully), and four children required gastrostomy tubes (three removed when they later became unnecessary) (78). Only 65% required shunt diversion of CSF. Seventy-one percent have required one shunt revision (78). Myelocele and myelomeningocele appear to result from deranged neurulation, although other theories have been offered to explain limited numbers of cases (38,79,80). If the neural folds fail to flex and to fuse into a tube, they persist instead as a flat plate of neural tissue (Fig. 19.14) (81,82). This flat plate of unneurulated neural tissue is designated the neural placode. Because the neural tube does not close, the superficial ectoderm cannot disjoin from the neural ectoderm and remains in lateral position. 1427

Therefore, the skin that develops from the ectoderm also lies lateral in position, leaving a midline defect. Mesenchyme then cannot migrate behind the neural tube, and so the bony, cartilaginous, muscular, and ligamentous elements are also deficient in the midline. Instead, the bones, cartilage, muscle, and ligament develop in an abnormal position ventral-lateral to the neural tissue and appear bifid and “everted.” The unfused neural plate is thus exposed to view in the midline of the back at the site of the midline deficiency of skin, bone, cartilage, muscle, and ligament. The exposed neural tissue appears as a raw, reddish, vascular oval plate (19-15A). The raw surface represents the interior of what should have been the closed spinal cord. A midline groove runs down the center of this plate. This groove is the residuum of the ventral neural groove and is directly continuous with the central canal of the normally formed cord above.

FIGURE 19.14 Unneurulated neural placode. Proposed embryogenesis for spina bifida aperta by failure to neurulate the neural plate with consequent nondisjunction of epidermal from neural ectoderm. A: Mammalian embryo. B: Diagrammatic representation. Images oriented like axial magnetic resonance imaging (MRI) with ventral toward the top. (From Naidich TP, Gorey MT, Raybaud C, et al. Malformations congénitales de la moelle. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.) C: Resulting spina bifida with widely everted laminae. Axial T1 MRI in a 4-year-old girl. If the neural folds fail to close, the neural plate appears to open widely and to evert with the lateral margins ventral to the rest of the plate. The neural placode thus remains in a nearly coronal plane. The epidermal ectoderm (c) (large curved arrows) cannot disjoin from the neural ectoderm (NE). Instead, it remains attached to the neural ectoderm far laterally and does not pass dorsal to the neural tissue. With future development, the skin that arises from the epidermal ectoderm will also lie far laterally, leaving a midline defect in the skin cover. Adherence of the epidermal ectoderm to the neural ectoderm prevents migration of mesenchyme behind the neural plate (placode). Therefore, no bone, muscle, or fascia can develop in the midline dorsal to the neural tissue; all skin, fascia, muscle, and bone must lie lateral or ventral to the neural tissue. Thus, the dorsal surface of the unneurulated neural placode will remain visible in the midline. Despite absence of neurulation, the notochord on the ventral aspect will still migrate ventrally to become separated from the neural plate. Perichordal mesenchyme will develop into vertebral centra and disks ventral to the neural tissue. The mesenchyme that should have migrated dorsal to the neural tube must instead condense in abnormal position, ventral–lateral to the neural tissue, forming widely everted (bifid) laminae (L, L). C, vertebral centrum. Compare the contours of the bifid laminae with the mesenchyme ventral–lateral to the recurved neural placode. Because the laminae (L) are widely everted, the sagittal dimension of the spinal canal is markedly reduced, crowding the neural structures. Acutely angled kyphosis, often associated with wide spina bifida, stretches the skin and subcutaneous tissue, and prevents the surgeon from mobilizing enough tissue to cover the spina bifida. There is consequently little tissue and no high-signal subcutaneous fat overlying the spina bifida (arrowheads). The neurocentral synchondroses (white arrows) have nearly fused. (From Naidich TP, McLone DG. Congenital pathology of the spine and spinal cord. In: Taveras JM, Ferucci JT, eds. Radiology—Diagnosis/Imaging/Intervention. Philadelphia, PA: Lippincott; 1986, with permission.)

The pia-arachnoid membrane that covers the ventral surface of the neural plate and encloses the cerebrospinal fluid (CSF) may bulge posteriorly to present at the surface of the back as a thin ring surrounding the neural tissue. The size of this membranous ring varies. When the subarachnoid space is small, the membranous ring is narrow, and the neural plate lies flush with the back. This situation is 1428

designated myelocele (Figs. 19.15 and 19-16A). When the subarachnoid space is very large, the membranous ring is wide, and the neural plate is elevated far above the skin surface. This condition is designated myelomeningocele (Figs. 19.15B and 19-16B). Together, myelocele and myelomeningocele are the most common forms of spinal dysraphism. When used colloquially, spina bifida usually means myelocele or myelomeningocele. In both myelocele and myelomeningocele, the membranous ring itself is encircled by normal skin peripheral to the midline defect. Epithelial cells may later grow inward from the skin margins to cover the membranes and even the neural tissue that lie within the defect (19-15B). If infection does not cause early death, the entire site may become epithelialized secondarily by a thin dysplastic skin layer. Deep to the visible surface, the ventral face of the neural plate represents the neural tissue that should have formed the entire outer circumference of the spinal cord. The two ventral motor nerve roots arise from the ventral surface of the neural plate just to each side of the midline ventral sulcus. The paired dorsal sensory roots also arise from the ventral surface of the neural plate, lateral to the corresponding ventral roots. They arise in this position because the tissue that should have folded dorsally to close the tube unfolds instead to lie lateral to the motor tissue on each side. The ventral and dorsal nerve roots traverse the subarachnoid space and exit via the neural foramina in the usual manner.

FIGURE 19.15 Myelocele and myelomeningocele. Photographs of the backs of two newborn patients. A: In myelocele, the neural placode lies nearly flush with the surrounding skin surface. The edges of the skin (white arrows) are separated from the edges of the neural plate (white arrowheads) by variably epithelized membranes. Note the midline groove and the two paramedian grooves (open white arrows). These would have formed the ventral neural groove and the sulci limitans of the ventral canal of a closed, well-neurulated spinal cord. B: In myelomeningocele, expansion of the subjacent subarachnoid space is associated with elevation of the neural plate well above the surrounding back. In this patient, skin partially encloses the meningocele, so the edge (black arrows) of the skin lies along the lateral margins of the neural plate with little intervening nonepithelialized membrane. Note the drop of cerebrospinal fluid (open arrow) that has passed from the central canal over the external surface of the neural placode and runs down the slope of the myelomeningocele.

The pia-arachnoid membrane covers the ventral surface of the neural plate and continues around the entire subarachnoid space as one continuous sheet (Fig. 19.16) (81). This membrane is given the name pia mater where it is contiguous with neural tissue and the name arachnoid mater where it is separated from the neural tissue. The relationship of pia to arachnoid mater is analogous to the relationship of visceral to parietal pleura. The dura mater lies peripheral to the arachnoid. The dura forms a distinct layer ventrally but becomes lost in the margins of the defect dorsally. Because the neural plate and meninges are anchored to the skin surface, the spinal cord is tethered and relatively immobile.

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FIGURE 19.16 Diagrammatic representation of myelocele and myelomeningocele. A: Myelocele. The myelocele is nearly flush with the surface of the back. The neural tissue has the flat configuration of the unneurulated neural placode (NP). The dorsal surface, exposed to the exterior, exhibits midline and paramedian sulci (arrows) corresponding to the ventral neural groove and sulci limitans (unless secondary trauma or infection distorts the tissue further). The ventral surface is lined by pia that becomes continuous with arachnoid at the lateral edge of the neural plate. This pia-arachnoid (dashed line) is one continuous sheet of membrane that encloses the subarachnoid space (SAS). The dorsal roots (D) arise from the ventral surface of the neural plate lateral to the ventral roots (V), not dorsal to them, because the plate has not flexed into a tube. G, the dorsal root ganglion. The pia-arachnoid continues along the ventral and dorsal roots but is not shown, to simplify the diagram. The dura (dark line superficial to the piaarachnoid) encloses the cerebrospinal fluid ventrally and laterally and then becomes lost in the tissue lateral to the neural placode. No dura forms dorsal to the neural placode. The laminae (L) are widely everted (wide posterior spina bifida). B: Myelomeningocele. The myelomeningocele exhibits the same basic anatomy, but expansion of the SAS displaces the neural placode posteriorly, everts it, and elevates it well above the surface of the surrounding back. (From Naidich TP, Gorey MT, Raybaud C, et al. Malformations congénitales de la moelle. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989; and Naidich TP, Gorey MT, McLone D. Congenital anomalies of the spine and spinal cord. In: Putman CE, Ravin CE, eds. Textbook of Diagnostic Imaging. Philadelphia, PA: WB Saunders; 1987, with permission.)

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FIGURE 19.17 Extensive untreated myelomeningocele. Newborn. Sagittal T1-weighted (A) and T2-weighted (B) magnetic resonance imaging (MRI) and axial T1-weighted MRI (C). There is lumbosacral spina bifida with widely everted laminae and midline discontinuity of the subcutaneous fat, deep lumbosacral fascia, and posterior spinal elements (between white arrows). The low-lying distal cord (c, larger arrowheads) extends posteriorly beneath the last intact spinal element, opens into the neural plate, and becomes the thin posterior wall of the large myelomeningocele sac. Because the cord lies in low position, there is no cauda equina. Instead, the ventral and dorsal nerve roots (smaller arrowheads) arise from the ventral (deep) surface of the neural plate and pass nearly horizontally across the sac to reenter the spinal canal before exiting at their normal neural foramina.

Rarely, one is able to study the untreated myelomeningocele (Figs. 19.17 and 19.18). Nearly always, however, patients with myelocele and myelomeningocele do not require detailed radiologic evaluation in the newborn period because the pathology is already evident on visual inspection. The back is simply repaired surgically to protect against infection and to free the spinal cord, so that later growth of the child does not cause neurologic dysfunction by cord stretching. As a result of this primary repair, the child’s neurologic function is stabilized or is improved to some “best” level for the child. Thereafter, the child should maintain that level of function (72). Any subsequent deterioration in neurologic function represents a complication that must be evaluated for potential surgical correction. The usual role of radiology is to elucidate the cause for late deterioration in patients who have already undergone primary repair of the myelomeningocele. Such complications include retethering of the cord to the wall of the spinal canal, abnormal spinal curvature, inclusion epidermoid, inclusion lipoma, hydromyelia, and arachnoid cyst. Devascularization of the Placode In patients with myelomeningocele, the placode is supplied by radiculomedullary branches and by many large vessels that pass directly to the neural tissue via the lateral dural reflections. Surgery may injure 1431

these lateral dural vessels, especially superiorly at the junction between the neurulated cord and placode, leading to focal cord infarction and atrophy (1,30,73). Local Wound Site The most common complications at the site of the closure of the myelomeningocele include skin necrosis, CSF leak at the repair site (6% to 17%), CSF pseudocyst (2%), and local wound infection (3% to 12%, higher for patients undergoing delayed closure) (57,74,83–92).

FIGURE 19.18 Untreated myelomeningocele. A: Patient photograph. The surface of the myelomeningocele has become covered by skin through secondary epithelialization from the margins of the defect. B: Sagittal T1-weighted magnetic resonance demonstrates features characteristic of untreated myelomeningocele: dehiscence of high-signal subcutaneous fat (F), fascia, muscle, and bone in the zone of spina bifida; low position of the spinal cord (C); acute angulation (arrow) of the cord under the last intact lamina at the upper margin of the spina bifida; and posterior herniation of the neural tissue (white arrowheads) forming the dorsal wall of the cerebrospinal fluid space (S) that protrudes through the spina bifida. (From Naidich TP, Radkowski MA, Britton J. Real-time sonographic display of caudal spinal anomalies. Neuroradiology 1986;28:512–527, with permission.) This patient also exhibits thoracolumbar kyphos.

Latex Anaphylaxis From 18% to 51% of patients with myelomeningocele (and up to 6% of medical personnel) show latex sensitivity, including latex antibodies in their sera (87–107). This occasionally leads to life-threatening anaphylaxis during surgery (87). Of 162 patients with latex allergy in Holzman’s study (90), 26% had previously manifested an anaphylactic reaction in the operating room. The powder on surgical gloves may be a vehicle for transmitting protein allergens from the latex gloves to the patients. Careful washing of gloves and careful histories of prior reactions need to be obtained to avoid these problems. Retethering by Scar When the spinal cord is freed from the back at the time of primary repair, it is replaced into the spinal canal. The dura and skin are closed over it. Because dura and skin are deficient in the midline, it may be technically difficult to mobilize sufficient tissue to provide a relaxed cover over the spinal canal, subarachnoid space, and cord. The raw surfaces of the neural tissue may adhere to the surgical closure and scar densely to it (Figs. 19.19 and 19.20) (91). In approximately 27% of patients with repaired myelomeningocele, retethering of the cord by scar causes new symptoms that necessitate a second procedure to release the cord at an average age of 6 years (92). These symptoms include new or progressive weakness of the lower extremities (55%), change of gait requiring added mechanical support (54%), new or progressive scoliosis (51%), pain localized to the back and legs (32%), progressive orthopedic deformities of the foot or hip (11%), and/or new urinary incontinence (6%) (83). In such cases, surgical photographs (Fig. 19.20) and radiologic studies (Figs. 19.21 and 19.22) show that the posterior surface of the spinal cord becomes lost at the level of closure (93). The spinal cord remains attached to the dorsal wall of the spinal canal despite placing the patient prone and flexing the 1432

back. The subarachnoid space is obliterated dorsal to the cord and is unusually wide ventral to the cord. The entire thecal sac lies unusually far posteriorly and protrudes partially through the posterior spina bifida. The ventral epidural fat space is consequently enlarged. The cord itself appears thin and pursues a very straight, stretched, “bowstring tight” course down the length of the spinal canal. Because the cord extends so far caudal, there is no cauda equina. Instead, the nerve roots that arise from the cord at the level of the spina bifida pass horizontally or even cephalically to their root sleeves. These roots tend toward a plexiform arrangement (Fig. 19.20).

FIGURE 19.19 Repaired myelocele. Retethering by scar. Axial anatomic specimen oriented like magnetic resonance. The site of repair exhibits thinner atrophic skin with a thin subcutaneous layer (white arrows). The neural tissue (NP) is tethered to the surgical repair site by thick collagenous scar (black arrows). L, L, everted, widely bifid laminae. (From Naidich TP, Gorey MT, Raybaud C, et al. Malformations congénitales de la moelle. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

FIGURE 19.20 Repaired myelocele. Retethering by scar, 2-year-old girl. Sagittal surgical exposure demonstrates the low-lying distal spinal cord (C), horizontal segmental origin, and course of the lumbosacral roots through the subarachnoid space (S) with no cauda equina, somewhat plexiform arrangement of these roots, dorsal surface of the spinal canal along the zone of repair (R), adherence (black arrows) of the distal neural tissue to the repair zone at two sites, and clear cerebrospinal fluid–filled space behind the neural tissue between the two sites of adherence.

Re-operation for tethering after primary myelomeningocele repair may be complicated by coexisting pathology. In 123 patients, Reigel et al. (94) found concurrent lipoma (50%), fibrolipoma (9%), dermoid (12%), epidermoid (16%), arachnoid cyst (11%), and diastematomyelia (11%). Approximately 10% of these patients had two concurrent lesions (94). Surgical release of the adherent cord is effective, leading to improved motor function in 79% (including unexpected improvement in many patients who had been considered “stable” before untethering). Re-operated patients show improved gait and stance in 72% of cases, improvement of orthopedic deformities in 54%, improved scoliosis in 51%, and improved urinary and social continence in 33% (83). However, 16% of patients initially untethered later require surgical procedures to again untether a re-scarred cord (94). Vertebral subtraction osteotomy to reduce the height of the spinal column may allow for reduced 1433

tension on the still-tethered spinal cord and presents an alternative to surgical untethering of the cord without risk to the adherent neural tissue (101,102). Inclusion Cysts (Epi)dermal inclusion cysts are found in both the unoperated newborn and the previously repaired back (74,97–99). Before closure of the myelomeningocele, the placode and central canal are open to the environment and exposed to desquamated skin, laguno, and hair in the amniotic fluid. Thus, Storrs (97) found epidermoid cysts in 29% and dermoid cysts in 6% of newborns during the initial closure of their myelomeningocele, including epidermoid “pearls” floating freely in the spinal subarachnoid space. McLone and Naidich (74) reported delayed occurrence of dermoid and epidermoid tumors in up to 16% of patients after myelomeningocele repair. During the repair of a myelomeningocele, the surgeon must trim all the skin away from the cord, lest some skin elements become included within the closure. This is hard, probably impossible, to do perfectly. In some cases, therefore, these included (epi)dermal elements may later grow into epidermoid (12% to 13%) and dermoid cysts (2% to 5%) (Fig. 19.23) (85,97). Scott et al. (100) found that 15% of repaired myelomeningocele patients who later presented with a symptomatic tethered cord had a dermoid or epidermoid. In their experience, (epi)dermoids found within the scar, dorsal to the placode, were more likely to be inclusion (epi)dermoids resulting from surgery, whereas those found ventral to the neural tissue and those containing unusual features such as respiratory epithelium were more likely to be congenital in origin (100). Lipomas are found in 6% of newborn untreated myelomeningoceles and 7% of operations performed to release tethered cords. Emery and Lendon (101) found filar fibrolipomas in 67% of myelomeningocele patients coming to postmortem. It may be difficult to distinguish inclusion lipomas from inclusion dermoids by imaging procedures alone (1,102–104). Hydromyelia Before the back is repaired, the central canal of the spinal cord is directly continuous with the midline groove on the dorsal surface of the neural plate. As a result, CSF passes freely down the central canal to discharge over the dorsal (external) surface of the neural plate (19-15B). After repair of the back, this egress for CSF is blocked, potentially leading to dilation of the central canal of the spinal cord (i.e., hydromyelia) (Fig. 19.24). Reviews of CSF pulsations (105,106) and of spinal cord cysts (107,108), however, suggest that hydromyelia may also be expected whenever the subarachnoid space is narrowed around the spinal cord and whenever the spinal cord is tethered, offering other possible mechanisms by which hydromyelia could arise.

FIGURE 19.21 A 15-year-old boy with uncomplicated prior repair of a sacral myelomeningocele. A: Midsagittal T2 MRI. B: Axial sacral T2 MRI. The spinal cord extends inferiorly through the lumbar canal and becomes adherent to the posterior wall of the canal along the surgically repaired sacral myelomeningocele (white arrow).

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FIGURE 19.22 A 6-year-old boy with prior repair of a thoracic myelocele, atrophic segment of cord and hydromyelia. A: Midsagittal T2 MRI. B–D: Serial axial T2 MRIs. A: Following repair, the spinal cord demonstrates hydromyelia from T8–T10, an atrophic segment adherent to the posterior wall of the spinal canal at T10–T11, and a more nearly normal segment distally.

FIGURE 19.23 Repaired myelomeningocele with epidermoid inclusion in a 4-year-old child. Sagittal T1-weighted (A) and T2-weighted (B) magnetic resonance imaging disclose a repaired lumbosacral myelomeningocele. The low-lying spinal cord (c) is tethered inferiorly by a mass (arrowhead) that is nearly isointense to the cord on the T1- and T2weighted images. Closure of the sac has created dorsal fluid compartments with restricted communication. Such compartments appear brighter on T2-weighted images because of reduced dispersal of signal by cerebrospinal fluid pulsations and perhaps because of higher protein concentrations within them.

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FIGURE 19.24 Repaired myelomeningocele with hydromyelia. A 9-month-old boy. A: Sagittal T2 MRI. B: Axial T2 MRI. Cephalic to the repair (white arrows), the spinal cord is distended by hydromyelia (H). Jack-knife kyphus is also noted.

Hydromyelia is observed at necropsy in 30% to 50% of patients with myelomeningocele (101,109–112). The precise incidence varies from series to series (101,112). The hydromyelia is holocord or nearly holocord in 11%, cervical in 2%, cervicothoracic in 7%, thoracic in 7%, thoracolumbar in 11%, and lumbar in 9%. Seven percent of patients show hydromyelia at two different levels (112). When severe, hydromyelia may cause neurologic dysfunction and rapidly progressive scoliosis (113). In any patient with myelomeningocele and rapidly progressive scoliosis, cranial imaging studies should be performed to rule out hydrocephalus or occult shunt malfunction. Spinal imaging should be performed to detect any hydromyelia present. On occasion, a severe hydromyelia may expand the cord remarkably, thin its wall, and bulge outward partially exophytically, perhaps at its upper or lower pole (114). The hydromyelic cavity may appear to spiral around a portion of the circumference of the cord. On MR, hydromyelia usually appears as a CSF-intensity space within the center of a dilated cord. The sides of the cavity may be indented periodically by bands that resemble the haustra of the colon. Hydromyelia may also present as an ovoid, sagittally flattened, atrophic cord (collapsed hydromyelia). In some cases, the central canal is so wide and the cord so thin that only one wall of the cord is visible, usually the anterior wall. In these cases the thin anterior wall may be mistaken for the entirety of a very atrophic spinal cord. In other cases it may be very difficult to distinguish hydromyelia with scoliosis from intraspinal arachnoid cyst. Such arachnoid cysts are found in 2% of patients with myelomeningocele (Fig. 19.25) (26,115). Diastematomyelia and Hemimyelocele Diastematomyelia is seen in 31% to 46% of patients with myelomeningocele (76,79). It affects the cord cephalic to the plaque in 31%, the plaque itself in 22%, and the cord caudal to the plaque in 25% (101). Hemimyelocele is a special form of myelomeningocele-with-diastematomyelia that is reported in 9% of patients with Chiari II malformations (116). In 1%, paired hemicords each exhibit a myelomeningocele at different levels. In the other 8%, one posteriorly situated hemicord exhibits a myelomeningocele, whereas the other hemicord is normal. The normal hemicord is usually smaller, usually lies ventrally, and may be isolated within a separate ventrolateral hemicanal formed by an oblique bone spur. In such cases, the visible hemimyelocele may be mistaken for a complete myelomeningocele, so that the diastematomyelia and other hemicord are not recognized until the child presents with tethering sometime after the initial repair. Strikingly asymmetric motor strength in the lower extremities, with one normal or nearly normal leg, should suggest the diagnosis of hemimyelocele in the newborn period. Spinal Curvature in Myelomeningocele The incidence of spinal curvature in patients with myelomeningocele depends on the level of the myelomeningocele, patient age, and the type of curvature assessed (Fig. 19.16, Table 19.1) (117–121). TABLE 19.1 Spinal Curvature and Myelomeningocele

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FIGURE 19.25 Cervicothoracic arachnoid cyst with Chiari II malformation. A: Sagittal T1-weighted magnetic resonance imaging (MRI) reveals the Chiari II malformation with kink and spur where medulla (M) buckles behind the cord (C) (see Figs. 19.28 and 19.29).The tapering of the cord inferiorly could indicate scoliosis alone, hydromyelia with thin undetectable posterior wall, and/or dorsal arachnoid cyst. B: Axial T1-weighted MRI demonstrates a large

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low-signal space posterior to the cord (C) and suggests that the space does not represent hydromyelia at that level. Cord contour is slightly “dumbbell” shaped. C: Computed tomographic myelography reveals a less wellcommunicating compartment dorsal to the cord representing a subdural arachnoid cyst (A). The cord exhibits a mild form of diastematomyelia. D: Operative exposure in another patient, a 3-year-old boy, with Chiari II malformation and myelomeningocele. The dura is tented laterally by stay sutures. The thin-walled, transparent, sausage-shaped arachnoid cyst lies within the subdural space and displaces the spinal cord anteriorly. It contained clear fluid resembling cerebrospinal fluid. E: Opening the cyst reveals the spinal cord (C) situated ventral to the cyst. The dorsal surface of the spinal cord was deeply indented by the cyst. (Panels D and E: From Naidich TP, McLone DG, Fulling KH. The Chiari II malformation. Part IV. The hindbrain deformity. Neuroradiology 1983;25:179–197, with permission.)

SCOLIOSIS. In patients with myelomeningocele, 23% of the scolioses are congenital structural scolioses that result from vertebral anomalies such as hemivertebrae, solid bony bars, and unilateral unsegmented bars. In such cases, the arc of curvature is very sharp and the apex of the curve lies at the site of the bony anomaly (1,122). Sixty-five percent of scolioses are developmental scolioses that result from muscle imbalance and distal pelvic and extremity malformations in the absence of congenital spinal anomalies (122). In these patients the arc of curvature is usually less sharp and lies in the dorsolumbar region. The incidence of scoliosis associated with myelomeningocele varies with the functional spinal level of the patient: 85% for thoracic myelomeningocele, 100% for L1–L2 myelomeningocele, 50% for L3–L4 myelomeningocele, and 6% for sacral myelomeningocele (123). Overall, 80% of patients with myelomeningocele have scoliosis by age 10 years (92). Progression of scoliosis occurs in the first decade and dramatically increases during the second decade for patients with functional levels at the thoracic or upper lumbar (L1–L3) spine (94). After 10 years of age, 43% of myelomeningocele patients have scoliosis of 20 degrees or greater (87). Although spinal curvatures are widely thought to be most rapidly progressive at the time of growth spurts, careful study of spinal curvatures in 23 patients receiving growth hormone showed no significant change in the scoliotic curve and no evidence of neurologic change over 3 years, despite patient growth at a rate of 7 to 8 cm/year (94). In patients with myelomeningocele, retethering of the spinal cord should always be considered the likely cause of scoliosis. In these patients, surgical untethering of the cord stabilizes most cases and actually improves the curve in 21% of patients (92). The greatest incidence and greatest severity of scoliosis occur with thoracic myelomeningoceles (94). These are also the most refractory to therapy (94). LUMBAR LORDOSIS. In normal patients, the usual lumbar lordosis develops rapidly during infancy and again at puberty, reaching a plateau of about 50 degrees at maturity. Significant lordosis, defined as more than 55 degrees, develops by age 20 years in 43% of patients with repaired myelomeningocele and tethered cord. As with scoliosis, more-cephalic lesions show a greater incidence of lordosis and a more rapid progression. After release of the tether, the improvement of lordosis is greatest for those patients with severe thoracic myelomeningocele. THORACIC KYPHOSIS. In myelomeningocele patients, a thoracic kyphosis develops slowly and “normally” reaches 40 degrees by 20 years. Thoracic kyphosis of more than 40 degrees is seen in 21% of patients with tethered cord after myelomeningocele repair and exhibits the same craniocaudal gradient of incidence and severity as do scoliosis and lumbar lordosis. However, release of the cord does not seem to affect the progression and incidence of thoracic kyphosis. LUMBAR KYPHOSIS. Congenital lumbar kyphosis is a major deformity in 8% to 21% of patients with myelomeningocele and is frequently associated with compensatory thoracic lordosis (118,124,125). It is usually located in the upper lumbar region, measures 80 degrees or more at birth, and progresses thereafter. The vertebra at the apex of the curve is typically hypoplastic and anteriorly wedged (Fig. 19.26) (1). The aorta lies well away from the kyphus and in 56% is strung like a bowstring across the kyphotic vertebral curve (126). The lumbar arteries originating from the aorta follow a long horizontal course from the aorta to the dorsum of the kyphos and are commonly variant (126,127). In one case, for example, a single trunk arose from the aorta distal to the renal arteries and ascended close to the vertebrae, giving rise to two intercostal arteries per segment over five lumbar segments. In patients with lumbar kyphosis, the sharp curvature leads to tight stretching of the skin over the closure, skin ulceration, breakdown, and infection. These patients suffer progressive respiratory 1438

difficulty because of incompetence of inspiratory muscles, crowding of abdominal content, and upward pressure on the diaphragm (124). Excision of the proximal lordosis stabilizes their curvature and facilitates ambulation. Children born with a thoracolumbar kyphos who function at or below L4 should be considered for kyphectomy before their second birthday (92). Carstens et al. (125) distinguished three subtypes of lumbar kyphosis in myelomeningocele: paralytic (less than 90 degrees at birth), sharp angled (greater than 90 degrees at birth), and congenital (resulting from structural malformations of the vertebrae, such as anterior vertebral malsegmentation). Paralytic kyphosis has nearly normal lumbar spinal curvature at birth but cannot maintain this because of muscle weakness. Such paralytic kyphosis accounts for 44% of lumbar kyphosis and progresses linearly with later development. Sharp-angled kyphosis typically has a more rigid curvature caused by the pathologic position of the paraspinal muscles. It accounts for 38.4% of lumbar kyphosis and also progresses linearly with growth. In both types, the actual progression also depends on the level of paralysis. Congenital kyphosis accounts for 13.9% of lumbar kyphosis and shows variable progression (125). Effect of Untethering on Spinal Curvature Sarwark et al. (128) studied the effect of surgery on the spinal curvature of 29 myelomeningocele patients operated on to release retethering. At 1 year after untethering, 75% of patients had stabilized their curvature or had improved it by greater than 10 degrees; 25% showed more than 10-degree progression of their curvature (128). Continued follow-up revealed that only 12% maintained an improvement in curvature of greater than 10 degrees; 47% remained stable, and 41% progressed at least 10 degrees (128). Reigel et al. (94) similarly assessed the effect of surgical untethering on spinal curvature in 216 myelomeningocele patients. Progression of scoliosis plateaued or declined after release of the tethered cord for patients with myelomeningoceles at the lumbar and sacral levels, but cord release did not halt the progression of scoliosis in patients with thoracic level lesions. Untethering improved the course of lordosis in patients with lesions at the L1–L3 levels but not in patients with L4, L5, or sacral-level lesions. Untethering did reduce the incidence and magnitude of kyphosis (94).

FIGURE 19.26 A 2-month-old infant with repaired myelomeningocele below T7 (see also 19-30A). A: Reformatted sagittal CT scan. There is “jack-knife” kyphus of the lumbar spine. The subcutaneous fat, fascia, muscle, and bone are markedly thinned in the zone of spina bifida. B: Corresponding 3D reformation of the spine. C: Midsagittal T2 MRI. The spinal cord (arrows) thins out into the zone of repair.

TABLE 19.2 Indications, Incidence and Outcomes for Untethering a Retethered Cord in 114 Patients with Repaired Myelomeningocele and Cord Retethering

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Cord Retethering and Release of the Retethered Cord Bowman et al. (78) analyzed the incidence of spinal cord retethering and the effect of detethering the cord in a large, single-institution cohort of myelomeningocele patients. Symptomatic retethering of the spinal cord was found in 114 of 502 children (23%) with myelomeningocele who underwent initial closure at that institution. The 114 children underwent 163 procedures for release of tethered cord: 81 children (71%) had one procedure, 20 (17%) had two procedures, 10 (9%) had three untetherings, and four (3%) had four. Indications and outcomes for untethering the retethered cord are given in Table 19.2. Caldarelli et al. (129) and Hayashi et al. (130) report similar findings in mixed populations of patients with repaired myelomeningoceles and repaired spinal lipomas. Fetal Repair of Myelomeningocele Increasingly, myelomeningoceles are being detected prenatally during fetal maternal sonography and then confirmed by subsequent fetal–maternal MRI (Fig. 19.27). This raises consideration of fetal surgery to repair the defect in utero. The Management of Myelomeningocele (MOM) study compared the results of prenatal surgery for myelomeningocele repair at 19 to 25 weeks of gestation (WG) versus postnatal surgery by the same team following delivery at 37 WG (131). Overall, the children in the group operated upon prenatally presented with higher, more severe lesions: 27% of lesions at L1 or L2 in the prenatal group versus 12% in the postnatally operated group (131). Nonetheless, this study found that prenatal surgery reduced the incidence of fetal and neonatal death and reduced the need for shunt therapy of hydrocephalus. The prenatally treated group had reduced incidence of hindbrain herniation, reduced severity of any hindbrain herniation present, motor function that was one to two levels better than predicted from lesion level of myelomeningocele, better Bayley Mental Development Index, and similar Wee FIM cognitive scores (a measure of pediatric functional independence) (131). Twice as many children treated prenatally were walking independently, and fewer were not walking at all (131). The study was terminated prematurely for early documentation of benefit from the prenatal surgery.

FIGURE 19.27 Fetal–maternal T2 MRIs. Two patients. A: Lumbar myelomeningocele (red arrow) at 25 weeks gestation. B: Thoracic myelomeningocele (red arrow) at 27 weeks gestation.

In a second study of 54 patients who underwent fetal repair of myelomeningocele, 16 (30%) 1440

presented with symptomatic tethered cord syndrome 4 to 93 months (median 27 months) after repair (132). Ten of the 16 (19% of the total) had an intradural inclusion cyst as part of the tethered cord syndrome (132). Four additional children (7% of the total) had evidence of an inclusion cyst on MRI but were asymptomatic at 60 to 94 months following repair (132). Histologically, eight resected cysts were dermoids, one an epidermoid, and one a mixed dermoid–epidermoid cyst (132). Fetal surgery does carry risk of adverse effects. Because of the uterine surgery, the mothers of the prenatal group are more likely to develop pulmonary edema, placental abruption, oligohydramnios, spontaneous rupture of membranes, or spontaneous labor (131). At the time of cesarean delivery, 25% of the women who underwent fetal surgery had a very thin hysterotomy site. Nine percent had an area of dehiscence along the scar, and 1% had complete dehiscence of the incision (131). To reduce these risks, the children must be delivered prematurely, with all the attendant risks of prematurity. Ultimately 8% of the children in this group required surgery for tethered cord versus 1% in the group operated upon postnatally (131). Chiari II Malformation Myelocele and myelomeningocele are nearly always associated with a specific deformity of the brainstem, cerebellum, and upper cervical spinal cord, designated the Chiari II malformation (Fig. 19.28) (26,115,133–135). This malformation presents clinically with hindbrain dysfunction. Historically, the hindbrain dysfunction was severe in 4% to 13% of all patients with myelomeningocele (136) (7% of infants and 2% of older patients) (75,136). Recent decades have brought significant improvement in the prognosis of patients with myelomeningocele (78). In an older cohort born in 1975 to 1979, mortality at the 20- to 25-year follow-up was 24% and continued to increase into young adulthood. A majority of the deaths occurred from hindbrain dysfunction during infancy and the preschool years (78). In a younger cohort born in 2000–2004, none of the children died during infancy or in the preschool years, and few required posterior fossa decompression, tracheostomy, or gastrostomy (78). The specific clinical signs of hindbrain dysfunction show very similar frequencies in different series (Table 19.3). Apnea may result from bilateral abductor vocal cord paralysis (obstructive apnea), from central neural dysfunction (centrally mediated expiratory apnea with cyanosis) (138), or from both together.

FIGURE 19.28 Chiari II malformation. Medullary protrusion and the cervicomedullary kink in an 11-month-old boy. A: Left lateral view of the uncut hindbrain. B: Midsagittal section of the same brain (larger field of view includes corpus callosum). Anterior is to the reader’s left. White arrows indicate the position of foramen magnum. Large white arrowhead indicates the site of the posterior arch of C1. The Chiari II medulla (M) protrudes below foramen magnum and C1 into the cervical spinal canal. The medulla buckles dorsal to the cervical spinal cord and forms a kink (crossed white arrow), where it forces the upper cervical cord to recurve on itself and forms a spur (double-crossed white arrow) at the true cervicomedullary junction. The medullary hernia overlaps the cervical cord. The fourth ventricle (small white arrowheads) is greatly elongated, extends into the cervical canal, and widens there. Choroid plexus (open white arrowheads) lies along the dorsal aspect of the intraspinal fourth ventricle. The vermis protrudes downward through the large foramen magnum, rests on the posterior arch of C1 (large white arrowhead), and extends a tongue or peg of tissue (V) through the C1 ring dorsal to the medulla and fourth ventricle. Note the sharp notch (large white arrowhead) where the posterior lip of the C1 ring indents the vermian peg. The cerebellar hemispheres (H) pass anteriorly to lie in front of and encompass the brainstem. Also demonstrated are the beaked midbrain (m) and the pons (P). (From Naidich TP, McLone DG, Fulling KH. The Chiari II malformation. Part IV. The

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hindbrain deformity. Neuroradiology 1983;25:179–197, with permission.)

TABLE 19.3 Clinical Signs of Chiari II Hindbrain Dysfunction

Multiple theories have tried to explain the diffuse manifestations of the Chiari II malformation and myelomeningocele (26,139). McLone and Knepper (139) presented experimental data suggesting that the Chiari II malformation could be the result of diversion of ventricular CSF to the amnion with consequent “collapse” of the developing ventricular system. The McLone–Knepper theory is based on the following facts: 1. The fluid-filled space of the developing brain and spinal cord is called the neurocele. 2. The medial walls of the thoracic neural tube normally appose and occlude the neurocele transiently during central nervous system (CNS) development in humans, mice, and chicks. 3. Experimental animals with distal myelomeningocele fail to occlude the neurocele, even at sites remote from the myelomeningocele. 4. This failure to appose the walls appears to result from the same biosynthetic defect in cell-surface glycosaminoglycans which prevents the neural tube from closing. That is, the mechanism that causes failure of neurulation also causes failure of apposition of the medial walls of the neurocele. Based on these findings, the theory proceeds as follows. 5. Because the neurocele is not occluded, CSF passes freely down the central canal and out the myelomeningocele to the amnionic cavity. 6. This abnormal shunt collapses the developing primitive ventricular system. 7. Therefore, the volume of the ventricular system and surrounding neural tissue is less than normal. 8. The mesenchyme condenses in relation to an abnormally small volume of developing CNS. This establishes a smaller-than-normal posterior fossa with low tentorium. 9. The developing CNS must then grow within an envelope of membrane, cartilage, and bone that is too small for it. 10. This leads to failure to form the pontine flexure, downward growth of the cervicomedullary junction, medulla, and cerebellum through the foramen magnum, and upward growth of the cerebellum through the incisura. 11. Reduced size of the third ventricle means closer approximation of the thalami with larger massa intermedia. 12. Collapse of the cerebral ventricles leads to disorganization of the developing hemispheres with gray matter heterotopias, disorganization of cerebral gyri, and dysgenesis of the corpus callosum. 13. The collapse of the ventricular system leads to disordered development of the membranous bone of the vault (139). Normally, the skull develops from centers in each cranial plate. As the brain expands, the collagen bundles are drawn out from those centers in an orderly radial fashion, much like the uniform expansion of the surface of an inflating balloon. As radial expansion proceeds, the collagen bundles become calcifiable and membranous bone forms. Failure to distend the brain mass by increasing volumes of CSF causes disordered arrays of collagen bundles. Thus, instead of radial lines of collagen, whorls, and coils of collagen form with varying density between them. 1442

Ossification of this disorganized collagen mat then leads to lükenshädel. In accord with the McLone–Knepper hypothesis, a study of 56 children with repaired myelomeningocele documented that the smaller size of the Chiari II posterior fossa and the reduced volume of the Chiari II cerebellum are both directly and linearly related to the level of the myelomeningocele (140). Further, the extent to which the cerebellum descends into the spinal canal is inversely related to the level of the myelomeningocele. These relationships strengthen in patients with no syringomyelia and are not significant in those groups with syringomyelia (140). In the Chiari II malformation the upper cervical cord is displaced caudally, so that the cervical nerve roots ascend retrograde to their exit foramina. The brainstem is also displaced caudally, so that the medulla and even the low pons lie within the cervical spinal canal. The medulla may descend purely vertically, so it remains in line above the spinal cord (30%). More commonly, the medulla buckles backward and downward as it descends, forcing the dorsal surface of the uppermost cervical cord to kink back on itself (the “kink”) and forming a spur of tissue at the cervicomedullary junction (the “spur”) (70%) (Figs. 19.28 and 19.29). The cuneate and gracile tubercles at the upper ends of the dorsal columns form the apex of the spur and point caudally, not cephalically. Emery and MacKenzie (115) demonstrated that the deformities at the cervicomedullary junction form a spectrum of pathology that falls into five major groups. In order of increasing severity (Fig. 19.29), these can be categorized as follows: Group A: In 4% of Chiari II patients the medulla and fourth ventricle do not descend below foramen magnum. The sole evidence of hindbrain deformity is mild inferior displacement of the spinal cord with ascending course of the cervical nerve roots. Group B: In 26% of cases, the medulla and fourth ventricle descend vertically, in line with and above the displaced cervical cord. In these cases the fourth ventricle leads directly inferiorly into the central canal of the cord (Fig. 19.30). Group C: In another 26% of cases the medulla shows mild buckling behind the cervical cord, so there is less than 5 mm of overlap of medulla on cord. Because of the buckling, the fourth ventricle lies partly behind the cord, and the central canal arises from the anterior surface of the cord.

FIGURE 19.29 Diagrammatic representation of the spectrum of cervicomedullary deformities in the Chiari II malformation. Lateral views oriented with anterior to the reader’s left. A–E: Graded series of increasingly more severe deformities discussed fully in the text. Curved lines at the top indicate the foramen magnum. Black shading indicates the fourth ventricle and central canal of the spinal cord. (From Emery JL, MacKenzie N. Medullo-cervical dislocation deformity Chiari II deformity related to neurospinal dysraphism meningomyelocele. Brain 1973;96:155– 162, with permission.)

Group D: In 23% of cases the medulla shows greater buckling, with greater than 5 mm overlap of medulla behind the cord (Figs. 19.25A and 19-28A). Group E: In a further 21% of cases, severe buckling of medulla is associated with a saclike process or diverticulum of the dorsal surface of the fourth ventricle. This protrudes behind the cord caudal to the kink (Fig. 19.31). The fourth ventricle descends with the brainstem and forms a craniocaudally elongated tubular structure that lies partially within the posterior fossa and partially within the spinal canal. The choroid plexus of the fourth ventricle may protrude inferior to the cerebellar tail to present as a contrastenhancing nodule (141). Structural lesions may be found within the Chiari II fourth ventricle, including arachnoid cysts, glial or choroidal nodules, and subependymomas (142). These lesions may be developmental or may arise in reaction to the chronic compression and ischemia (142).

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FIGURE 19.30 Chiari II malformation in a 9-month-old boy with myelomeningocele (see also 19-29B). Sagittal T2 MRI of the low posterior fossa and upper cervical spinal canal displays prominent concavity of the basiocciput (BO), low position of the medulla (M), thin elongated fourth ventricle (4), and protrusion of the vermis into the spinal canal below C3 (3). BS, basisphenoid; P, pons.

FIGURE 19.31 Chiari II malformation in a 2-month-old one with myelomeningocele (see also 19-29A). Sagittal T2 MRI displays a dilated third ventricle (3), kinked aqueduct with beaked tectum (black arrow), thin elongated fourth ventricle (4), caudal protrusion of the brainstem and vermis into the spinal canal, and a cystic elongation (c) of the 4th ventricle into the spinal canal, inferior to the vermis. Note inferior wall of cyst (white arrow), separate from the subarachnoid space. M, midbrain; P, pons.

The cerebellum usually protrudes caudally into the spinal canal behind the medulla. The major portion of the cerebellum that protrudes below the foramen magnum cannot fit into the C1 ring and appears to rest or “sit” on the posterior arch of C1. A smaller, thinner portion of cerebellum, designated the cerebellar “peg,” “tongue,” or “tail,” does extend further caudally within the C1 ring. Typically, the peg is formed by the nodulus (most inferiorly), the uvula (more superiorly), and the pyramis (often situated within the foramen magnum). The length of the peg is variable and does not correlate with the length of the medullary spur. In 75% of cases, the cerebellar tail terminates cephalic to the kink (Fig. 19.28). In 25%, the tail extends below the kink, behind the lower cervical cord. The overlapping herniations of cerebellum on medulla and of medulla on cord form a “cascade” of hernias, each of which displaces anteriorly and compresses all structures ventral to it. All the herniations are compressed in turn by impaction in foramen magnum and the small C1 ring. Because the tentorium is low in position, the midbrain is subjected to pressure from the distended hydrocephalic atria. This bilateral lateral pressure molds the tectum of midbrain into a conical “beak.” Numerous other anatomic 1444

distortions, also present, are delineated elsewhere (26,134,135,143,144). Curnes et al. (144) reported that 75% of myelomeningocele patients with symptomatic Chiari II malformation manifested a spur at C4 or below. No asymptomatic patient exhibited a spur lower than the C3–C4 level (144). Gilbert et al. (143) found evidence of brainstem dysplasia in 76% of 25 symptomatic myelomeningocele children evaluated pathologically at postmortem, including foci of abnormal myelination and hypoplasia/aplasia of cranial nerve nuclei, basal pontine nuclei, the olivary nuclei, and the tegmentum. The anatomic changes of the Chiari malformations are summarized in Cesmebasi (145). Cervical Myelomeningocele and Myelocystocele The cervical myelomeningocele and myelocystocele are two lesions that appear to arise by a common mechanism. Many authors (16,45,146–150) have suggested that these malformations develop when there is incomplete fusion of the neural folds, causing a narrow dorsal myeloschisis and incomplete disjunction of epidermal from neural ectoderm (Fig. 19.32). As a result, there is a weak, incomplete dorsal neural wall that is still adherent to the epidermal ectoderm. If there is significant hydromyelia, dilation of the central canal might cause the thinned dorsal wall of the cord to balloon backward. Because the meninges form in relation to the external surface of the neural tube, they would surround the ballooned neural tube, except at the dorsal midline. This would create a meningeal sac around the posteriorly bulging neural tube. The mesenchyme would then condense and mature around these structures, leaving a narrow spina bifida, through which the neural tissue would appear to herniate into the meningocele sac. A lesion of this type is designated cervical myelocystocele (syringocele). If there is no hydromyelia, the dorsal neural–epidermal connection might involute to a fibroglioneural stalk. Nearly complete involution of the stalk could lead to a form of meningocele manqué. Variably complete involution of the stalk and outward bulging of the meninges might form a meningocele that is traversed by a fibroglioneural stalk. Condensation and development of the mesenchyme around such a complex could then result in a skin-covered cervical myelomeningocele. With variation, the stalk could insert into the apex, the base, or one wall of the meningocele, and fibroglioneural nodules could persist along the wall of the sac. The pathogenesis of these cervical malformations closely resembles the pathogenesis of dorsal dermal sinuses (discussed in the next section). In cervical myelomeningoceles and myelocystoceles, a partial neural–epidermal adhesion draws the neural tissue outward toward the skin, whereas in dermal sinuses, a partial neural–epidermal adhesion draws the skin inward toward the neural tissue. Both types of lesions may exhibit partial dorsal myeloschisis. To date, however, no unifying theory has been elaborated to explain all of these malformations coherently. Children with cervical myelocystocele form a special group of myelomeningocele patients (3.7%) who present with a tough, skin-covered midline cervical mass and (nearly) normal neurologic function (151). The base of their lesion is covered by full-thickness skin, whereas the dome is covered by thick squamous epithelium (151). The spinal cord remains within the spinal canal but is tethered to the myelomeningocele by a midline or paramedian fibrous septum or by a band composed of neurons, glia, fibrous tissue, and peripheral nerves (Fig. 19.33) (146). The fibroglioneural band passes through a narrow cervical spina bifida to insert into small glial islands or into glial–neural disks along the adjacent dura or intrasaccular soft tissue. Treatment of these lesions requires opening the dura, with lysis of all adhesions and fibroneurovascular connections, lest the children deteriorate in the years after surgery (146). Clinically, these two groups of patients present differently. Patients with cervical myelomeningocele show no obvious neurologic deficits at birth, although they may develop mild orthopedic problems (147). Patients with myelocystocele develop motor deficits in the first year and show significant orthopedic problems, although sensory and urologic deficits are rare (147). The myelocystocele may be associated with Chiari II malformation (70), hydrocephalus, ectopic cerebellar tissue, and diastematomyelia (151,152). Dorsal Dermal Sinus If the superficial ectoderm fails to separate from the neural ectoderm at one point, then a focal segmental adhesion is created. As the spinal cord becomes buried beneath the surface by the developing spinal column and as different rates of growth between neural and spinal tissue lead to “ascent” of the cord, the local adhesion or “spot-weld” is drawn out into an elongated epithelial-lined tube that still connects the spinal cord with the skin of the dorsal surface of the child (Fig. 19.34) (1,5,153). Such an 1445

elongated segmental epithelial tract is designated a dorsal dermal sinus. The points of attachment of skin and cord remain segmental or metameric, and so the dermatome of involvement predicts the site of neural abnormality. In Wright’s collected series of 127 dermal sinuses (154), 57% were lumbosacral and 24% were occipital. The rest occur at uncommon sites. Dermal sinuses are found in 1 per 1,500 to 2,500 newborns (155–157). Males and females are affected equally. Clinically, the sinus most frequently appears as a pinpoint hole or a small atrophic zone in the skin. The sinus ostium is typically midline but may be paramedian in unusual cases. A tuft of short, sparse, wiry hairs may emerge from the ostium (153). Small hemangiomas commonly adjoin or surround the ostium (Fig. 19.35). Typically, the dermal sinus tract extends inward from the skin surface for a variable depth (Fig. 19.36). The deep end of the dermal sinus/stalk most commonly ends at the conus (9/14, 64%) or intradural portion of the filum terminale (4/14, 29%), but may end “short” at the dura mater (1/14, 7%) (158). In its course the dermal sinus passes deeply through the subcutaneous layer and through the median raphe (or between bifid laminae) toward the dura. It may end superficial to the dura, at the dura, or deep to the dura. In one-half to two-thirds of cases, the tract extends into the spinal canal (1,154,155,159). A small midline sleeve of dura and arachnoid, directed dorsally, marks the point at which the tract attaches to or penetrates the dura (Fig. 19.36). Rarely, the tract ends in the subarachnoid space as an open tube through which CSF discharges and through which infection may ascend retrograde to the spinal canal (159). Such infection may lead to arachnoiditis, epidural/subdural abscess, and intramedullary spinal cord abscess (160–162). The dermal sinus may also end in a fibrous nodule among the roots of cauda equina. In up to 60% of cases, the tract incorporates or ends in one or multiple dermoid or epidermoid tumors (Fig. 19.37). Approximately 25% of all spinal (epi)dermoids are associated with dermal sinuses (16). The (epi)dermoids may act as masses. Cyst rupture may cause sterile chemical meningitis and obliterative arachnoiditis. Lumbosacral dermal sinuses are usually associated with tethering of the spinal cord and low position of the conus (80%) (16,24). Thoracic and cervical dermal sinuses do not appear to influence conal position but may still produce symptoms by local cord tethering (163). Some 15% to 20% of patients with dermal sinus have concurrent lipoma, and vice versa, presumably because both lesions result from deranged disjunction of cutaneous from neural ectoderm (Fig. 19.38). Such an error in disjunction could lead to failed disjunction (dermal sinus), premature disjunction (spinal lipoma), or both at adjacent sites. Imaging studies typically demonstrate the small depression in the skin at the ostium. The extraspinal portion of the dermal sinus tract may appear as a single line or as double parallel (railroad) lines that traverse the midline and correspond to the lumen and walls of the tract (164). Infrequently, the tract is filled by the included (epi)dermoid. Lumbosacral sinuses typically first course inferiorly and ventrally as they pass from the skin surface to the lumbodorsal fascia. They then abruptly reverse direction to course superiorly as they pass further ventrally into the spinal canal (Figs. 19.38 and 19.39). Less commonly, the superficial portion of the tract appears horizontal or even ascends from the skin toward the spine. The precise course may depend on the degree of lumbar lordosis and the position of each sinus with respect to that curvature.

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FIGURE 19.32 Cervical myelomeningocele and cervical myelocystocele: proposed embryogenesis. Diagrammatic representations. The two forms of cystic cervical malformations begin as limited dorsal myeloschisis of the developing cervical cord and evolve differently in response to the presence or absence of hydromyelia. A: Limited dorsal myeloschisis. The dorsal neural tube fuses incompletely, and the epidermal ectoderm disjoins incompletely from the neural ectoderm. B,C: Cervical myelocystocele. Hydromyelia (B) distends the central canal and bulges it posteriorly. Subarachnoid cerebrospinal fluid forms a meningocele around the entire neural tube, except where the partly closed neural tube is adherent to the epidermal ectoderm in the midline. This results in a cervical myelocystocele in continuity with the central canal of the cord (C), within a meningocele that is continuous with the subarachnoid space. Condensation and development of the perineural mesenchyme create a narrow spina bifida traversed by the thinned, ballooned, dorsal wall of the neural tube and the surrounding meninges. D,E: Cervical myelomeningocele. In the absence of hydromyelia, the dorsal wall of the partly closed neural tube begins to regress and narrow, leaving a dorsal neural stalk that is still adherent to the surface (D). The subarachnoid space bulges dorsally to produce the meningocele. This results in an intracanalicular spinal cord tethered to the wall of the meningocele (E), either in the midline as shown here or at the base of the meningocele sac. Compare with the embryogenesis and development of the dorsal dermal sinus (Figs. 19.34–19.37). (Modified from Sun JCL, Steinbok P, Cochrane DD. Cervical myelocystoceles and meningoceles: long term follow-up. Pediatr Neurosurg 2000;33:118–122; Steinbok P, Cochrane DD. Cervical meningoceles and myelocystoceles: a unifying hypothesis. Pediatr Neurosurg 1995;23:317–322; and Steinbok P. Dysraphic lesions of the cervical spinal cord. Neurosurg Clin N Am 1995;6:367–376, with permission.)

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FIGURE 19.33 Cervical meningocele in an untreated 1-day-old boy. A: Sagittal T1-weighted magnetic resonance imaging (MRI). B: Axial T1-weighted MRI. No Chiari II malformation is evident. The low cervical meningocele traverses a narrow midline spina bifida (arrowhead). The adjacent portion of the cervical cord is enlarged sagittally and pointed posteriorly, indicating tethering to the sac. Inhomogeneous signal within the sac represents pulsations and proteinaceous material; no neural tissue was found within the sac at surgery.

The intraspinal portion of the tract is hard to identify. It may be indistinguishable from the filum or from the roots of cauda equina unless it is expanded by (epi)dermoids or contains fat (16). In one series of 28 dermal sinuses, females predominated (F:M = 17:11) (165). The sinuses were most commonly found in the lumbosacral (9), lumbar (9), thoracic (5), and cervical regions (4). One dermal sinus at L3 was associated with an additional coccygeal pit at L5. In one patient, two cutaneous openings overlay a single tract (165). Cutaneous stigmata were present in 27 of the 28 cases (165). Nineteen of the 28 cases (68%) had neurological deficit on initial examination, including motor weakness (11), sensory change (7), reflex changes (15), gait changes (5), decreased sphincter tone (6), or difficulty with bladder and bowel function (4) (165). Infection was present in three: two with infected skin lesions and one with a history of H. influenza meningitis (Fig. 19.39) (165). Patients with dermal sinuses commonly show concurrent vertebral anomalies (Table 19.4) (165).

FIGURE 19.34 Proposed embryogenesis of dorsal dermal sinus by incomplete disjunction. Diagrammatic representation. Focal failure of epidermal ectoderm (c) to disjoin from neural ectoderm (NE) results in a persistent segmental adhesion (arrows). As the mesenchyme migrates dorsally to thicken the retroneural tissue and as the cord ascends, this adhesion is drawn out into a long epithelial-lined tube. M, mesenchyme; cc, central canal. (From Naidich TP, Gorey MT, Raybaud C, et al. Malformations congénitales de la moelle. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

Recently, there has been an impetus to distinguish “true” dermal sinus tracts from dermal sinus–like stalks (166). True dermal sinus tracts are held to consist of a hollow, epithelium-lined tract lined by stratified squamous epithelium. This extends inward from the skin surface for a variable distance. Three key features of true dermal sinuses are (1) an open skin defect, (2) the common concurrence of (epi)dermoid inclusions along the tract, and (3) frequent infections (166). Conversely, dermal sinus–like stalks exhibit a skin dimple or a translucent layer of thinned skin, with no ostium (166,167). They have no lumen and no concurrent inclusion cysts. They consist instead of mesodermal elements such as connective tissue, fat, muscle, and nervous–dural elements. Because there is no hollow lumen, infection is very rare (166). Further, in two large series, the conus medullaris was found to be in low position more commonly with a dermal sinus–like stalk (90.5%) than a true dermal sinus (38.5%) (158,167). The embryogenesis of such stalks is not yet determined. 1448

FIGURE 19.35 Dorsal dermal sinus in a 1-month-old boy. Posterior view of the patient reveals the typical midline lumbosacral hemangioma. The hemangioma surrounds a small atrophic dimple that was the external end of the dermal sinus in this patient. These stigmata lie well above the anus and coccyx.

FIGURE 19.36 Dorsal dermal sinus. Diagrammatic representation. Note the cutaneous ostium, variable uncommon presence of a small tuft of wiry hairs protruding from the ostium, the course of the tract to the lumbodorsal fascia through the median raphe (or between bifid spinous processes), and passage of the tract through the dura and arachnoid, leaving a small triangular dorsal outpouching of the meninges akin to a root sleeve. The tract may then ascend within the spinal canal, incorporate one or several (epi)dermoid lesions, and end (variably) in an (epi)dermoid at the conus. The ascent of the extraspinal component of the sinus tract shown here is unusual in imaging studies. It may represent, in part, Matson’s experience with placing the patient in a prone flexed position for surgery. In our experience, imaging studies routinely show that the extraspinal component of the tract passes inferiorly and ventrally to the lumbodorsal fascia, before the deeper portion turns upward to ascend within the spinal canal (see Fig. 19.34). (From Matson DD. Neurosurgery of infancy and childhood. 2nd ed. Springfield, IL: Charles C Thomas; 1969, with permission.)

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FIGURE 19.37 Dorsal dermal sinus in a 22-month-old boy. Pathologic specimen resected in toto. From the skin surface (arrowheads), the tract passed ventrally through the subcutaneous fat to the lumbodorsal fascia, traversed the spina bifida, pierced the dura (arrow), ascended within the thecal sac, expanded into a dermoid (curved arrow) within the distal thecal sac, and then continued as a tract toward the conus, where it was ligated and resected.

FIGURE 19.38 Dorsal dermal sinus and lipoma in a young child. Sagittal T1 (A) and T2-weighted (B) magnetic resonance imaging (MRI). The superficial portion (arrowheads) of the dermal sinus descends from the skin surface to the deep lumbodorsal fascia (small arrowheads). The sinus then penetrates the fascia, traverses the sacral spina bifida, and inserts into the inferior aspect of the spinal cord, tethering it. A concurrent spinal lipoma (Li) lies along the dorsal aspect of the cord at L4–L5, just superior to the insertion of the dermal sinus. C: Axial T1-weighted MRI at L4– L5. The lipoma (Li) lies solely along the dorsal surface of the tethered cord.

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FIGURE 19.39 Dorsal dermal sinus and infection in a young child. Sagittal T1-weighted (A,B) and T2-weighted (C) magnetic resonance images reveal the oblique descending course of the superficial portion of the dermal sinus (arrowhead), slightly low position of the conus medullaris, and obliteration of much of the distal thecal sac by inflammatory debris. Ascending inflammatory changes alter the texture and signal of the distal cord.

Coccygeal Dimples Coccygeal dimples (synonyms: coccygeal pits, sacral dimples, pilonidal sinuses) are midline or pairedparamedian depressions and pits found in the skin overlying the low sacrum or coccyx in 2% to 6% of infants (Figs. 19.40 and 19.41) (155,168–171). They are classified as shallow if the bottom is visible, and deep if the bottom is not visible (172). Deep dimples typically extend inward for a variable distance and may reach to the dorsal surface of the coccyx (Fig. 19.42). In one series, shallow dimples and deep gluteal creases were seen in 4.3% of 1997 consecutive term newborns (155). Deep dimples were seen in an additional 1.4% of newborns (155). Analysis of 3,884 high-resolution (8 to 14 MHz) spinal sonograms performed for sacral dimple at two hospitals over a 12-year period disclosed 133 cases (3.4%) abnormal for low cord position, decreased motion of cord or roots, or abnormal filum terminale. Only 5 of these 3,844 patients (0.13%) were judged to merit surgical intervention, revealing four tethered cords and one enlarging ventriculus terminalis with reduced cord motion (173). Martinez-Lage et al. (167) found concurrent separate coccygeal pits in 3 of 8 children with true dermal sinus tracts, but no coccygeal pits in 12 children with dermal sinus–like stalks. De Vloo et al. (158,165) found a coccygeal pit in one of five patients (20%) with dermal sinuses and one of nine patients (11%) with dermal sinus–like stalks. Similarly, Ackerman and Menezes (165) found a coccygeal pit in 1 of 28 patients (4%) with dermal sinus. However, Harada’s (172) review of MR scans in 84 patients with sacral dimples revealed concurrent lipoma of the filum terminale in 14 patients (16.7%), 5 of 58 with shallow dimples (8.6%), and 9 of 26 with deep dimples (34.6%). For these reasons, we use spinal sonography to scan such patients during the first 6 weeks of life, when possible, or MR thereafter. TABLE 19.4 Radiographic and Operative Findings in 28 Patients with Dermal Sinus

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FIGURE 19.40 Sacral dimple in a 1-month-old girl. An ostium situated near to the anus may be a “sacral” dimple or a dorsal dermal sinus.

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FIGURE 19.41 Deep coccygeal dimple in a 3-year-old girl. The tract extends caudally to reach the coccyx.

FIGURE 19.42 Sacral dimple in a 2-month-old girl. Axial T1-weighted magnetic resonance imaging demonstrates that the dimple and tract (arrow) run directly to the coccyx (c) and thus that the lesion is a sacral dimple, not a dermal sinus tract.

Unless infected, sacral dimples cause no difficulty and are not directly associated with cord tethering or intraspinal anomalies (171). If infected, sacral dimples may cause painful local abscesses, requiring drainage or excision. Uncommonly, spread of infection from such an abscess may lead to meningitis and even death (155). Dermoid and Epidermoid Tumors Traditionally, a distinction has been made between epidermoid and dermoid cysts. Epidermoid cysts are masses lined by a membrane composed only of superficial (epidermal) elements of the skin. Dermoid cysts are unilocular or multilocular cystic masses lined by a simple or stratified squamous epithelium that contains skin appendages such as hair follicles, sweat glands, and sebaceous glands. More recently, it has been held that both epidermoids and dermoids derive from ectodermal elements (174). These (epi)dermoid tumors may arise as congenital rests in the absence of dermal sinuses (Fig. 19.43) or as the result of iatrogenic implantation of viable skin elements during back surgery or during spinal taps performed with needles without a trocar (1). Approximately 25% of (epi)dermoid tumors form in association with dermal sinuses (1,160). Spinal dermoid and epidermoid tumors constitute about 15% of all CNS (epi)dermoids, a cranial-tospinal ratio of 6:1 (103). They account for 1% to 2% of spinal cord tumors in patients younger than the age of 15 years (175). Dermoid and epidermoid tumors occur equally frequently (175). Approximately 40% are single epidermoids, 35% are single dermoids, and 5% are multiple dermoid or epidermoid tumors. In the series of Lunardi et al. (175), epidermoids were most frequently lumbar in location; dermoids were most frequently thoracic (25%) or thoracolumbar (75%). Thirty-eight percent were intramedullary, and 63% were intradural extramedullary (175). Of (epi)dermoids associated with dermal sinus, approximately 60% have both intramedullary and intradural extramedullary components 1453

(16). In van Aalst’s (176) series of 18 (epi)dermoids, 5 were associated with dermal sinuses, 9 with repaired myelomeningoceles, 1 with spinal lipoma, 2 with unspecified dysraphisms, and 1 (5.6%) with no concurrent malformation. By location, 2 were thoracolumbar, 2 lumbar, 10 lumbosacral, and 4 sacral (176). One was intraspinal extradural, nine were intradural, and eight intramedullary. All those associated with dermal sinuses were lumbosacral (176).

FIGURE 19.43 Intraspinal epidermoids in a 12-year-old boy. Sagittal magnetic resonance images: T1-weighted image (A), proton density-weighted image (B), and T2-weighted (C) image. Well-defined ovoid masses are related to the dorsal aspect of the conus medullaris at T12–L1 and to the cauda equina at L3–L4. No dermal sinus was identified on imaging studies or at surgery. D: Operative exposure after opening the dura in the midline reveals the two separate epidermoids (black arrows).

Most dermoid and epidermoid tumors are homogeneously isointense to CSF or spinal cord on T1- and T2-weighted MRI. Specific analysis of signal intensity in 17 noninfected (epi)dermoids showed that on T1-weighted images 7 lesions were isointense to CSF, 8 were isointense to spinal cord, and 2 were hyperintense to spinal cord. On T2-weighted images, 13 lesions were isointense to CSF and 4 isointense to spinal cord. Five of the 17 tumors were isointense to CSF on both T1- and T2-weighted images (176). A few (epi)dermoids showed heterogeneous signal (176). For these reasons, (epi)dermoids may be 1454

difficult to discern within the spinal canal. Intramedullary components do stand out in relation to the expanded cord (16,177), but extramedullary components may be invisible or poorly detectable on routine MR series, though readily demonstrable by diffusion-weighted sequences (16). Fat-containing portions of dermoids will typically manifest as lesions with high signal on T1 series and reduced signal on T2 series (178). Infected (epi)dermoids exhibit intense contrast enhancement within the tumor and at other sites to which the inflammation may spread (160,179,180). Spinal Lipoma By definition, spinal lipomas are distinct collections of fat and connective tissue that are at least partially encapsulated and have a definite connection with the spinal cord (1,27,181,182). They exhibit a gradient of fat and fibrous tissue, with larger proportions of fat superficially and larger proportions of fibrous tissue deeply, closer to the liponeural junction. Spinal lipomas are the most common type of occult spinal dysraphism and account for 35% of skin-covered lumbosacral masses (Fig. 19.44). Typically, the mass lies in the midline just cephalic to the intergluteal crease (Fig. 19.44) and extends caudally, asymmetrically, into one buttock. Spinal lipomas are found in approximately 1 per 4,000 newborns (183,184). Nearly all cases are sporadic. Familial spinal lipomas are exceptionally rare (183,185,186). The lipomas are equally common in males and females (187). The chief complaints are usually a mass on the back (59%), urinary incontinence (23%), or weak/deformed lower extremity, perhaps with trophic ulceration (11%) (Table 19.5) (188). In combined series of 177 spinal lipomas, physical examination disclosed a soft tissue mass in 100%, skin dimple in 23%, hemangioma in 19%, hairy patch in 7%, skin tag in 6%, hypopigmented patch in 3%, and atretic/denuded skin patch in 0.6% (189). Those patients with prominent subcutaneous lipomas and cutaneous stigmata (Table 19.6) are usually identified at a young age. Patients who are “missed” early on may present at older ages with neurologic deterioration (189,190).

FIGURE 19.44 Spinal lipoma in a 1-month-old girl. Photograph of the patient’s back reveals a skin-covered lumbosacral mass situated cephalic to the intergluteal cleft in the midline and extending asymmetrically to the reader’s right. (Same patient as in Fig. 19.51.) (From Naidich TP, McLone DG, Mutleur S. A new understanding of dorsal dysraphism with lipoma (lipomyeloschisis): radiological evaluation and surgical correction. AJNR Am J Neuroradiol 1983;4:103–116, with permission.)

TABLE 19.5 Preoperative Symptomatology and Postoperative Results in 87 Symptomatic Children with Lipoma of the Conus Medullaris

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TABLE 19.6 Cutaneous Stigmata in Spinal Lipoma

McLone et al. (1,191) suggested that spinal lipomas result from focal premature disjunction of epidermal ectoderm from neural ectoderm as follows: If the superficial ectoderm separates from the neural ectoderm prematurely, before the neural tube has closed completely, then mesenchyme may gain access to the interior of the closing neural tube (Fig. 19.45). Such mesenchyme could prevent closure of the neural tube focally, leading to dorsal myeloschisis. The dorsal and ventral surfaces of the closing neural plate are fundamentally different and are postulated to induce mesenchyme to differentiate in two distinct ways (Fig. 19.46). The mesenchyme adjacent to the dorsal surface of the closing plate (i.e., the future interior of the cord) is induced by the dorsal surface to form fat. This fat would “insert” into the entire dorsal surface of the neural plate. It would fill the complete dorsal cleft. Its lateral extent would necessarily be limited by the lateral edge of the dorsal surface, because only the dorsal surface would induce differentiation of the mesenchyme into fat. 1456

FIGURE 19.45 Spinal lipoma. Proposed embryogenesis by focal premature disjunction of epidermal from neural ectoderm. The mechanism proposed is detailed in the text. Labels as in Figures 19.3 and 19.4, except that curved arrows are also used to indicate the course of mesenchyme migrating through the focal disjunction to the dorsal surface of the closing neural folds.

The mesenchyme surrounding the ventral surface of the closing plate (i.e., the future exterior of the neural tube) is induced by the ventral surface to form meninges. The dorsal-medial extent of the meninges would be limited by the lateral margin of the ventral surface at the neural ridge, because only the ventral surface would induce differentiation of the mesenchyme to meninges. Therefore, the meninges would attach to the neural tissue laterally, exactly at the neural ridge. No meninges would form in the midline dorsally, because there is no ventral surface to induce them there, unless successful neurulation closes the folds into a tube. This would leave a midline dorsal defect in the meninges. Similarly, improper neurulation would prevent proper development of the neural arches, fascia, and muscle, creating a posterior spina bifida. The fat induced by the dorsal surface of the neural plate could then extend directly posteriorly, through the gap in the meninges and through the spina bifida into the subcutaneous tissue of the back. The fat would be anatomically extradural. The junction of fat and meninges would necessarily lie at the neural ridge that divides the dorsal and ventral surfaces of the neural folds. Depending on the degree of spina bifida, the size of the spinal canal and the subarachnoid space, and the volume of the lipoma, the spinal cord, and placode could remain in the canal, herniate partially, or herniate completely. The liponeural junction could be intracanalicular or extracanalicular. Depending on whether the premature disjunction was unilateral or bilateral, the spinal lipoma could be asymmetric to either side or nearly midline. Depending on “packing” considerations, the lipoma could remain truly posterior to the placode or could bulge laterally, bilaterally, to compress the posterolateral borders of the placode. The dorsal surface of the placode could rotate to either side or become folded. The mechanism of premature disjunction and the subsequent mechanical effects considered previously appear to account for all of the features observed in spinal lipomas that involve the portion of the cord formed by neurulation (1,27,192). Because the process of neurulation creates all of the spinal cord except the distal most conus medullaris and filum terminale, premature disjunction could account for all spinal lipomas affecting the midconus or higher. Lipomas that involve the distal conus and filum must be explained differently, as a disorder of secondary neurulation. Spinal lipomas are usually considered in three groups: lipomas with intact dura, lipomas with deficient dura, and filar lipomas. (See later section on Secondary Neurulation for discussion of filar lipomas.) Spinal Lipomas with Intact Dura The intradural lipomas are a small group of intramedullary tumors that appear to arise in the dorsal midline of a cleft spinal cord and then bulge outward to form subpial masses of fat (Figs. 19.47A and 19.48). They constitute approximately 4% of the lipomas in our series and affect the cervical and thoracic spinal cords predominantly (1,103,186,193). They may constitute 6% to 20% of lipomas in the lumbosacral region (186,194). In this group the spinal column is usually nearly normal with narrow spina bifida or focal segmentation anomalies (Fig. 19.49). The spinal canal may be expanded by the mass. The dura is thinned, perhaps translucent, but remains intact and is displaced peripherally by the combined mass of cord and lipoma (Fig. 19.48). The lipoma typically lies dorsal or dorsolateral to the cord, and frequently causes cord rotation and high-grade stenosis or block. The upper or lower pole of the lipoma may protrude from the surface of the cord as an exophytic intradural extramedullary component of the mass. Subdural lipomas are associated with hydromyelia in approximately 2% of cases (186). Subpial lipomas can be regarded as formes frustes of the more common lipomas. A special 1457

subgroup of intradural lipomas involves the dorsal aspect of the high cervical spinal cord (15%). Nearly half of these (44%) ascend in continuity along the dorsal medulla and may bulge into the fourth ventricle (Fig. 19.50) (195–200). In these cases, cervical and cranial nerve roots are reported to traverse the lipomas en route to their exit foramina (196,199,200). Any concurrent superficial lipomas are not contiguous with the subpial masses (198,199).

FIGURE 19.46 Animal model for spinal lipoma. Axial anatomic sections of 21-day-old myeloschistic chicken embryo with dorsal glycogen body. Myelin stain. Ventral lies toward the top. The relations of the normal avian lumbosacral glycogen body and dura depicted here are believed to be a paradigm for human lipomyeloschisis. A: Intact skin (single-crossed arrow) covers the spina bifida. Bifid laminae (L) are joined by a fibrovascular band (open arrowheads). Dura (black arrowheads) underlies the entire inner surface of the vertebral canal except directly beneath the spina bifida. Instead of crossing under the spina bifida, dura is reflected onto the posterolateral aspect of the neural placode (P) at the ipsilateral neural ridge, just behind the ipsilateral dorsal nerve root entry zone (asterisks). This leaves a median dorsal dural deficiency (DDD). The left and right halves of the neural tissue are joined only ventral to the remnant of the central canal (double-crossed arrow) of the spinal cord. The pia-arachnoid lines the deep surface of the dura and is reflected from the lateral wall of the canal (where it is called arachnoid mater) onto the ventral surface of the neural plate (where it is called pia mater) as one continuous sheet. This is exactly analogous to the arrangement of pia-arachnoid in myelocele and myelomeningocele. The subarachnoid space (SAS) has the shape of a horseshoe, open end directed posteriorly. The subarachnoid space is crossed by multiple arachnoid trabeculae. The normal avian glycogen body (black G) occupies the midline between the dorsal halves of the neural placode and projects posterior to the neural tissue within the dorsal deficiency of leptomeninges and dura. Note that the lateral extent of the glycogen body lies exactly at the neural ridge. White G’s and M’s indicate the dorsal root ganglia and the paraspinal musculature, respectively. B: The neural arch (A) is intact 5 mm cephalad. Paired ventral (V) and dorsal (D) nerve roots arise from the pial surface of the neural tissue. The glycogen body has ascended within the dorsal myeloschisis and within a pocketlike extension of the meningeal defect to underlie the intact laminae of the more-cephalic vertebra. Although the glycogen body appears to be intradural at this level, it remains anatomically extradural. (From Naidich TP, McLone DG, Mutleur S. A new understanding of dorsal dysraphism with lipoma (lipomyeloschisis): radiological evaluation and surgical correction. AJNR Am J Neuroradiol 1983;4:103–116, with permission.)

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FIGURE 19.47 Diagrammatic representations of spinal lipomas. A: Intradural lipoma. The laminae (L) are bifid. The dura (dark line) is intact. The pia-arachnoid (dashed line) encloses the spinal cord and the lipoma. The lipoma lies predominantly within a midline cleft in the dorsal spinal cord but fungates beneath the pia to bulge into the dorsal subarachnoid space (SAS). D, dorsal root; V, ventral root; G, dorsal root ganglion. B: Lipomyelocele. There is posterior spina bifida with everted laminae. The spinal cord is cleft dorsally and oriented like the original unneurulated neural placode (NP) in a nearly coronal plane. The dura (heavy line) inserts into the lateral aspect of the cord just lateral to the edge of the cleft and just dorsal to the entry zones of the dorsal roots (D). The pia and arachnoid (light dashed line) are one continuous membrane that lines the inside of the dura and the ventral surface of the spinal cord, enclosing the subarachnoid space (SAS). This pia-arachnoid membrane also encloses the nerve roots but is not drawn there, to simplify the diagram. The nerve roots arise directly from the cord and traverse the subarachnoid space to their root sleeves. They do not cross through fat. The skin is intact. The lipoma passes ventrally from the subcutaneous space through the spina bifida toward the spinal cord. As it nears the cord, the lipoma becomes increasingly fibrous and inserts along the dorsal face of the cleft, reaching the midline groove that should have become the central canal of the spinal cord. As shown, the lipoma lies entirely outside the dura and the arachnoid. From this site it may ascend into the central canal of the “normal” cord above and/or into the extradural space of the spinal canal. No fat lies within the subarachnoid space. A pseudocapsule usually delineates portions of the superficial surface of the lipoma. C: Lipomyelomeningocele. The basic anatomic relationships remain. Gross expansion of the subarachnoid space (SAS) causes the cord and pia-arachnoid to herniate out of the spinal canal, either symmetrically or asymmetrically. When the lipoma lies partially off midline, it tethers the spinal cord to one side, so that the cord rotates as it herniates posteriorly. The meningocele bulges to the contralateral side. As a consequence the nerve roots on the side of the meningocele are unusually long and easy to mobilize at surgery. The nerve roots on the side of the lipoma may be very short and may pass out of the spinal canal into the neural foramina nearly immediately. Such short roots may be very hard to mobilize at surgery and may themselves limit cord mobility after complete “untethering” of the cord from the lipoma.

Spinal Lipomas with Dural Deficiency The more common form of spinal lipomas involve extension of the spinal lipoma through a dural and osseous defect into the subcutaneous soft tissue of the back (Figs. 19.47, 19.51–19.57). Lipoma Classification Pang et al. classified the spinal cord lipomas that arise outside the filum teminale into three groups on the basis of the relationship of the fat to the neural tissue: dorsal lipomas, transitional lipomas, and chaotic lipomas (187). DORSAL LIPOMAS. In this group, the lipoma–neural interface lies entirely on the dorsal surface of the spinal cord above the conus and sparing the conus (187). The fusion line forms an oval that can be traced entirely around the entry of the lipoma into the cord. The dura attaches to the neural tissue along the ovoid fusion line, so that: (1) the lipoma extends from the subcutaneous tissue into the spinal canal and “enters” the spinal cord through a dorsal dural defect, medial to and dorsal to the attachment of the dura to the neural tissue; and (2) the dorsal nerve roots enter the spinal cord ventral and lateral to the dural attachment, such that the lipoma never contains nerve roots. In these cases the conus and filum are free of lipoma. TRANSITIONAL LIPOMAS (INTERMEDIATE TYPE OF CHAPMAN) (187,201). In this group, the rostral portion of the lipoma is identical to the dorsal lipoma described above. Caudally, however, the transitional lipoma extends obliquely and ventrally to involve the conus. There may or may not be a discrete filum. The lipoma–neural interface may be undulating and tilted, such that the lipoma is very asymmetrical and the neural placode is rotated to one side, even so far as the midsagittal plane. However, the dura still attaches along the lipoma–neural interface, so that: (1) the lipoma still extends 1459

from the subcutaneous tissue into the spinal canal and “enters” the spinal cord through a dorsal dural defect, medial to and dorsal to the attachment of the dura to the neural tissue; and (2) the dorsal nerve roots enter the spinal cord ventral and lateral to the dural attachment. No nerve roots traverse the lipoma (187).

FIGURE 19.48 Operative exposure of intradural lipoma in a 2-year, 11-month-old girl. A: Dissection of midline structures uncovers the intact dura (arrows). The dura is thin and translucent. B: Midline dural incision and retraction of dura (D) with tenting sutures reveals the glistening pia-arachnoid that covers the spinal cord (C) and lipoma (Li). C: After dissection of pia-arachnoid and partial laser vaporization of the lipoma, one sees the insertion of the lipoma (Li) into the midline cleft in the dorsal aspect of the distal cord (C).

FIGURE 19.49 Intradural lipoma. A: Sagittal T1-weighted magnetic resonance imaging (MRI). The dorsal subcutaneous fat, lumbodorsal fascia (black arrows), and posterior spinal elements are intact. The normal dorsal epidural fat appears as discontinuous patches of high signal. The lipoma (Li) lies deep to and is separate from the epidural fat, has a longer continuous extent, and is adherent to the dorsal surface of the distal cord (c) at the conus. 2,3, the L2, L3 bodies. B: Axial T2-weighted MRI. The lipoma (curved arrow) is identified by its markedly reduced signal intensity on T2-weighted images and its location within a partial cleft in the dorsal midline of the cord (arrowheads). The high-signal spinal fluid, dura, and spine are intact posterior to the lipoma. T2-weighted images often show the anatomic relationships of neural tissue, lipoma, spinal fluid, and spinal canal most clearly.

CHAOTIC LIPOMAS. In this group, the cephalic portion of the lipoma may resemble the dorsal type, but the caudal portion passes ventrally to engulf the neural tissue and nerve roots. The lipoma–neural fusion line becomes blurred caudally, and the relation to the nerve roots is variable. This type has a high association with (partial) sacral agenesis (82%) (187). In Pang’s series of 238 patients (excluding filar lipomas), there were 35 dorsal lipomas (14.7%), 185 transitional lipomas (77.7%), and 18 chaotic lipomas (7.6%). There was no gender predilection. Spinal 1460

lipomas are nearly always single lesions. Rarely, two levels of the cord may be affected producing double discontinuous lipomas. Both may be lipomas with dural deficiency, or one may be a filar lipoma (202,203). Surgical Considerations Pang et al. reported that three factors influence the success of surgery and risk of postoperative retethering (187). 1. Residual fat: The amount of residual fat may be determined by MRI 3 months postoperatively. In Pang’s series, 58% had no residual fat, 36% had less than 20 mm3 (typically as small bits wrapped up within the “re-neurulated neural tube”), and 7% had more than 20 mm3 of residual fat (especially those with chaotic lipomas) (187). 2. Success of detachment of the cord from the lipoma: In Pang’s series, the cord was successfully detached from the lipoma in all cases (100%). 3. Cord-to-sac ratio: The ratio of the diameter of the cord to the diameter of the reconstructed dural sac is one measure of the freedom of motion of the spinal cord within the postoperative spinal canal. This ratio is evaluated on the postoperative MRI and grouped as less than 30%, 30–50%, and greater than 50%. In Pang’s series, 68% were less than 30%, 25.6% were 30% to 50%, and 6.4% were greater than 50% (187).

FIGURE 19.50 Intradural lipoma in a 21-day-old child with upper-extremity paralysis and a prominent cervical subcutaneous fat pad. (A) Sagittal T1-weighted and (B) axial T1-weighted magnetic resonance images. The highsignal intraspinal lipoma ascends along the dorsolateral border of the cervical cord and medulla to the vallecula.

FIGURE 19.51 Spinal lipoma (lipomyelomeningocele) in a 1-month-old girl (same patient as in Fig. 19.44). A: Operative field viewed from the patient’s left side and posterior. The skin has been incised and retracted and the bone resected to expose the lipoma (Li) that passes into the spinal canal medial (and external to) the dura (D) through the dorsal dural deficiency. The dura is incised (black arrowheads) well ventral and away from the dorsal root entry zone (open white arrowheads) that lies beneath the lipodural junction. This incision exposes the glistening arachnoid and the dorsal and ventral nerve roots (small black arrows) that run in the subjacent subarachnoid space. B: Circumferential incision of dura and arachnoid exposes the distal well-neurulated spinal cord (C), the expanded (dorsally cleft) placode (P, long arrows), the dorsal nerve roots (small black arrowheads), the ventral nerve roots

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(small black arrows), and their passage through the subarachnoid space to their exit foramina. The flap of dura (D) has been lifted up and reflected medially to expose the dorsal nerve root entry zone (open black arrowheads). Note that the lipoma (Li) passes into the cord extradurally, medial and external to the insertion of the dura into the edge of the cleft in the cord. The lipoma lies entirely outside the subarachnoid space. Because the cord is tethered and low lying, there is no cauda equina. Note also that the lipodural junction lies immediately dorsal to the dorsal root entry zone and serves as a landmark for that zone. (From Naidich TP, McLone DG, Mutleur S. A new understanding of dorsal dysraphism with lipoma [lipomyeloschisis]: radiological evaluation and surgical correction. AJNR Am J Neuroradiol 1983;4:103–116, with permission.)

FIGURE 19.52 Lipomyoceles. Midline sagittal T1-weighted magnetic resonance images of four patients. In each the high-signal lipoma (Li) extends inward from the subcutaneous plane, through a defect (arrowheads) in the lumbodorsal fascia (arrows) into the spinal canal, where it inserts into the dorsal surface of a low-lying tethered spinal cord (c). A: The posterior defect is narrow. The lipoma has an elongated, bilobed cylindrical configuration. The cord remains entirely within the canal. B: The posterior spinal bifida is larger. The cord (c) extends (open arrow) out of the canal into the defect, but there is no meningocele. C: The lipoma (Li) tethers the cord (c) inferiorly and is associated with distal hydromyelia.

FIGURE 19.53 Lipomyeloceles. Midsagittal T1-weighted magnetic resonance imaging in two patients. A: A 7-year-old child. The subcutaneous lipoma (Li) extends through the midline defect (arrowheads) to form a large intracanalicular component (Li) that inserts into the dorsal aspect of the spinal cord (c), tethers it inferiorly, and displaces it anteriorly, causing increased lumbar lordosis and scalloped erosion of the posterior borders of the L4, L5, and S1 vertebral bodies. B: The lipoma (Li) enters the spinal canal via a narrow defect in the lumbodorsal fascia, expands into a bulky mass (Li) that tethers the cord inferiorly, displaces the cord anteriorly, and causes terminal hydromyelia (H).

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FIGURE 19.54 Large lipomyelomeningocele. Operative exposure. Broad opening into the meningocele (white arrows) reveals the subarachnoid space (SAS), the distal cord (C) that widens into the placode, the typical shape of the placode resembling the bowl of a porcelain Chinese soup spoon, the insertion of dura (D) into the edge (black arrowheads) of the placode (P), and the entry of the lipoma (Li) into the placode extradurally, medial and external to the dura via the dorsal dural deficiency. (Case courtesy of Francisco Gutierrez, MD, Chicago, IL. From Naidich TP, McLone DG, Mutleur S. A new understanding of dorsal dysraphism with lipoma [lipo-myeloschisis]: radiological evaluation and surgical correction. AJNR Am J Neuroradiol 1983;4:103–116, with permission.)

FIGURE 19.55 Lumbosacral lipomyeloceles. Axial T1-weighted magnetic resonance imaging in three patients: an 11year-old girl (A), a 16-month-old girl (B), and a 9-year-old girl (C,D). The shape of the liponeural interface varies widely. A: When the lipoma is prominent and the distal cord is thin, the neural tissue may be difficult to discern. One still detects entry of high-signal lipoma into the spinal canal via the midline spinal dysraphism. B: When the lipoma remains as a single dorsal mass, it displaces the cord (white arrow) anteriorly and thins it sagittally. C: When the lipoma bulges toward each side, deformation of the distal cord (white arrowhead) causes it to resemble an arrowhead with the tip pointing posteriorly. There is a keel-shaped iliac bone (black arrow) articulating with the right sacroiliac joint. D: This patient also exhibits hydromyelia with expansion of the central canal of the cord (white arrowhead) just superior to the liponeural junction (D). (Panel B: From Naidich TP, McLone DG. Congenital pathology of the spine and spinal cord. In: Taveras JM, Ferucci JT, eds. Radiology—diagnosis/imaging/intervention. Philadelphia, PA: Lippincott; 1986, with permission. Panels C and D: From Zimmerman RA, Bilaniuk LT, Bury EA. Magnetic resonance of the pediatric spine. Magn Reson Q 1989;5:169–204; with permission.)

Complications of Surgery Near-term complications: At 3 months following surgery, 4.2% of the patients in Pang’s series 1463

manifested neurologic/urologic complications. 2.5% manifested CSF leaks and/or wound infection/dehiscence (187). Longer-term complications: Overall, 95% of patients had symptom stabilization or improvement in the short term (187). Long term, 98.4% of Pang’s patients showed progression-free survival at 16 years, versus 67% at 9 years for a nonsurgical group (187). Of all factors, the cord–sac ratio proved most predictive of outcome, with progression-free survival seen in 96% of those patients with postoperative cord–sac ratios less than 30% and in 80.6% of those with ratios of 30% to 50%, but a threefold increase in recurrence risk for those patients whose postoperative cord–sac ratios were greater (187).

FIGURE 19.56 Lipomyelomeningocele in a 7-week-old child. T1-weighted sagittal (A) and axial (B) magnetic resonance images demonstrate an exaggerated lumbar lordosis, high-signal subcutaneous lipoma (Li), low-signal meningocele (M), sacral spina bifida, and insertion of the lipoma into the tethered spinal cord (c). The lipoma attaches to the dorsal surface of the distal cord, deforms it, and rotates it such that the right edge of the neural plate is oriented in the sagittal plane posteriorly with the origins of the right roots in the midline.

FIGURE 19.57 Lipomyelomeningocele. Axial T1-weighted magnetic resonance image. An asymmetric, right-sided, high-signal lipoma (Li) inserts into the dorsal surface of the distal cord, tethers the cord (c, white arrowheads) inferiorly, and rotates the cord 90 degrees so that its dorsal surface faces rightward. Thus, the right nerve roots are very short and the left roots (white arrows) are elongated (see also Figure 19.47C, in which the dorsal surface faces leftward). In cases of this type, midline incision to the meningocele may be dangerous because it comes down directly onto the dorsal roots of the rotated cord. The short, deep roots may prevent complete “untethering” and mobilization of the cord despite successful resection of the lipoma.

Prophylactic Surgery versus Conservative Management of Spinal Lipomas 1464

For many years, early prophylactic untethering of spinal lipomas was considered the best possible therapy for this condition. This is now under intense review. PROPHYLACTIC SURGERY. Koyanagi et al. analyzed the success of early prophylactic surgery in 58 patients with conal lipomas (23 dorsal and 35 transitional), dividing them into initially asymptomatic and initially symptomatic subgroups (204): 1. In 15 initially asymptomatic patients, the short-term complications of prophylactic surgery included two CSF leaks, one requiring re-operation for dural repair. Long term, 4 of the 15 patients had urinary (1) or urinary plus motor deficits (3) from 1 to 15 years after initial surgery. Three of these four underwent a second untethering procedure 10 to 15 years after the first operation. The other 11 patients remained asymptomatic with a mean follow-up of 9 years (204). 2. In 43 initially symptomatic patients, the short-term complications included 10 CSF collections, 4 of which required surgical repair of the dura. Seven of the 43 patients (16%) had early postoperative neurologic/urologic worsening, with gradual improvement over time (204). Long term, 12 patients (28%) with 2 dorsal and 10 transitional lipomas showed neurologic or urologic deterioration (5 motor deficits, 4 motor plus urinary deficits, and 3 urinary deficits) from 1 to 12 years following initial surgery (204). Nineteen patients (44%) were unchanged, and 12 (28%) showed improvement of symptoms (better motor function in 6, better motor and urinary function in 1, and better urinary function in 5) (204). No patient achieved complete recovery from their initial deficits (204). CONSERVATIVE MANAGEMENT. In contrast, conservative, nonsurgical management of 53 initially asymptomatic conus lipomas was associated with a 25% rate of later deterioration (at a mean interval of 4.4 years) (204,205). In the group of symptomatic patients with conal lipomas, 26% to 67% were improved after surgery, whereas 18% to 41% showed late deterioration at a mean follow-up of 5.2 to 6.6 years (204). Concurrent Malformations Cutaneous stigmata are common with spinal lipomas. In Kumar’s series of 147 consecutive patients with spinal lipoma, cutaneous stigmata were found in 83 patients (56%), including subcutaneous lipoma and lipomyelomeningocele (56%), hypertrichosis (7%), dermal sinus (4%), dermal pit (4%), and hyperpigmented patch (2%) (206). Dermoids and teratomas are seen in 3% to 7% of patients with spinal lipoma, diastematomyelia in 1% to 6%, and hydromyelia/syrinx in 2.5% to 24% (19-54D) (27,156,188,190,194,207,208). Chiari I malformation has been seen in 1% to 3% of cases in some series (27,190) but not in others (1,19,24,102–104,188,208). Review of concurrent vertebral column anomalies found spina bifida in 97% of cord/conal lipomas but only 82% of filar lipomas (194). The sacrum was involved in 90% of cases (102,194). Sacral agenesis was seen in 25% of all cases and showed a higher incidence in those with anal–urogenital malformations (194). Vertebral fusions (6%) and hemivertebrae (7%) were also found (194). MR Spectroscopy of CSF Sharma et al. studied the MR spectra of aliquots of CSF obtained from patients with (i) normal spinal cord, (ii) with tethered cords, and (iii) following the release of tethered cords (210). They found high levels of lactate, alanine, acetate, glycerophosphorylcholine, and choline in dysraphic patients prior to surgery, and normalization of these metabolic levels following surgery. Further, increased levels of alanine and lactate were identified in patients in whom there was cord retethering (210). They attributed these differences to hypoxia and anaerobic metabolism in the tethered cord, with resolution of those processes following successful surgery. Hypoxic metabolites reappeared with retethering (210).

SECONDARY NEURULATION Normal Embryogenesis and Anatomy The distal spinal cord (Fig. 19.58) forms by the processes of secondary neurulation, formerly designated canalization and retrogressive differentiation (10–13,32). Caudal Cell Mass and Canalization After primary neurulation is complete by days 25 to 27, the distal spinal cord has yet to be formed. The 1465

remnant of the primitive streak at the caudal pole of the embryo forms a large aggregate of undifferentiated cells designated the caudal cell mass (Fig. 19.59). The caudal cell mass extends between the posterior neuropore and the cloacal membrane in the tailfold. It lies adjacent to the distal end of the spinal cord already formed by primary neurulation, as well as the posterior notochord, the distal end of the developing hindgut, and the mesonephros. This juxtaposition of developing genitourinary, notochordal, and neural structures within the tailfold appears to account for the common concurrence of distal vertebral, neural, anorectal, renal, and genital anomalies. The caudal cell mass will give rise to the caudal neural tissue and the vertebrae caudal to S2 (32).

FIGURE 19.58 Normal anatomic specimen of distal neural structures. Opening the dorsal dura and arachnoid (between open black arrows) exposes the dorsal aspect of the distal spinal cord (C), the tapering conus medullaris (large black arrow), and the filum terminale (multiple small black arrows). The roots of cauda equina are normally oriented nearly vertical but appear here artifactually tortuous and redundant. The normal filum is as thick as two to three nerve roots combined.

The mechanism of secondary neurulation appears to be species specific (32). In the chick, dorsal cells from the caudal cell mass give rise to a medullary cord composed of a tightly packed external cell layer surrounding a loosely packed core. Multiple small cavities form between the outer and inner cell layers. The inner cells are lost, and the cavities coalesce into multiple canals. One large canal merges with the central canal of the spinal cord formed by primary neurulation, “canalizing” the caudal cell mass (Fig. 19.60A,B). The surrounding epithelial cells orient around the vacuoles, begin to resemble neural cells, and become the distal spinal cord. In chicks, the secondary neural tube forms independent of the primary neural tube and only later fuses with the primary neural tube in an overlap zone (32). In the overlap zone the primary neural tube lies dorsally, while the secondary neural tube lies ventrally. A focal widening of the newly formed central canal at the distal conus or proximal filum is designated the terminal ventricle (19-60C) (32,211,212). In the mouse, the distal spinal cord extends caudally from the posterior neuropore and is always directly continuous with the primary neural tube. The central cavity of the distal cord is always single. Future neural cells aggregate around a central lumen formed by cavitation, creating a small medullary rosette. Then, extension of the cavitation and recruitment of additional cells elongate the distal spinal cord caudally (32,213).

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FIGURE 19.59 Caudal cell mass in a mammalian embryo. At the start of canalization, the caudal end of the neural tube and the caudal end of the notochord lie within a large aggregate of undifferentiated cells—the caudal cell mass —that extends into the tailfold.

The mechanism of secondary neurulation in humans is unresolved. Nievelstein et al. (214) found that the human pattern resembled that of the mouse. The caudal neuropore closed at the level of somites 32 to 34 in both species. The lumen of the secondary cord was always single and was always directly continuous with the lumen of the primary neural tube. A cluster of neuroectodermal cells at the caudal end of the closed primary neural tube gave rise to the cells that aggregated around the single lumen of the secondary neural tube to form the distal spinal cord. Müller and O’Rahilly (221) similarly found direct continuity between a single lumen in the newly forming distal cord and the single central canal in the primary neural tube above. Similarly, they found direct continuity of the secondary neural tissue with the primary neural tissue, and no zone of overlap (32). However, Lemire et al. (182) and Bolli (216) found multiple separate lumina with no connection to each other or to the primary neural tube.

FIGURE 19.60 Secondary neurulation (previously called canalization and retrogressive differentiation. Diagrammatic representation of proposed embryogenesis. A: As small vacuoles (v) form in the caudal cell mass (small black arrows), cells situated near the vacuoles begin to orient themselves around the vacuoles and assume the configuration of ependymal cells. As more vacuoles form and coalesce, two to three layers of cells surrounding the vacuoles begin to resemble neural cells. B,C: The coalescing vacuoles merge with each other and with the central canal (cc) of the neurulated spinal cord (NT) above, canalizing the caudal cell mass. Accessory lumina may also form. The lumen of the spinal cord distal to the 32nd somite (large black arrows) (future S3–S4) becomes narrower (small black arrows) than the lumen cephalic to the 32nd somite. At about the 32nd somite (large black arrow), focal expansion of the hollow canal creates the terminal ventricle (VT). This may lie within the distal conus or the proximal filum terminale. The distalmost portion of the involuting tube remains hollow for long periods as the coccygeal medullary vestige (small open arrow). (From Naidich TP, Gorey MT, Raybaud C, et al. Malformations congénitales de la moelle. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

Because vacuoles form at many sites and link up variably, accessory central canals, lateral or dorsolateral to the true lumen, may be observed in the distal cord of embryos. Lendon and Emery (217) showed major forking of the canal in the conus medullaris in 10% of normal adults and minor forking in 35% of cases. Within the filum terminale, major forking of the canal was seen in 35% of individuals (217). If the chick model has application to humans, then the “chisel shape” of the distal end of the remnant cord seen in some cases of sacral agenesis could be explained as the zone of overlap, with the persistence of primary neural tube dorsally and loss of the secondary neural tube ventrally at the overlap zone. Retrogressive Differentiation 1467

Once secondary neurulation is complete, the major portion of this distal cord undergoes involution in a process designated retrogressive differentiation. The lumen distal to future somite 32 (S3–S4) becomes progressively narrower than the lumen above (13). The secondary neuroectodermal cells differentiate into a neuroglial layer (214). Mesenchyme surrounding this neuroglial layer differentiates into pia mater. Together the neuroglial tissue and the pia form the primordium of the future filum terminale, the terminal ventricle, and, perhaps, a portion of the conus medullaris (Fig. 19.60B,C) (218–220). The filum extends caudally from the apex of the primitive conus to the 29th to 30th vertebra, corresponding to S5 or coccygeal-1. The caudal spinal column also forms by a less-organized process than that responsible for the more cephalic portions of the spine. The caudal cell mass formed by notochord, mesoderm, and neural tissue simply segments into somites to form the sacral, coccygeal, and tail vertebrae. Retrogressive differentiation then leads to reduction of most of these segments with loss of the tail. Thereafter, the vertebral column elongates with growth and grows faster than the cord. The so-called “ascent” of the cord actually results from disproportionately greater longitudinal growth of the vertebrae, not involution; the bones simply grow faster and descend away from the cord. Position of the Conus Medullaris The position of the tip of the conus medullaris is of significance in the diagnosis of the caudal spinal anomalies and the occult dysraphisms (Table 19.7) (221–229). Barson (221) studied the position of the tip of the conus medullaris with respect to the vertebral elements at different gestational ages (Fig. 19.61). Accepting a wide range of normal variation, he found that the tip “ascended” rapidly with respect to the vertebral elements from 12 to 16 weeks and rose more slowly thereafter. In his study, the tip of the conus lay at coccygeal-5 at 12 weeks, at L4–L5 by 18 weeks, at L2–L3 by term, and at adult levels of L1–L2 by about 3 months postpartum. Hawass et al. (222) analyzed the position of the cord in situ in 146 “normal” fetuses and found that the tip of the conus lay at the level of S5 at gestational age 7 weeks, ascended thereafter, and showed great variability in position between gestational ages 12 to 25 weeks. Between 35 and 38 weeks, the conus lay at or above the level of L3 (222). In collected series totaling 801 patients, James and Lassman (5) found that, by term, the tip of the spinal cord typically lay at or above the L2–L3 interspace in 98% and overlay the L3 vertebra in 1.8% of cases (Fig. 19.62).

FIGURE 19.61 Position of the tip of the conus medullaris (dark circles with error bars) with respect to the vertebral level and gestational age. (From Barson AJ. Radiological studies of spina bifida cystica: the phenomenon of congenital lumbar kyphosis. Br J Radiol 1965;38:294–300, with permission.)

Soleiman et al. (230) analyzed the position of the conus medullaris in 635 patients with normal spinal columns: 297 women and 338 men. The mean (and median) position of the tip of the conus medullaris was the mid one-third of L1, with a range extending from the lower third of T11 to the upper third of L3 (230). There was a small, but significant, correlation with age and gender, with older individuals and females showing a slightly lower position of the conus (230). More recently, Thakur et al. (231) found an isolated conus medullaris between L2–L3 and mid L3 in approximately 9% to 12% of screening lumbar spine sonograms, suggesting the conus may normally lie as low as mid L3. Therefore, a conus that lies below mid L3 is best regarded as abnormal until study demonstrates that it is not anchored or “tethered” in an abnormally low position by a bone spur, a fibrous band, or a terminal mass such as lipoma. Conversely, patients with appropriate signs and symptoms (with or without cutaneous stigmata) may have a clinically significant tethering of the cord, even if the tip of the conus falls within the normal range of position (232). Tethered cords in which the position of the conus 1468

is normal may account for 18% of cases (232). Configuration and Termination of the Dural Sac The termination of the dural sac most commonly appears as a long, tapering point (75%), but it may normally appear bullet shaped (5%) or rounded (20%) (229). The tip of the normal dural sac begins to rise from S5 after 14 weeks gestation (233). In adults, the tip of the dural sac terminates between the S1–S2 interspace and the S2–S3 interspace, inclusive, in 86% of patients (229). The modal position is S2 (63%) (Table 19.8) (229). Hansasuta et al. (234) similarly found that the tip of the thecal sac lay between the S1–S2 interspace and the S2–S3 interspace, inclusive, in 78% (Table 19.8). In Soleiman’s (230) series of 297 women and 338 men with normal spinal columns, the mean position of the tip of the thecal sac was the upper one-third of S2, with a range extending from the lower third of L3 to the upper third of S5. There was no significant gender correlation (230). There is a clear tendency to maintain a standard interval between the tip of the conus and the tip of the dural sac (Table 19.9), with both ending “high” or “low” concordantly (229). Departure from this pattern is one sign of abnormality. TABLE 19.7 Vertebral Level of Conus Medullaris Tip by Age

FIGURE 19.62 Normal spinal canal, thecal sac, and spinal cord. Sagittal anatomic section, newborn (A), and sagittal T1-weighted spin echo MRI (B), sagittal anatomic specimen (C), and sagittal T1-weighted spin-echo MRI (D) in a 12year-old boy. A: In the newborn, the marrow-containing central ossification centers (V) are relatively small compared with the cartilaginous endplates and the disks. The tip of the conus medullaris lies at L2–L3. The posterior elements are intact. The filum is not visualized. B: The tip of the conus lies at L1–L2. The ossification centers are thicker and more nearly rectangular. Note the normal pointed termination of the thecal sac at S1 and the ventral epidural fat (f) at the lumbosacral junction. C: The vertebral bodies are now more nearly adult in shape and are far larger than the intervertebral disks. The tip of the conus lies at L1. Ventral epidural fat (f) and dorsal epidural fat (d) are more prominent, partially because the section is off midline. The thecal sac tapers to a point at S2. D: Sagittal image depicts the normal relationships among the vertebral bodies, discs, epidural fat, cerebrospinal fluid, and cord. The

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thecal sac ends at lower S2. (Panels A,C: Courtesy of Victor Haughton, MD, Madison, WI. Panel D: From Naidich TP, McLone DG. Congenital pathology of the spine and spinal cord. In: Taveras JM, Ferucci JT, eds. Radiology— Diagnosis/Imaging/Intervention. Philadelphia, PA: J.B. Lippincott; 1986, with permission.)

TABLE 19.8 Termination of the Thecal Sac

TABLE 19.9 Conal–Dural Interval: Comparison Between the Vertebral Levels of Termination of the Conus Medullaris and the Thecal SAC in 300 Lumbosacral Magnetic Resonance Images

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Hansasuta et al. (234) found that the filum fused to the midline dorsal dura over a broad range of L5 to S3, with 52% fusing at the S2 level, and 15% fusing above the S1 level. Three of 27 fila (11%) fused off midline (234). In our experience, the filum terminale normally inserts exactly into the point of the dural termination, whether that lies in the midline or not. Apparent fusion away from the very point of the dural sac should be considered as possible sign of abnormality. Thickness of the Normal Filum Gryspeerdt (246) measured the thickness of the normal filum terminale at myelography and concluded 1471

that fila thicker than 2 mm were abnormal. Yundt et al. (236) confirmed that observation by direct measurement of the filum terminale in the operating room in 31 children 2 to 14 years of age with no evidence of tethered cord. In their series, the normal filum measured 1.2 ± 0.2 mm (236).

DERANGED SECONDARY NEURULATION Tight Filum Terminale Syndrome Incomplete involution of the secondary spinal cord could lead to the tight filum terminale syndrome. The term tight filum terminale syndrome signifies traction on the spinal cord as a result of an abnormally short, abnormally thick filum terminale (Fig. 19.63). In this condition, by definition, the filum must measure greater than 2 mm in diameter and no other cause for tethering can be present (1,237,238). The tip of the conus medullaris lies below L2 in 86% of these cases. In 10% to 15% of cases, the spinal cord continues caudally to attach to the distal thecal sac without distinct termination. Filar fibrolipomas are present in 29% of cases. Kyphoscoliosis is present in 15% to 25% of these cases and improves after section of the filum in one-third of cases (237,239). In a large series, 100% of cases had midline defects in the arches of the lumbosacral spine, usually at L4, L5, and/or S1, leading Hendrick et al. (237) to suggest that normal spine radiographs almost exclude this diagnosis. Treatment is typically by section of the filum terminale. Very exceptionally, the previously sectioned, now-untethered filum may coil up among the roots of the upper cauda equina, exert local mass effect, and present to medical attention as a symptomatic intradural mass at L2 (240).

FIGURE 19.63 Tight filum terminale syndrome. Intradural filar lipoma in an 11-year-old girl with scoliosis. A: Midline entry into the thecal sac. The dura has been tented laterally by stay sutures. The filum terminale (F) is abnormally thick (see Figure 19.58). The distal filum exhibits altered coloration (white arrow) representing fat. B: The thick filum has now been elevated and isolated in preparation for focal coagulation and section. Before section, it is essential to tease away from the filum lower sacral nerve roots that run with it and have filamentous adhesions to it.

Nazar et al. (241) reported a controversial group of 32 pediatric patients with symptoms of urinary dysfunction, stool incontinence, and/or severe back or leg pain, in all of whom the tip of the conus medullaris lay above L2 and in all of whom the filum terminale measured less than 2 mm in width. Only 2 of the 32 (6%) had midline cutaneous stigmata. However, 97% are reported to have experienced significant (greater than 50%) relief of symptoms after surgical section of the fila (241). These authors suggested the existence of an “occult filum terminale syndrome” (241). Others disagree (242). Yong et al. (243) described 152 patients operated upon for tight filum terminale syndrome. There was no gender predilection. The most frequent indications for initial untethering were bladder/bowel dysfunction (43%), neuro-orthopedic problems (24%), pain (16%), and scoliosis (12%) (243). Thirty percent were operated on prophylactically (243). In this group, the surgical procedure improved pain in 87%, improved neuro-orthopedic abnormalities in 73%, improved bladder/bowel dysfunction in 72%, and reduced the scoliosis in 44% (243). The filum was histologically abnormal in only 100 of the 125 patients (87% of specimens submitted) (243). The position of the conus was similar in those with and without normal fila (243). Postoperative complications were observed in 12%, including bacterial meningitis (1), aseptic 1472

meningitis (1), CSF leaks (3), pseudomeningoceles (8), and superficial wound infections (7) (243). Retethering of the filum was observed in 8.6% of patients and was observed in two distinct groups. Patients who retethered within 2 years of initial surgery (early retetherers) were older at the time of initial surgery (median: 9.4 vs. 0.9 years), had a higher level of the conus medullaris (median L1–L2 vs. L3–L4), had greater arachnoiditis after initial surgery, and required a greater number of repeat untethering procedures. Late retetherers were younger at initial surgery than those who did NOT retether (243). In a separate series of 225 children treated for tight filum terminale by transection of the fatty filum, Ogiwara et al. (244) found a 3.3% retethering rate. Lipoma of the Filum Terminale Persistence of caudal cells that differentiate toward fat could produce filar lipomas. The presence of fat within the filum terminale may be observed incidentally in 4% to 6% of normal adults and may be considered a normal variation if the fat is not associated with cord tethering or neurologic dysfunction (245–247). Typically, fatty fila thicker than 2 mm are regarded as filar lipomas (48,248). Uchino et al. (249) found 4 such lipomas in 1,691 MR scans of the lumbar spine (0.24%) but regarded each of them as incidental, because the conus lay in the normal position and the patients’ symptoms were judged to be unrelated. The patient symptomatology and the results of surgery for filar lipomas are given in Table 19.10. Filar lipomas may involve the intradural portion of the filum, the extradural portion, or both. Intradural lipomas tend to be fusiform in shape and taper down toward a point where the filum pierces dura (Fig. 19.64). They exhibit increased signal intensity on T1-weighted images, exhibit lower signal intensity on T2-weighted images, and are easily observed on good sagittal and axial sections. Lipomas of the extradural portion of the filum are far more diffuse, tend to be larger, and tend to merge with adjacent extradural fat. They commonly elevate and distort the distal thecal sac. Filar lipomas may be associated with lipomas of the distal half of the conus medullaris—the portion of the conus that is also formed by secondary neurulation (246). In some instances accessory fila are present and may also exhibit lipomas. Filar lipomas are commonly associated with the tight filum terminale syndrome and may require sectioning of the filum for untethering of the cord. Infrequently, the proximal end of the severed filar lipoma may adhere to the posterior wall of the spinal canal, retethering the cord (250). TABLE 19.10 Summary of Outcome Data by Clinical Indicator for Tethered Cord Release

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FIGURE 19.64 Intradural filar lipoma. Sagittal (A) and axial (B) T1-weighted magnetic resonance images (MRIs). The filum terminale (white arrows) is thickened by high-signal fat. It is closely applied to the dorsal surface of the canal but may be distinguished from normal dorsal epidural fat by its continuous extension over multiple segments, its slight line of separation from the segmented dorsal epidural fat, and its classic round midline appearance in axial MRI (B). The conus (C) ends in normal portion at T12–L1, with no evidence of tethering. The subcutaneous fat, lumbodorsal fascia, and posterior spinal elements are normal.

Filar lipomas are equally frequent in men and women (245). Nearly all patients are asymptomatic. In Cools’ series of 436 patients with filar lipomas, for example, symptoms of tethered cord were seen in only 22 (5%) (245). Among symptomatic patients, the most common complaints are urologic symptoms (59%), back pain (32%), and leg pain (32%). Syrinx was present in 21 (5%) (245). Vertebral anomalies were present in 11, including hemivertebra (7%), congenital fusions (2%), and segmentation abnormalities (2%) (245). As a group, symptomatic patients showed a statistically lower position of the conus medullaris (245). Among symptomatic patients, the conus lay in low position in 64 (15%), especially in children. However, although most symptomatic patients had a low-lying conus (17 of 22, 77%), most patients with low-lying conus had no symptoms (47 of 64, 73%) (245). Long-term follow-up has shown that no adult with filar lipoma developed new or worsening symptoms over time. Even in the subgroup with low-lying conus medullaris, no adult developed either new or worsening symptoms. Since surgery for filar lipomas has been associated with complication rates as high as 12% (including wound infection, pseudomeningocele, and meningitis), and since the postoperative retethering rate varies from 2.7% to 8.6%, prophylactic surgery is not presently recommended for most asymptomatic individuals found to have filar lipomas on MRI (245). Sacrococcygeal Teratomas Sacrococcygeal teratoma is a congenital tumor of the caudal pole of the body and, by definition, contains tissues derived from all three germ layers (251). It is the most common newborn tumor, the most common tumor of the sacrococcygeal region in childhood, and the most common sacrococcygeal germ cell tumor (Figs. 19.65 and 19.66) (252). Sacrococcygeal teratomas most probably arise from totipotential cells derived from Hensen’s node (11). The location of the majority of these at the distal coccyx raises suspicion that they may be related to the coccygeal medullary vestige (24). Because of the relation to the coccyx, coccygectomy is mandatory at the time of initial tumor resection (251). Failure to excise the coccyx with the tumor is associated with increased incidence of tumor recurrence (as high as 37%) (253). Sacrococcygeal teratomas occur in 1 per 35,000 to 40,000 births. Females predominate (80%) (169,170,182,252,254–261). Hereditary forms have been reported (255,262,263). The incidence of twinning is increased 10% to 53% in families with sacrococcygeal teratomas (253,262). Patients may present clinically in utero with large-for-dates uterus, polyhydramnios, elevated amnionic alpha-fetoprotein, or visualization of the lesion by prenatal sonography (251). Such patients are best delivered by cesarean section to avoid dystocia, tumor rupture, or bleeding into the tumor (264). In these patients, prenatal placentomegaly and hydrops at less than 30 weeks gestation is highly associated with fetal demise (264). 1474

Postnatally, patients may present asymptomatically because of an external mass, or they may manifest hydrops, high-output cardiac failure, respiratory failure, and renal insufficiency related to the bulk and vascularity of the mass (264–266).

FIGURE 19.65 Sacrococcygeal teratoma in a 7-day-old boy. Posterior view. The intergluteal crease is obliterated and discolored by the dorsal component of a predominantly presacral teratoma. The mass obstructed the ureters leading to urine ascites, which communicated with the scrotum, distending the scrotal sac.

FIGURE 19.66 Sacrococcygeal teratoma in a 6-month-old boy. Lateral (A) and posterior (B) views of the patient show a moderate-sized, skin-covered mass within the midline intergluteal cleft suggesting teratoma, not lipoma. The intraoperative photograph (C) and specimen (D) show the large cystic deep portion of the mass that had to be shaved away from the rectum to deliver it from the presacral space. The total mass was 14 cm in length, classified as Altman type III.

Most sacrococcygeal teratomas are visible externally (80% to 90%) (Figs. 19.65 and 19.66) (267). They may be small or huge (2.6 kg), representing up to 50% of total body weight (251). Sacrococcygeal teratomas account for 25% of skin-covered lumbosacral masses (11) and typically lie within or below the intergluteal cleft (Figs. 19.65 and 19.66). Only rarely do teratomas present as masses situated cephalic to the intergluteal cleft (Fig. 19.67). Conversely, spinal lipomas nearly always lie cephalic to the upper end of the intergluteal cleft. Grossly, sacrococcygeal teratomas are classified by their relationship to the skin surface and the pelvis (254). Altman type I tumors (47%) lie predominantly external to the normal body and have minimal presacral component. Altman type II tumors (35%) are evident externally but have significant intrapelvic extension. Altman type III tumors (9%) can be detected externally but lie predominantly within the pelvis and abdomen. Altman type IV tumors (10%) are entirely presacral. Only 2% of sacrococcygeal tumors grow into the spinal canal. Rare lesions connect to the distal filum terminale (268).

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FIGURE 19.67 Unusual teratoma in a 10-month-old boy. In this patient, the skin-covered lumbosacral mass and hemangiomatous nevus signified a teratoma despite their location cephalic to the intergluteal cleft. There is an incidental concurrent sacral dimple.

Most sacrococcygeal tumors are mixed solid and cystic lesions (Fig. 19.68) that form a large mass caudal to the coccyx. Five percent are predominantly cystic. Calcification is found in about 50% of benign teratomas. Histologically, sacrococcygeal teratomas may be mature (containing recognizable adult tissues only; 50% to 66%), immature (having embryonic tissues; 16% to 20%), or frankly malignant (30%) (269), including embryonal cell carcinomas, endodermal sinus tumors, and anaplastic carcinoma (Fig. 19.69). Malignant carcinoid has now been found within a number of sacrococcygeal teratomas (270). Tumors that are predominantly solid are more likely to be embryonal cell or anaplastic carcinoma than teratoma. The incidence of malignancy is higher in males than females and increases with age in both sexes (252,254,256,257). At birth 90% to 94% of these tumors are benign (251,252). Malignant transformation appears to occur between 4 months and 5 years of age (251). Analysis of 26 adult cases of sacrococcygeal teratoma (SCT) revealed female predominance (3:1), predominant intrapelvic location (accounting for the late diagnosis), and a malignancy rate of 19% (271). By histology the malignant lesions were adenocarcinoma in 60%, adenosquamous tumor in 20%, and low-grade neuroendocrine carcinoma in 20% (271). The mean age was higher in those with malignant teratomas (53 years) than in those with benign histology (37.8 years) (271). Long-term follow-up indicates that initially “benign” teratomas may recur locally or distally in 4% to 21% of cases. The “recurrences” may show either benign or malignant histology (252,261,272). Initial tumor size and Altman classification of extension do not predict recurrence rate (261). In the series of Bilik et al. (261), most recurrences were seen with mixed solid and cystic lesions. One totally solid tumor recurred. No purely cystic mass recurred.

FIGURE 19.68 Presacral and caudal teratoma in a 6-week-old girl. A,B: Sagittal T1- and T2-weighted magnetic resonance images (MRIs). C: Coronal T1-weighted MRI. The large, partially solid, partially cystic pelvic mass bulges rostrally anterior to the sacrum and caudally below the coccyx. The spine is normal.

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The average survival of patients with malignant sacrococcygeal teratoma has been 9 months (range, 1 to 28 months) (252). With modern chemotherapy initially malignant teratomas may have a 43% survival at a mean follow-up of 4 to 5 years (252). Serum alpha-fetoprotein levels and immunochemical markers do not predict malignancy during the first month of life (252,261). After the initial total tumor resection, elevation of serum alpha-fetoprotein is a (usually) reliable indicator of recurrent malignancy (261). However, teratoma may recur without elevation of alpha-fetoprotein (252). Patients with completely successful resection of a benign sacrococcygeal teratoma may still suffer sciatic palsy with lower-extremity weakness (7%), fecal and urinary incontinence (up 50%), and urinary tract infections (258,259,272). In one series, these complications were found more often with larger tumors that extended into the pelvis and abdomen (258), but in other series tumor size and extension did not correlate with late dysfunction (259,272). It is unknown whether the dysfunction observed reflects some effect of the tumor or results from the surgical procedure itself.

FIGURE 19.69 Malignant teratoma in an 11-month-old boy. The large pelvic lesion shows heterogeneous signal consistent with calcification (arrow) and mixed solid tissue. It invades into the gluteal musculature on the left.

In patients with sacrococcygeal teratoma, the spine may be normal, may show bone destruction, or, rarely, may show widening of the canal by intraspinal extension. Concurrent sacrococcygeal malformation suggests an autosomal dominant form of sacrococcygeal teratoma in which anorectal stenosis, retrorectal abscess, vesicoureteral reflux, and cutaneous stigmata concur (see also the later discussion of OEIS complex, Currarino triad, and VATER association).

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Prenatal Diagnosis and Prognosis The prognosis for patients with SCT first diagnosed postnatally is relatively good if there is early postnatal surgery (273). The prognosis for patients with SCT first diagnosed in utero is poorer, with a survival between 47% and 83% overall, but near zero for fetuses that develop hydrops (273). Predictors of poor fetal outcome include: (1) a tumor volume to fetal weight ratio of >0.12 before 24 WG and >0.11 up to 32 WG; (2) a solid tumor volume to head volume ratio of >1, and (3) a predominantly solid tumor morphology (>60% solid) (273). Large solid hypervascular tumors may cause high-output cardiac failure with placentomegaly, hydrops, and fetal demise. In severe cases, the mother develops similar symptoms (maternal mirror syndrome) (273). Of 15 patients who underwent fetal intervention, 5 survived (33%), 5 had neonatal death (33%), 1 was terminated after fetal intervention (7%), and 4 suffered intrauterine fetal demise after fetal intervention (27%) (273). Terminal Ventricle and Conal Cyst The terminal ventricle is the normal slight expansion of the central canal of the cord within the distal conus and/or proximal filum. It appears to represent the point of union between the portion of the central canal made by neurulation and the portion made by canalization of the caudal cell mass. MR studies often demonstrate a tiny drop of CSF at the site of the terminal ventricle. Slight expansion of the terminal ventricle in patients without other pathology is regarded as normal (274,275). Progressive expansion and cephalic extension of such a cavity may explain terminal hydrosyringomyelia, a variably large cystic expansion of the distal one-third of the cord found alone or in association with diverse forms of occult spinal dysraphism (Figs. 19.70 and 19.71) (208).

FIGURE 19.70 Dilated terminal ventricle in an asymptomatic 10-month-old boy with sacral dimple. A,B: Sagittal magnetic resonance images (MRIs): T1-weighted image (A) and fast spin echo T2-weighted image (B). C,D: Axial MRIs at conus. T1-weighted image (C) and fast spin-echo T2-weighted image (D). The minimally dilated central canal of the cord (c) expands into a symmetric, dorsally directed terminal ventricle of cerebrospinal fluid signal intensity. There is no tethering, no abnormal signal to suggest gliosis, and no abnormal contrast enhancement (not shown). Over the next 12 months, the cyst and the central canal expanded slightly.

Caudal Spinal Anomalies with Anorectal and Urogenital Malformations During normal embryogenesis, union of the hindgut, allantois, and Wolffian duct forms a common 1478

cloaca just ventral to the notochord and near to the caudal cell mass (276–283). Appearance of a urorectal septum then divides the cloaca into a dorsal hindgut and a ventral urogenital sinus. At 7 weeks gestation the cloacal membrane is bisected to form the anal membrane and the urogenital membranes (276,279). Maldevelopment of the cloaca, urorectal septum, anal membrane, and urogenital membrane may lead to high imperforate anus (above the levator), low imperforate anus (below the levator), anal stenosis, rectovaginal fistula, exstrophy of the bladder or cloaca, persistent cloaca, and/or genital anomalies. Perhaps 10% to 15% of all patients with anorectal anomalies have concurrent spinal cord anomalies (276,278). In 86 patients studied by Long et al. (281), occult myelodysplasia was seen in 27% of all patients with low-level lesions, 33% of those with intermediate-level lesions, and 44% of those with high-level lesions. In 92 patients studied by Appignani et al. (282), dysraphic myelodysplasia was found in 17% with low imperforate anus (ectopic anus), 34% with high imperforate anus (with fistulization), 46% with cloacal malformations, and 100% with cloacal exstrophy. In the 45 patients of Tsakayannis and Shamberger (283), however, no correlations were found among the presence of tethered cord, gender of patient, high versus low form of imperforate anus, or the presence of bony sacral malformations. Overall, experience indicates that patients with more severe midline ventral caudal anomalies such as persistent cloaca, cloacal exstrophy, and imperforate anus have a markedly increased incidence of midline dorsal spinal malformations, including tethered cord (92%), terminal myelocystocele (27%), lipomyelomeningocele (27%), blunt conus with terminal syrinx (40%), dorsal lipoma with short roots (4%), and fatty filum terminale (35%) (276,278). As a group (i) those with high imperforate anus have more complex spinal lesions than those with low imperforate anus, and (ii) those with cloacal exstrophy display more complex spinal cord anomalies (275). Terminal Myelocystocele (Syringocele) Terminal myelocystocele is a complex malformation of the distal spine, meninges, and spinal cord that is believed to result from deranged secondary neurulation of the caudal cell mass (Figs. 19.72 and 19.73). As a result, it is typically associated with multiple other anomalies of the tailfold. Terminal myelocystoceles constitute 1% to 5% of skin-covered lumbosacral masses (151,182) and 2.3% to 5% of lumbar lipomas (152,186,194). They are typically associated with the OEIS constellation (omphalocele, exstrophy of the bladder, imperforate anus, and spinal anomalies in the same patient), cloacal exstrophy, caudal regression syndrome, and other severe anomalies of the hindgut and genitourinary systems (16,151,284,285). Chromosomal studies are normal. Nonetheless, none of the 30 cases of terminal myelocystocele reported by Tandon et al. (286) exhibited cloacal extrophy (though one had an accessory phallus).

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FIGURE 19.71 Benign conal cyst in a 42-year-old woman with perineal numbness and paraparesis. A: Sagittal T2weighted fast spin echo image. Axial T1-weighted (B) and T2-weighted fast spin-echo (C) images. The conus is tensely expanded by a cerebrospinal fluid-intensity cyst not associated with tethering, gliosis, or abnormal enhancement (not shown). D,E: Intraoperative photographs. (Courtesy of Dr. Sergio Gonzalez-Arias, Miami, FL.) Opening and retraction of the dura with stay sutures exposes the glistening arachnoid and the expanded conus beneath (D). Opening the arachnoid exposes the conus and the translucent midline dorsal cyst wall at the lower edge of the field (E). There was no discoloration and no sign of infection, inflammation, or tumor. Histology revealed an ependyma-lined cyst.

Terminal myelocystoceles may also be related to the teratogenic effects of RA (287). Experimentally, RA can produce myelocystoceles in golden hamster fetuses when the drug is given to the pregnant mother before or after the fetus closes the posterior neuropore (288). Pathologically, the changes induced by the RA appear to represent necrotizing damage to a limited zone of the spinal cord and adjacent mesoderm. The precise site and extent of involvement depend on the dose and time of drug administration. Whatever the specific etiology, the pathogenesis of the lesion may be conceptualized as follows: 1. For unknown reasons, CSF is unable to exit from the early neural tube. 2. This CSF vents into the terminal ventricle after canalization occurs. 3. The terminal ventricle dilates. 4. The expanding terminal ventricle bulges into and disrupts the dorsal mesenchyme but not the superficial ectoderm. 5. Consequently, the dorsal spine is bifid (posterior spina bifida), but the skin is intact.

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FIGURE 19.72 Terminal myelocystocele. The left lateral view of the patient reveals a tensely distended, skin-covered lumbosacral mass. Patient is status post partial repair of cloacal exstrophy. (From McLone DG. Naidich TP. Terminal myelocystocele. Neurosurgery 1985;16:36–43, with permission.)

6. As the terminal ventricle balloons into a cyst, it distends the arachnoidal lining of the distal cord, forming a meningocele. The meningocele does not communicate with the terminal ventricle. 7. The bulk of the cyst prevents ascent of the cord, producing tethered cord. 8. After formation of the arachnoid, progressive distention of the distalmost cord causes it to bulge caudally, below the end of the meningocele. 9. This portion then lies extra-arachnoid and is covered by fat.

FIGURE 19.73 Terminal myelocystocele, left lateral view. Diagrammatic representation. The lesion consists of posterior spina bifida, tethered spinal cord (arrows) with hydromyelia; protrusion of the spinal cord, meninges, and subarachnoid space (1) into the dorsal subcutaneous plane; compression of the cord and meningocele by a fibrous band (hatch marks) at the upper margin of the spina bifida; ballooning of the distal central canal into an ependymalined terminal cyst (2); bulging of the terminal cyst caudal to the arachnoid, where it becomes covered by fat; origin of the nerve roots from the intra-arachnoid portion of the cord; absence of nerve roots in the terminal cyst; free communication of the cyst (2) with the central canal; free communication of the meningocele (1) with the spinal subarachnoid space; and no direct communication between the cyst (2) and the meningocele (1). (From McLone DG, Naidich TP. Terminal myelocystocele. Neurosurgery 1985;16:36–43, with permission.)

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FIGURE 19.74 Terminal myelocystocele in a 2-day-old boy with spina bifida. Sagittal T1-weighted magnetic resonance imaging reveals sacral spina bifida with focal deficiency in the dorsal fat, fascia, muscle, and bone. The skin-covered, fluid-filled, lumbosacral mass (arrow) appears to arise at the spina bifida and balloon outward from the flaring distal end of a low-lying tethered spinal cord (c) as a terminal myelocystocele (2). 1, subarachnoid space.

10. The cyst also bulges cephalically to expand the distal cord, producing a trumpetlike flaring of the cord within the meningocele (151). The anatomic components of this lesion are depicted diagrammatically in Figure 19.73 and illustrated in Figures 19.74 and 19.75. At the caudal end of the meningocele (compartment 1), the pia-arachnoid membrane is reflected from the “parietal” (arachnoid) wall of the meningocele onto the “visceral” (pial) wall of the spinal cord. The cord itself bulges caudal to this reflection into the extra-arachnoid space. This caudal portion of the cord contains the very enlarged ependyma-lined cyst within a sac of edematous dysplastic glial tissue. The extra-arachnoid cord is partially covered by fat that merges with the subcutaneous tissue, typically forming a concurrent lipoma. No spinal nerves traverse the cyst. Rather, all the spinal roots arise from the dorsal and ventral aspects of the intra-arachnoid segment of the cord. In a study of 30 cases of terminal myelocystocele, the lesion showed no gender predilection. All patients showed a skin-covered lumbosacral mass that was present from birth. The mass obliterated the intergluteal cleft and ascended for a variable distance. Cutaneous stigmata such as hemangioma, hairy patch, and hyperpigmentation were present in 8 (26.7%). Dermal sinuses concurred in six cases (20%). Tethering of the cord was observed in 97%. A thickened filum terminale was present in 27 (90%). Six (20%) had associated syringomyelia. Four patients had Chiari I malformation (13%) and one had a Chiari II malformation (3%). Three patients (10%) had hydrocephalus. Fourteen patients had lipomyelocystocele (47%) (286). Syndrome of Caudal Regression The syndrome of caudal regression designates a constellation of anomalies of the hind end of the trunk, including partial agenesis of the thoracolumbosacral spine, imperforate anus, malformed genitalia, bilateral renal dysplasia or aplasia, and pulmonary hypoplasia (1,289–297). Sirenomelia is a disorder characterized by extreme external rotation and fusion of the lower extremities. It is variably discussed in the literature as either a severe form of the syndrome of caudal regression, or as a separate entity with a distinct etiology. In this chapter, it is discussed in the next section.

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FIGURE 19.75 Terminal myelocystocele in a 2-day-old girl with normal genitalia and anterior abdominal wall. A: Left lateral view shows a low-lying, skin-covered lumbosacral mass. B,C: Midline skin incision and dissection through the dura and arachnoid show distal flaring of the spinal cord as it extends through the subarachnoid space to insert into the distal end of the meningocele. D: Direct posterior view. Immediately caudal to the meningocele, the tethered cord balloons into an ependymal-lined extra-arachnoid terminal cyst, surrounded by fat. (From McLone DG, Naidich TP. Terminal myelocystocele. Neurosurgery 1985;16:36–43, with permission.)

Sacral agenesis occurs in approximately 1 per 7,500 births (292). Males and females are affected equally. Nearly all cases are sporadic. It may be seen in one of otherwise identical monozygotic twins (298). Siblings are affected rarely (299). Sacral agenesis arises early in gestation, probably before the seventh week of gestation (300). There is a definite but incomplete association of sacral agenesis with diabetes mellitus, including maternal prediabetes and latent diabetic states: 1% of offspring of diabetic mothers will have a form of this syndrome. Up to 22% of patients with this syndrome have diabetic mothers (300). The lesion may be related to hyperglycemia early in gestation in genetically predisposed fetuses (301,302,303) or to a teratogen or other insult acting on the caudal eminence (tail bud) after closure of the posterior neuropore (302). In animals, deficiencies of the caudal vertebrae have been created by subjecting the embryo to elevated temperatures, microtrauma, lithium salts, X-irradiation, and administration of insulin in the presence of 2-deoxy-d-glucose (304). These insults could cause failure of secondary neurulation or excessive retrogression, leading to partial sacral agenesis, to distal thoracolumbosacral agenesis, and/or to concurrent anorectal and urogenital anomalies. A dominantly inherited form of sacral agenesis has been shown to result from defects in the homeobox gene MNX1 (Motor neuron and pancreas homeobox 1; formerly termed HLXB9) on chromosome 7q36 (296,305). This gene is also expressed in the pancreas, perhaps accounting for the association of sacral agenesis with insulin and diabetes (296,305). Bohring et al. (306) advanced the concept that the sacral agenesis and all of its multiple concurrent malformations may be explained by defects in signaling by RA and SHH during blastogenesis and gastrulation. Clinically, most patients with sacral agenesis exhibit poorly developed “rumps” with short, shallow intergluteal clefts and poor gluteal musculature (Fig. 19.76). They show narrow hips, distal leg atrophy, and talipes deformities (302). Approximately 20% have additional subcutaneous dysraphic lesions such as skin-covered lipomeningoceles (6%), terminal myelocystoceles (9%), or limited dorsal myeloschises (3%) (302). In the series of Jeelani et al. (307), among 22 patients with caudal regression, 13 had thickened filum terminale, 9 had lipomatous cord malformations, 5 had thoracic meningoceles, and 3 had split cord malformations. 1483

Motor deficits are present and correspond to the level of vertebral agenesis (32). Function of the quadriceps and the hip girdle is typically preserved, unless there is concurrent lumbosacral dysraphism (302). Sensation is better preserved than motor function (308). Thus, total sacral agenesis may be associated with complete motor paralysis below the quadriceps but relatively intact sensation in the perianal region (302). Urinary and bladder dysfunction are constant (302). The preservation of sensory function may reflect preservation of neural crest cells at the affected level or “replacement” of neural crest by migration from more cranial levels (32). Because untreated occult dysraphisms may lead to later neurologic deterioration in these patients, Jeelani et al. (307) recommend MRI screening early in infancy even in the absence of cutaneous markers.

FIGURE 19.76 Sacral agenesis in a 4-year-old boy. Posterior view of the patient reveals the short, shallow intergluteal cleft and poorly developed gluteal musculature.

Associated problems include multiple congenital malformations such as OEIS complex, VATER syndrome (see later discussion), and congenital heart defects (24%); genitourinary complaints including hydronephrosis, unilateral renal agenesis, pelvic and horseshoe kidneys, epispadias, and hypospadias (24%); orthopedic deformities including hip dislocation, flexion contractures, genu recurvatum, posterior compartment atrophy, talipes deformities, and scoliosis (12%); and progressive neurologic deficits and/or back and leg pain (38%) (302). Females show bicornuate uterus, didelphic uterus, vaginal duplication, partial vaginal atresia, and rectovaginal rectovesicular fistulas. The position of the conus defines two distinct groups of patients with sacral agenesis (302). In group 1 (41%), the conus ends cephalic to the lower border of L1 (Fig. 19.77) (302). The conus is typically deformed (92%) and terminates abruptly at T11 or T12, as if the normal distal “tip” were absent (Fig. 19.77) (16,303). It is nearly always club shaped (64%) or wedge shaped (extending lower dorsally) (28%) and infrequently normal (8%). The median fissures are absent inferiorly (309–311). The normal distinction between gray and white matter becomes unrecognizable, and there may be a terminal glial nubbin. The distal central canal may be slightly dilated and appear as a terminal ventricle or substantially dilated as a terminal hydromyelia (312). In this group with high conus, the sacral deficit is typically large, and the sacrum usually ends at or above S1.

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FIGURE 19.77 Partial sacral agenesis, group 1, in an 8-year-old boy. (A) Sagittal and (B) axial T2-weighted magnetic resonance images (MRIs) display a high, chisel-shaped termination of the distal spinal cord, with greater preservation of the dorsal sensory portion of the conus. There is mild hydromyelia. The distal thecal sac tapers to a narrow channel that descends through the lumbosacral epidural fat in company with the nerve roots. C: Coronal T1weighted MRI shows the “Christmas tree” configuration formed by the distal thecal sac, root sleeves, and nerve roots within the epidural fat of the spinal canal.

FIGURE 19.78 Partial sacral agenesis, tethered cord and lipoma. A 3-year-old girl. Midsagittal T1 (A), midsagittal T2 (B), and axial T1 (C) MRIs demonstrate partial agenesis of the sacrum, flat umbosacral angle, widened distal spinal

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canal, widened distal subarachnoid space (SAS), tethered spinal cord with hydromyelia (H) and distal lipoma (Li).

In group 2 (59%), the conus ends lower, below L1, and is elongated, stretched caudally, and tethered by a thick filum (65%), terminal myelocystocele (15%), transitional lipoma (10%), or elongated cord with terminal hydromyelia (10%) (Fig. 19.78). In these patients the sacrum tends to be relatively well preserved, with identifiable portions of S2 or lower vertebral segments. The clinical courses of the two groups differ: Neurologic deterioration is frequent in patients with low tethered cords but not in those with short, high, blunt coni (302). In this chapter, group 2 patients have been classified by their concurrent neural pathology rather than by the sacral defect alone. In patients with sacral agenesis, the distal bony canal usually shows smooth tapering that does not constrict the thecal sac (35%). In 6% of cases, hyperostosis indents the distal thecal sac. In 18%, the distal sacral canal is enlarged and bifid dorsally (302,313). The lowest vertebra present is T11 or T12 in one-third of patients, L1 to L4 in 40% of patients, and L5 or below in 27% of patients. The distal agenesis may be bilaterally symmetric or unilateral. The orthopedic deformity depends on the extent of the vertebral agenesis, the (a)symmetry of sacral involvement, and whether the ilia articulate with the sides of the last intact vertebra (relatively wide pelvis) or with each other inferior to the last vertebra (narrow pelvis) (Fig. 19.79) (302). Unilateral sacral agenesis leads to marked pelvic tilt and scoliosis. Isolated agenesis of the coccyx is an incidental finding in some patients. The diverse forms of sacral agenesis have been classified by Pang (302) (Table 19.11). In most cases, the dural sac shows nonstenotic tapering and shortening (47%). The tapering is greater and the sac ends higher with higher levels of spinal agenesis (302). In 9% of cases, severe dural stenosis constricts the caudal dural tube to pencil size and is associated with crowding of roots and neurogenic claudication (302,313). Surgery may be required to decompress bony or dural stenosis for relief of pain and for preservation of neurologic function. Sirenomelia Sirenomelia (sympodia) is a condition characterized by fusion of the pelvic girdle and the lower extremities into a single conical structure (Fig. 19.80). The distal end of this fused structure may exhibit no feet (sirenomelia apus) (35%), one foot (sirenomelia monopus) (26%), or two feet (sirenomelia dipus) (29%) (314,315). The lower extremity is always inverted and externally rotated, so that the knee is situated posteriorly, the leg flexes forward on the thigh, and the foot points posteriorly (1). Rare sirens exhibit two separate lower extremities, each flexed and rotated externally (anchipod form) (291,315). In these children, the coccyx is absent and the sacrum is partially or wholly absent (316). If present, the residual portion of the sacrum is loosely attached to the ilia (317). The iliac bones and the acetabula may be nearly normal but are often fused. A single acetabulum may be observed on the posterior aspect of the pelvis (318). The fused lower extremity may have a normal number of bones, partial fusions of the bones, or no bones at all. Most frequently, the femur is single or partially fused. The patella lies posteriorly. There are two to three leg bones with the fibula(e) situated medial to the tibia(e). Infrequently, there are additional numbers of vertebrae, such as 14 thoracic vertebrae with 14 pair of ribs (317). The etiology of sirenomelia remains the subject of debate, with two dominant hypotheses. The blastogenesis hypothesis describes a failure of late gastrulation in which cells migrating through the primitive streak do not become integrated into midline structures, resulting in the approximation and merging of the lower extremities. In this model, sirenomelia may be understood as an extreme manifestation of the syndrome of caudal regression. This hypothesis has been contested in part because, unlike the syndrome of caudal regresion, sirenomelia has no demonstrated association with maternal diabetes. In the vascular steal hypothesis, sirenomelia represents a distinct entity arising from a primary vascular defect: A single umbilical artery of vitelline origin shunts blood from the high abdominal aorta to the placenta, resulting in hypoperfusion of caudal structures (395). While children with sirenomelia almost invariably have a single umbilical artery, this may not to be causative or essential, because a single umbilical artery is present in about 0.5% of the general population (319). These two hypotheses are not mutually exclusive, and a primary defect in blastogenesis may conceivably account for concurrent vascular abnormalities.

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FIGURE 19.79 Partial agenesis of the lumbosacral spine in a 16-year-old girl. 3D reformatted CT images displayed from anterior (A) and posterior (B). C: Midsagittal reformatted CT. D: Axial CT at the “lumbosacral” junction. There is marked hypoplasia—absence of the anterior and posterior elements of the sacrum and marked narrowing of the lumbosacral spinal canal.

TABLE 19.11 Classification of Lumbosacral Agenesis

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FIGURE 19.80 Sirenomelia monopus. (A) Frontal and (B) lateral views of a stillborn. The caudal portion of the body has developed into a conical sireniform shape that exhibits marked hyperrotation, such that the monofoot points backward, the knee lies posteriorly, and the leg flexes forward over the thigh.

Anterior Sacral Meningoceles Anterior sacral meningoceles are diverticulae of the thecal sac that protrude anteriorly into the extraperitoneal presacral space (Fig. 19.81). They usually have thin walls composed of an outer layer of dura and an inner layer of arachnoid and typically communicate via a narrow stalk with the intraspinal thecal sac. Most anterior sacral meningoceles occur sporadically. They may be seen in conditions with dural ectasia such as neurofibromatosis and Marfan syndrome (321) or may be associated with the Currarino triad of anorectal malformations, sacral defects, and presacral masses (321). A familial form with concurrent anterior sacral meningocele, tethered cord, lipomas, teratomas, and dermoids may be inherited in families as an autosomal dominant trait with incomplete penetrance (321–323). Clinically, anterior sacral meningoceles account for 1.7% to 5.3% of retrorectal tumors (324,325). They may be detected at any age. In adults, females appear to be affected more commonly than males (approximately 4:1) (326). However, the lesion is equally frequently in boys and girls under age 10, suggesting that increased detection of anterior sacral meningoceles during pregnancy accounts for the female predominance in adult patients (323,327). Local pressure on pelvic organs causes unremitting constipation, urinary frequency and incontinence, dysmenorrhea, dyspareunia, and back pain. Pressure on the nerve roots causes sciatica, diminished rectal and detrusor tone, numbness and paresthesias in the lower sacral dermatomes, reflex asymmetry, and occasional motor impairment (328–330). Severe headaches may result from fluid shifts related to changes in body position or to Valsalva maneuvers such as straining at stool. Women of child-bearing age may present with a pelvic mass on prenatal examination or with dystocia at labor and delivery. Bicornate uterus, double vagina and uterus, bifid renal pelvis, imperforate anus, anal atresia and stenosis, and perianal fistulas are common (323). Meningitis may occur spontaneously but is most often iatrogenic, secondary to manipulation of the sac. In anterior sacral meningocele, the spinal canal is usually widened with smoothly scalloped margins. The defect in the sacrum is typically asymmetric (Fig. 19.81). The defect may be pinpoint, may be limited to one wide neural foramen, or may involve a large portion of the sacrum and affect multiple adjacent neural foramina. Serial studies over time show that the typical smooth curvilinear defect designated the “scimitar sacrum” often starts as a partial unilateral sacral agenesis that becomes remodeled around the hernia ostium with time (72). In approximately 20% of cases the sacral defect is midline (331). The sacral dural sac is often widened and patulous. The stalk is typically narrow. The meningocele sac 1488

may be unilocular or multilocular. Large meningoceles nearly fill the pelvis and may contain 1,500 mL of CSF (Fig. 19.82) (332). Small anterior sacral meningoceles just protrude beyond the sacral defect. In 20% of cases, nerve roots and the filum terminale may be contained within the meningocele sac, or nerve fibers and spinal ganglia may be present in the sac wall (323,330,332,333). Surgery for anterior sacral meningoceles is now usually performed via a posterior transsacral approach, through the sacral thecal sac, with careful inspection of the stalk and the ostium of the sac to detect any contained neural structures and any thickened filum, tethered cord, or concurrent lipoma and (epi)dermoid. If no nerve roots traverse the stalk, the sac is aspirated and the stalk is closed in a watertight fashion to prevent recurrence. If nerve roots are present, it may not be possible to obliterate the stalk of the meningocele. Some anterior sacral meningoceles are treated via an open anterior transabdominal approach with oversewing of the meningocele neck. This approach carries the risk of rectal injury with subsequent infectious complications (334) but may be favored in cases associated with masses (321) or cases in which a wide stalk precludes closure via the transsacral approach (327). Successive surgeries using both posterior and anterior approaches may be required to evacuate large or recurrent meningoceles. Operative mortality, previously high, is now near zero (321). Newer laparoscopic techniques have been recently described as a supplementary or alternative procedure in select cases (334,335). Lateral Lumbar and Thoracic Meningoceles These lesions are characterized by CSF-filled protrusions of dura and arachnoid through one or several enlarged neural foramina into the paraspinal extrapleural and retroperitoneal tissue (1,336,337). They may be unilateral or bilateral and are commonly associated with scoliosis (Fig. 19.83). Lateral meningoceles are most common in patients with mesenchymal disorders such as neurofibromatosis and Marfan and Ehlers–Danlos syndromes. Indeed, neurofibromatosis is present in 85% of lateral thoracic meningocele (336). Depending on the level of the lesion and the degree of scoliosis, the spinal cord and cauda equina may lie away from the meningocele along the opposite side of the spinal canal or may be pulled toward the meningocele by traction from the herniating meninges.

NORMAL EMBRYOGENESIS OF THE NOTOCHORD Development of the notochord is related to the caudal regression of the primitive streak and Hensen’s node (14,32). Appreciation of the precise steps by which the notochord forms and its relation to the underlying endoderm is being reassessed. Classically, it was believed that notochordal cells first arose in Hensen’s node, and ascended cephalically from Hensen’s node to reach the prochordal plate. It is now thought that that there is no cephalic migration of notochordal cells from Hensen’s node. Rather, the notochordal process that is the precursor of the notochord is simply laid down by Hensen’s node as the node regresses caudally with the elongating neural placode (Dr. Luis Puelles, Murcia, Spain, personal communication). Further, it was previously believed that (i) the primitive pit then deepened and invaginated into the solid notochordal process, converting it into a hollow notochordal canal; (ii) the ventral wall of the notochordal canal fused with the underlying endoderm to form the notochordal plate; (iii) breakdown of ventral notochordal cells opened the notochordal canal to the underlying yolk sac, establishing a transient communication designated the neurenteric canal of Kovalevsky; and (iv) that between days 17 and 19 the notochordal tissue then separated from the gut to re-establish a solid core of notochordal tissue designated the true notochord (14,32,338,339). The precise series of events is presently under reconsideration and may vary in different species. It remains true, however, that the notochord does induce formation of the neural plate, guide formation of the vertebral bodies, and contribute to the nuclei pulposi (35,36). The ectoderm forms the spinal cord and skin (Fig. 19.84) (32).

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FIGURE 19.81 Anterior sacral meningocele. Diagrammatic representation of five different types, some associated with concurrent intrasacral meningoceles. A: Cyst fills sacrum, extends anteriorly through the left third sacral foramen and posteriorly via prior laminectomy defect. B: Large intrapelvic anterior sacral meningocele with broad neck. C: Anterior sacral meningocele with crescentic sacral defect. D: Small anterior sacral meningocele found incidentally at myelography. E: Large intrasacral cyst and large presacral cyst communicating via broad neck extending through the right second sacral neural foramen. (From Amacher AL, Drake CG, McLachin AD. Anterior sacral meningocele. Surg Gynecol Obstet 1968;126:986–994; Naidich TP, McLone DG, Harwood-Nash DC. Arachnoid cysts, paravertebral meningoceles, and perineurial cysts. In: Newton TH, Potts EG, eds. Modern Neuroradiology. Vol. 1. Computed Tomography of the Spine and Spinal Cord. San Anselmo, CA: Clavadel Press; 1983, with permission.)

FIGURE 19.82 Anterior sacral meningocele in a 1-year-old girl. A: Sagittal T1-weighted magnetic resonance image (MRI) reveals partial hemisacral agenesis with anterior spina bifida, continuity of low-signal cerebrospinal fluid into a bulbous anterior sacral meningocele (S), low-lying tethered spinal cord (C) that tapers progressively inferiorly, and mural cyst (arrow) that probably represent (epi)dermoid. B: Axial T1-weighted MRI reveals the lower portion of the scimitar hemisacrum (arrow) on the left and the large meningocele (S) that passes into the pelvis through the defect in the contralateral right half of the sacrum. (From Naidich TP, Gorey MT, Raybaud C, et al. Malformations congénitales de la moelle. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989; and Naidich TP, McLone DG. Congenital pathology of the spine and spinal cord. In: Taveras JM, Ferucci JT, eds. Radiology—Diagnosis/Imaging/Intervention. Philadelphia, PA:Lippincott; 1986, with permission.)

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FIGURE 19.83 Multiple lateral lumbar and thoracic meningoceles in a 14-year-old girl. Coronal T1-weighted magnetic resonance image demonstrates scoliosis and multiple bilateral low-signal diverticula (arrows) of the leptomeninges. These balloon through and enlarge the neural foramina and expand the sacral spinal canal. (From Naidich TP, Gorey MT, Raybaud C, et al. Malformations congénitales de la moelle. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989; and Naidich TP, McLone DG. Congenital pathology of the spine and spinal cord. In: Taveras JM, Ferucci JT, eds. Radiology—Diagnosis/Imaging/Intervention. Philadelphia, PA: Lippincott; 1986, with permission.)

DERANGED EMBRYOGENESIS OF THE NOTOCHORD Persistence of a midline adhesion between ectoderm and endoderm could cause deflection or splitting of the notochord by deranging the caudal elongation of the notochordal process as Hensen’s node regresses (Fig. 19.85) (340,341). Alternatively, an unusually wide primitive streak could prevent paired notochordal anlagen from merging into a single midline notochordal process, leaving separate streams of cells to ascend as paired paramedian notochordal processes (Fig. 19.86). By either mechanism, the separate notochords could induce development of separate hemineural plates, leading to paired hemicords (diastematomyelia). Persistent endodermal–ectodermal adhesions and communications could lead to dorsal enteric fistulas and NECs.

FIGURE 19.84 Classical representation of the development of the notochord, notochordal canal, and canal of Kovalevsky, days 16 to 20. Diagrammatic representation of midsagittal sections. Cephalic is toward the reader’s left; dorsal is toward the top. Note: the existence of this canal is presently being reconsidered. A: The cells that entered the primitive pit formed a midline cord of cells between the ectoderm and the endoderm. This is the notochordal

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process. The primitive pit deepens and invaginates into this process, forming the notochordal canal (curved arrow). B,C: The ventral wall of the notochordal canal breaks down at one or multiple points, affording communication between the notochordal canal and the primitive yolk sac (secondary vitelline sac). This communication between the amnion (dorsally) and the secondary vitelline sac (ventrally) is the canal of Kovalevsky. One canal or multiple accessory canals may be present. D: The endoderm then reforms a cell layer along the ventral surface of the notochord, obliterating much of the notochordal canal. This reestablishes a solid core of notochord, now designated the true notochord. The canal of Kovalevsky may persist for a time. 1, buccopharyngeal membrane; 2, cloacal membrane; 3, allantois; 4, cardiac evagination; 5, canal of Kovalevsky; A, amnionic cavity; V, vitelline sac. (From Raybaud CA, Naidich TP, McLone DG. Développement de la moelle et du rachis. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

Dorsal Enteric Fistula and Neurenteric Cyst Persistence of a complete communication between the primitive gut and the neural placode would create a patent fistula extending from the mesenteric surface of gut; through the mesentery and prevertebral tissue; through the vertebral bodies, spinal canal, and spinal cord; and through bifid laminae to a midline ostium in the skin of the back (Fig. 19.87). Such a complete communication is designated the dorsal enteric fistula. It is exceedingly rare (342). With variable points of origin and variable degrees of repair of the defect in the embryo, portions of the entire fistula might persist as diverticula or patent duplications arising from the mesenteric border of the gut and extending into the mesentery or through the diaphragm into mediastinum; as persistent cords between gut and vertebrae; as enteric-lined cysts in the mesentery, mediastinum, spinal canal, and midline back; as anterior and/or posterior spina bifida; as diastematomyelia; as NECs; or as various combinations of these. Such a mechanism could also explain some of the dorsal dermal sinuses (presented earlier as a failure to disjoin cutaneous from neural ectoderm).

FIGURE 19.85 Embryogenesis of split notochord syndrome. Diagrammatic representation of midsagittal section with cephalic toward the reader’s left. A: Sagittal section displays the endoderm, which lines the primitive gut (archenteron); the ectoderm, which forms the outer surface of the embryo and gives rise to the primitive streak; and the intervening mesoderm. Proliferating cells in Hensen’s node, at the cephalic end of the primitive streak, form a cylindrical cell mass, the notochord. B: The primary event in the split notochord syndrome may be formation of an adhesion between ectoderm and endoderm. C–E: If such an adhesion exists, the notochord must split around the adhesion to form a focally ringlike notochord, or must deviate around the adhesion to one side as the notochordal is tissue laid down by the caudally regressing Hensen’s node. (From Beardmore HE, Wiglesworth FW. Vertebral anomalies and alimentary duplications: clinical and embryological aspects. Pediatr Clin N Am 1958;5:457–473, with permission.)

FIGURE 19.86 Possible embryogenesis of split cord malformations and other complex caudal malformations, as proposed by Dias and Walker (280). Diagrammatic representation. View from above onto the dorsal surface. The

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caudal pole of the embryo is oriented toward 11 o’clock. During gastrulation, if the primitive streak is abnormally wide, prospective notochordal cells in Hensen’s node may begin ingressing more laterally than usual. The paired notochordal streams would not integrate into a single midline notochord and would remain instead as paired paramedian notochordal processes. The caudal neuroepithelium induced by the paired notochordal processes would fail to integrate into a single midline neural plate and would form paired “hemineural plates” instead. Totipotential tissue from Hensen’s node could pass into the gap between the two notochordal processes and form a number of different caudal tissue types. (From Dias MS, Walker ML. The embryogenesis of complex dysraphic malformations: a disorder of gastrulation? Pediatr Neurosurg 1992;18:229–253; and Dias MS, Pang D. Split cord malformations. Neurosurg Clin N Am 1995;6:339–358, with permission.)

FIGURE 19.87 Split notochord syndrome. Diagrammatic representation of developmental posterior enteric remnants. Varying segments of the prototypical dorsal enteric fistulas leave diverse posterior enteric remnants. Each of these types may happen at any segmental level. (From Bentley JFR, Smith JR. Developmental posterior enteric remnants and spinal malformations: the split notochord syndrome. Arch Dis Child 1960;35:76–86, with permission.)

FIGURE 19.88 Neurenteric cyst in a 34-year-old man. A: Midsagittal T1-weighted magnetic resonance image shows enlargement of the cervicothoracic spinal canal, posterior displacement of the cord (C), and marked cord compression by a sharply defined ventral cyst (arrowheads). At surgery, the posterior wall of the cyst was attached to the ventral pia of the cord. B: Pathologic specimen shows the thin-walled cyst. Histologically, the wall was composed of pseudostratified ciliated columnar epithelium resembling the lining of the respiratory tract. (Courtesy of Glenn Geremia, Eric Russell, and Raymond Clasen, Chicago, IL. From Geremia GK, Russell EJ, Clasen RA. MR imaging characteristics of a neurenteric cyst. AJNR Am J Neuroradiol 1988;9:978–980, with permission.)

NECs are enteric-lined cysts that present within the spinal canal and exhibit a definite connection with the spinal cord and/or vertebrae (Figs. 19.88 and 19.89). They may pass around a hemivertebra or 1493

through a butterfly vertebra to communicate with an extraspinal component of cyst in the mesentery or mediastinum, and/or they may attach by a fibrous stalk to the vertebra, mesentery, or gut (Fig. 19.90). The vertebral column usually exhibits a wide spinal canal with widened interpediculate distance. Spina bifida and segmentation anomalies of the bodies are common but not invariable. In older patients, the vertebrae may be normal, aside from pressure erosion. Most cysts lie at the cervicothoracic junction or in relationship to the conus medullaris (1,332–344). The majority of NEC lies ventral to the spinal cord, flattening, widening, and thinning the cord (345). The cyst may invaginate deeply into cord with firm attachment to the pia or lie within the cleft between two hemicords. There is variable attachment to dura. MR displays the cyst and displaced cord plus any bone abnormalities. CSF flow studies reveal a high-grade stenosis or complete block to flow of CSF. Brooks et al. (344) and Gao et al. (346) reviewed 40 surgically proven enterogenous cysts of the craniovertebral axis (Table 19.12). Of these, 13% were intracranial, 10% were craniovertebral junction, and 77% were purely intraspinal. Overall, 16 of the 40 (40%) lay between C5 and T3 inclusive (344,346). Eighty-five percent lay in the midline, 72.5% anteriorly, and 12.5% posteriorly (346,346). Ninety-three percent were intradural extramedullary, 5% were intramedullary with exophytic components, and 3% were extradural (346). The cord was tethered in 7% and showed hydromyelia in 7% (346). One of the 40 cases (2.5%) was associated with a posterior mediastinal mass (Fig. 19.90) (344). In the 31 patients of Gao et al. (346), bony anomalies of the canal were found in 43% of cases, specifically spina bifida in four cases, vertebral body fusions in two cases, and clefts and butterfly vertebra in five cases.

FIGURE 19.89 Recurrent enteric cyst of the conus medullaris in a 5-year-old boy. Sagittal T1-weighted magnetic resonance image reveals prior extensive laminectomy, low position of distal cord (L3–L4), and the expansive cyst (arrow) within the dorsal portion of the conus medullaris.

NECs typically appear as homogeneous ovoid to lobulated masses. They are isointense to hyperintense to CSF on T1-weighted images and hyperintense to CSF on T2- and T2 FLAIR-weighted images, presumably due to their high protein content, described at surgery as “sugary” or “milky” (344–346).There is no mural nodule, though mucinous debris within the cyst may mimic a nonenhancing nodule (345). NECs typically show no contrast enhancement (346). However, abscesses within an NEC and granulomatous NEC have been reported to show peripheral enhancement (345). Nearly all NECs are benign, though rare instances of de novo malignancy or malignant transformation into adenocarcinoma have been reported (347). Intracranial NECs constitute 10% to 17.9% of all NECs (347). Of these, 14% are supratentorial, 34% are solely posterior fossa, 44% are craniocervical, and 9% lie at other sites (347). Rarely, intracranial NECs may be found at multiple sites (347). Histologically, spinal NEC may be subclassified into three groups (types A–C) of increasing histologic complexity (347). Type A cysts have an epithelial lining composed of pseudostratified cuboidal or columnar epithelial cells mimicking the respiratory or gastrointestinal epithelium. Type B cysts, in addition, may be arranged in complex invaginations and have associated glands secreting mucinous or serous fluid. These cysts may be composed of a range of associated tissue, including smooth muscle, striated muscle, fat, cartilage, bone, elastic fibers, lymphoid tissue, nerve fibers, ganglion cells, or Vater Paccini corpuscles. Type C cysts, in addition may be associated with glial elements such as ependymal cells of the wall. Immunohistochemistry is typically positive for endodermal markers such as anti-carcinoembryonic 1494

antigen antibody, anti-cytokeratin (CK) monoclonal antibody, and anti-epithelial membrane antigen (EMA). They are typically negative for ectodermal markers such as glial acidic fibrillary protein, neuron specific enolase, and vimentin (347).

FIGURE 19.90 Neurenteric cyst in a 5-month-old child with butterfly cleft vertebrae. A: Sagittal T2-weighted magnetic resonance image (MRI) reveals a high-signal cystic structure (Cy) in the prevertebral space just anterior to malsegmented cervicothoracic vertebrae. A faint tract ascends across the ventral subarachnoid space to a slight contour deformity of the ventral cord. B: Coronal T2-weighted MRI shows a large right intrathoracic high-signal mass (large Cy) compressing the lung and ascending superomedially toward the prevertebral cyst (small Cy). C,D: Sagittal T2-weighted (C) and axial T1-weighted (D) MRI obtained 18 months later. An intramedullary cyst has now developed in the midventral cord at the site of attachment of the tract.

TABLE 19.12 Neurenteric Cysts (Enterogenous Cysts) (N = 40)

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FIGURE 19.91 Diastematomyelia in a 4-year-old girl. Posterior view of the patient reveals the large patch of long, silky hairs overlying the diastematomyelia and a small sacral dimple (arrow). (From Schlesinger AE, Naidich TP, Quencer RM. Concurrent hydromyelia and diastematomyelia. AJNR Am J Neuroradiol 1986;7:473–477, with permission.)

Diastematomyelia By definition, diastematomyelia signifies a sagittal clefting of the spinal cord, conus medullaris, and/or filum terminale into two, not necessarily symmetric, hemicords (1,25,348,349). Diastematomyelia is typically sporadic in origin. Few cases have been familial (350). Clinically, patients usually present in childhood at one of three age ranges: 0 to 2 years (20%), 4 to 8 years (40%), or 12 to 13 years (17%) (351). Most cases occur in females: 80% overall, up to 94% in some series. Cutaneous nevi overlie the site of diastematomyelia in 45% to 85% of cases (Table 19.13) (352,353–355). The most nearly characteristic of these is the nevus pilosus, a large patch of long, silky hairs (Fig. 19.91). In children, the common presenting complaints are musculoskeletal deformities (98%), including asymmetric lower extremities and pes cavus; neurologic deficits (84%), including weakness, reflex asymmetry, reduced sensation, and incontinence of bladder and bowel; and scoliosis (79%) (352). In adults, sensorimotor changes (69%) and pain (58%) are the most frequent complaints (353). There are multiple theories of origin of diastematomyelia. The following three seem most worthy of review. (1) Rilliet et al. (356) studied the embryogenesis of diastematomyelia by microsurgical manipulation of chicken embryos. Simple incision of the distal neural plate and notochord in the midline to create a communication between the amnion and the yolk sac did not lead to diastematomyelia. The embryos healed or showed an open posterior spina bifida. Similar incision plus placement into the cleft of a resorbable agar screen resulted in open anterior spina bifida, cleft notochord, and protrusion of a tonguelike process of the spinal cord into the anterior defect. This anterior process could coalesce with the primitive gut. The central canal of the cord could be dilated, but the central canal was not doubled. Therefore, this condition was judged not to represent diastematomyelia, despite intriguing similarities. To us, this condition has some similarities to less severe forms of cervicothoracic myelocystocele (syringocele). When Rilliet et al. (356) incised the embryo and placed into the gap a nonresorbable wedge-shaped piece of membranous shell, diastematomyelia resulted: There were two hemicords, each with its own central canal. Some canals had hydromyelia. Some embryos showed anterior spina bifida with protrusion of the spinal cord through the anterior defect. Some had small cysts along the midline incision, and others had partial sacral agenesis. The authors concluded that diastematomyelia cannot be a simple failure of neurulation. Instead, diastematomyelia requires in part the noninvolution of a firm midline structure, rapidly surrounded by mesodermal cells originating from the notochord (356). (2) If there is a midline adhesion between the ectoderm and endoderm, then the notochordal cells would encounter an obstruction as Hensen’s node regresses caudally (Fig. 19.85) (343,357–359). The notochordal cells might deviate leftward or rightward around the adhesion or to both sides of the adhesion. As a result the notochord could develop with a focal left-sided or right-sided notch or a central “donut hole.” These alterations in the notochord would create a local unilateral vertebral agenesis with contralateral hemivertebrae or a ring of laterally displaced hemivertebrae with posterior spina bifida and the paired hemicords of diastematomyelia. (3) Dias and Walker (279) proposed that diastematomyelia could be the consequence of abnormally wide primitive streak (Fig. 19.86). In such case, the prospective notochordal cells in Hensen’s node would begin to ingress more laterally than is normal. Because of the distance between them, the two 1496

streams of notochordal cells could not merge into the single normal notochordal process but would persist instead as two separate notochordal processes. The neuroepithelium flanking the primitive streak would also fail to integrate into a single midline neuroepithelial sheet and would form, instead, paired hemineural plates (279). The laterally displaced somitic tissue would then form an abnormally widened spinal canal with multiple concurrent vertebral anomalies, including clefting, malsegmentation, and duplication. In such a case, the tissue situated between the separated hemicords would be composed of pluripotential primitive streak cells, potentially explaining the diverse fibrous tissue, cartilage, bone, vessels, lipomas, renal tissues, gastrointestinal tissue, (epi)dermoids, and Wilms tumors found between the hemicords in this condition (279,360–363). TABLE 19.13 Cutaneous Stigmata in Diastematomyeliaa

TABLE 19.14 Diastematomyelia: Sites of Involvementa

Diastematomyelia affects the lumbar or lumbosacral spine in 45% of cases, the thoracic spine in 31%, and the thoracolumbar spine in 12%. The cervical spine is affected in 7% and the sacrum in 1% (Table 19.14) (352–354). Lengthy diastematomyelias may extend widely over multiple segments in continuity (352–354). “Double” diastematomyelia at two separate sites is found in less than 1% of cases (352–354). A rare diastematomyelia has been seen to extend from the cervical spine into the spondylocranium, which is formed from the occipital somites (364,365). In diastematomyelia, the conus medullaris is usually low in position. The two hemicords are each narrower than normal and nearly always (91%) reunite distally into a reformed cord below the cleft (Fig. 19.92) (366). In 30% of cases, the hemicords are grossly asymmetric in size. When the hemicords are asymmetric, the cord above and below the cleft is usually asymmetrically smaller on the side of the smaller hemicord, and the smaller hemicord often lies ventral to the larger hemicord. The filum terminale is usually-perhaps always-thickened and may itself tether the reunited cord. Hydromyelia is present in up to 50% of cases of diastematomyelia. It may affect the cord above the cleft and extend into one or both hemicords (356,367). 1497

FIGURE 19.92 Diastematomyelia and hydromyelia in an 11-month-old girl. A,B: Coronal magnetic resonance imaging demonstrates separation of the spinal cord into two hemicords (h) that reunite inferiorly and continue into a thick filum terminale (white arrowheads). The cord above the cleft exhibits hydromyelia (H). The bone spur (black arrowhead) appears as a small, round, low-signal structure at the lower end of the interdural cleft (between small black arrows). C: Surgical exposure of the dorsal aspect of the diastematomyelia (after resection of the bone spur). The dura (D) has been opened and retracted. The medial walls of the two dural tubes have been resected. The two hemicords (h) reunite below the cleft. A prominent blood vessel typically courses along the dorsal aspect of the thickened filum terminale (white arrowheads), partially obscuring it. D: Axial computed tomography after myelography demonstrates the thin bone spur arising from the laminae and traversing the spinal canal between the two hemicords. (From Naidich TP, Gorey MT, Raybaud C, et al. Malformations congénitales de la moelle. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

The origins of the nerve roots from the hemicords vary. Each hemicord may give rise to the ipsilateral dorsal and ventral nerve roots. Alternatively, when the hemicords are asymmetric, one hemicord may give rise to three of the four roots and the other to only one. Accessory nerve roots may also be present. The meninges that surround the cord may also be cleft, or not. The exact relationship of the arachnoid and dura to the hemicords is highly significant and defines two distinct forms of diastematomyelia that require two different approaches to treatment (Fig. 19.93) (25). Single Dural–Arachnoid Tube (Pang Type II) In the slight majority of all cases of diastematomyelia (50% to 60%), the two hemicords are enveloped together in a single arachnoid–dural sheath (Figs. 19.93B,C–19.95). In these cases, there is no bone spur (Figs. 19.94 and 19.95). However, adherent fibrous bands and median nerve roots may still tether the hemicords to the midline dural sleeve (358). In more than 80% of these cases, median nerve roots also course dorsally beyond the midline dura to end along the undersurface of the laminae or within the subcutaneous tissue as a “meningocele manqué” (355,357,368). Therefore, surgical intervention may be required to release the hemicords from adhesions, aberrant nerve roots, or a thick filum terminale, even though no bone spur is present.

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FIGURE 19.93 Anatomic relationships in diastematomyelia. Sequential changes in the cord, meninges, and vessels as one passes from above the diastematomyelia into the region of abnormality. Ventral is toward the top of each image. A: The normal cervical cord above the lesion shows a single central canal (black dot in cord), single anterior and posterior horn on each side (stippling), a deep ventral median sulcus, and a single anterior spinal artery (arrow). The cord has normal pial investment. B: Lower cervical cord. Partial ventral diastematomyelia at the zone of transition. The ventral median sulcus (arrowheads) shows dorsolateral invagination and beginning bifurcation. There is partial duplication of the anterior spinal artery representing persistence of the paired ventral longitudinal trunks of the embryo (arrows), formation of two well-separated central canals (two black dots in cord), and beginning separation of gray matter (stippling) into two not necessarily symmetric parts. Each part may contain one ventral and one dorsal horn, or they may separate asymmetrically. Pial investment follows the deepening ventral sulcus. The arachnoid (large arrowhead) lies more superficial. C: Complete diastematomyelia with one arachnoid (and one coaxial dural) tube. Progressive dorsolateral invagination of the ventral sulcus (small arrowheads) causes complete sagittal diastematomyelia with formation of two adjacent, nearly symmetric thoracic hemicords, each containing one central canal (black dot in each hemicord). The anterior spinal artery (arrows) is duplicated. Each hemicord has its own pial investment (double-headed horizontal arrow). At this level, both hemicords are contained together in single arachnoid tube (large arrowheads) and single coaxial dural tube (not shown). In patients with diastematomyelia and single arachnoid and single dural tubes, the hemicords and meninges remain in this form for the length of the medullary cleft. D: Complete diastematomyelia with double arachnoid and double dural tubes. In these patients, the two hemicords and anterior spinal arteries (uncrossed arrows) usually separate more widely. Arachnoid and dura (curved arrows) also become duplicated, forming separate arachnoid and dural tubes about each hemicord. The two medial walls of the two dural tubes form a double layer of dura between the two hemicords. This is the fibrous partition that separates the two hemicords. The region between the medial walls of the two dural tubes (i.e., between the curved arrows) is designated the interdural cleft. This is usually occupied by an osteocartilaginous bone spur (Sp). Depending on age, this spur may be purely cartilage, may be cartilage (hatch lines) with one or several ossification centers (as shown here), may be a nearly complete bone spur separated from the vertebral body by a thin layer of cartilage (the synchondrosis), or may be a completely united bone lamina. E: Below the spur, the two hemicords may remain separate in separate dural and arachnoid tubes, may remain separate in a reformed single

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dural-single arachnoid tube, or may reunite to form a nearly normal distal spinal cord within nearly normal meninges. (From Cohen J, Sledge CB. Diastematomyelia: an embryological interpretation with report of a case. Am J Dis Child 1960;100:257–263, with permission.)

Dual Dural–Arachnoid Tubes (Pang Type I) In the other 40% to 50% of cases, the meninges are also cleft, focally, so that each hemicord is contained in its own arachnoid–dural sheath (Figs. 19.92, 19.93D,E, 19.96, 19.97). The single cord above the cleft is contained in a single meningeal sheath that divides to surround each hemicord, and that then reunites to a single meningeal sheath when the hemicords reunite to one cord below the cleft. Typically, the spinal cord divides first into two hemicords within one coaxial arachnoid–dural tube. Further inferiorly, the arachnoid and dura also divide into paired coaxial arachnoid–dural tubes, with one coaxial meningeal tube surrounding each hemicord. Therefore, in this group with cleft meninges, the cleft in the cord is always longer than the cleft in the meninges; often it is far longer. In these cases, the medial walls of the two dural tubes form a double layer of dura between the two hemicords, inside the cleft in the cord. This double layer of dura is the so-called fibrous partition. The space between the two layers of dura may be called the interdural cleft.

FIGURE 19.94 Asymmetric diastematomyelia, Pang type II, in a 3-year-old child with a small left foot and a weak left leg (neuro-orthopedic syndrome). (A) Axial and (B) sagittal T1-weighted magnetic resonance images. A: Paired hemicords lie within a single arachnoid and dural tube. The smaller hemicord is on the symptomatic side. B: The substantial filar lipoma (arrow) tethers the hemicords. Magnetic resonance limited to the sagittal plane may fail to reveal diastematomyelia.

In nearly all cases with cleft meninges, a bone spur forms in the interdural cleft between the two dural tubes—medial and external to the two dural tubes. The spur forms in cartilage from one or several ossification centers that mature with age (1,24,103,109). Depending on age, then, one may see no bone; several small fragments of bone separated by cartilage; a nearly complete bone spur still separated from the vertebra or laminae by cartilage; or a solid septum of bone completely crossing the spinal canal. The presence of cartilage along the spur signifies the site at which the bone spur will fracture away at surgery. In patients with several ossification centers, fracture between ossification centers could lead to regrowth of the spur, perhaps explaining the rare reports of regrowth of bone spurs after surgery. Perhaps 25% of cases of diastematomyelia with double dural tubes show additional tethering of the hemicords by aberrant, medially directed nerve roots or fibrous bands (358). Variant Forms Patients with variant relationships of hemicords, meningeal tubes, fibrous bands, and bone spurs have also been reported (353,369–371). In the series of Russell et al. (353), 39% of operated cases showed the archetypal relationship of the two dural tubes with an intervening bone spur. Eleven percent manifested an incomplete bone spur posteriorly, invaginating a single dural tube; 11% had fibrous bands separating the two hemicords within a single dural tube; and 7% had a fibrous connection that extended from the subcutaneous tissue through a single dural tube to insert into the cleft in the cords (353). In one case (4%), a bone spur is stated to have been present within a single dural tube, but no 1500

details are given (353). In patients with diastematomyelia, the bone spur may lie along the midline, dividing the canal into two symmetric hemicanals, or it may lie obliquely and asymmetrically. Nearly always, the spur appears to be more intimately associated with the laminae than the vertebral body and appears to arise from the laminae. It fuses with the vertebral body only later. In 6% of cases, the spur projects posteriorly between bifid laminae. In approximately 5% to 6% of cases, double (rarely multiple) spurs are present near to or distant from each other (366).

FIGURE 19.95 Partial ventral diastematomyelia with hydromyelia, Pang type II. Axial T2-weighted magnetic resonance imaging. A: Superiorly. Paired dilated central canals flank a very deepened ventral sulcus (partial ventral diastematomyelia). B: Inferiorly. The partially cleft cord reforms into a single, grossly uncleft cord with paired dilated central canals.

FIGURE 19.96 Diastematomyelia. A 10.5 year old boy. Midsagittal (A), coronal (B) and axial (C) T2 MRs demonstrate a bone spur (arrows, asterix in B) that traverses the spinal canal at L2. The spinal cord (c) and meningeal canal above the spur divide into paired meningeal tubes and paired hemicords that pass ipsilateral to the bone spur on each side, and then reunite into a single meningeal tube and single cord caudal to the spur.

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FIGURE 19.97 Diastematomyelia. A 6.5-year-old girl. Serial axial T2 MRIs displayed from cephalic to caudal through the zone of diastematomyelia demonstrate A: hydromyelia (H) above the separation. B: deepening of the ventral medial sulcus (white arrow) within the single spinal cord (c). C,D: Separation of the cord into paired hemicords (c,c) within a single meningeal tube. E,F: Close approximation of the paired hemicords (c,c) with the smaller hemicord passing ventrally. G: Reunion of the hemicords into a single distal spinal cord (c) caudal to the separation. Arrow in G indicates a remnant bone spur.

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In patients with cleft meninges, the fibrous partition and/or bone spur may tether the cord inferiorly. The bone spur typically lies at the caudal end of the cleft in the cord and appears to press against the medial surfaces of the two hemicords and the top of the reunited cord. In these cases, surgery may be required to resect the bone spur and the fibrous partition to release the spinal cord. When the bone spur detected does not lie at the caudal extreme of the cleft, there is increased likelihood that either a second, perhaps cartilaginous, spur lies at the caudal end of the cleft or the cord is tethered inferiorly, and pulled away from the spur, by a thickened filum terminale (354). Complete untethering of the cord often requires section of the thickened filum terminale as well, by separate surgical incision if need be (354). The spinal canal is nearly always markedly abnormal in patients with diastematomyelia (366). Focally narrowed intervertebral disk spaces are present in approximately 85% of patients. The sagittal dimension of the vertebral bodies is frequently decreased, and the interpediculate distance is characteristically widened at the level of diastematomyelia. The laminae are abnormal in nearly all patients and exhibit spina bifida, thickening of the laminae, and fusion between laminae of adjacent segments. The combination of spina bifida and intersegmental fusion of laminae is present in 60% of patients and is highly suggestive of the diagnosis (Fig. 19.98). Eighty-five percent of patients with diastematomyelia show segmentation anomalies such as hemivertebrae, butterfly vertebrae, and block vertebrae. Scoliosis and kyphosis are present in 50% to 60% of cases of diastematomyelia and are usually directly related to the segmentation anomalies. In the series of Miller et al. (352), 41% of scolioses were caused by a unilateral bar, 31% by block vertebrae, 21% by complex spinal deformities, and 7% by hemivertebrae. Overall, diastematomyelia accounts for about 5% of all congenital scolioses (61). Because the scoliosis results predominantly from the congenital vertebral anomalies rather than from neuromuscular imbalance, untethering the cord does not affect the progress of the scoliosis (352). Concurrent lesions seen with diastematomyelia include Klippel–Feil syndrome (2% to 7%) (352,354), Sprengel deformity (7%) (335–337), Chiari I malformation (3%) (363), dermal sinus (3%) (354), lipomyelomeningocele (3%) (354), and teratomas (3%) (Fig. 19.99) (354). These may lie distant from the site of diastematomyelia (369). Spinal lipomas may be seen in relation to the bone spur. Diverse other forms of spinal dysraphism are found in about 35% of patients (352). However, the presence or absence of concurrent dysraphism is not related to the particular vertebral level affected by the diastematomyelia. Horseshoe kidneys are found in about 10% of patients (354). Patients with untreated diastematomyelia usually show deterioration over time (352). The longer the delay in surgery, the greater is the likelihood of progressive neurologic compromise (352). In the series of Miller et al. (352), 30% of children managed nonoperatively showed progressive deterioration during the follow-up period. Two patients, initially asymptomatic, developed complete paraplegia after minor trauma, with nearly complete recovery after resection of the spur and release of the tethering (352). Conversely, no child that was operated on had damage to the cord or acute deterioration after surgery. Thirty percent had improvement of at least one neurologic symptom, 55% had no change in neurologic status, and 3% had improvement in some but deterioration in other neurologic functions.

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FIGURE 19.98 Diastematomyelia in a 2-month-old boy. A: Photograph of back, showing early hairy patch (arrow). B,C: Coronal T1-weighted magnetic resonance images (MRIs) through the vertebrae (B) and spinal cord (C) display slight scoliosis, butterfly ossification centers (large arrow), low position of the spinal cord (c), diastematomyelia with lateral separation of the hemicords (between the arrows), reunion of the two hemicords, thickened filum terminale (white arrowhead), and very low-signal “dot” in the lower end of the interdural cleft at the site of the bone spur. D: Sagittal proton density–weighted MRI demonstrates three short, squat vertebral centra (V) with hypoplastic intervertebral disks and the bone spur (arrow) traversing the spinal canal between the two hemicords. E–J: Serial axial MRIs displayed from superior to inferior demonstrate “budding” of the single cord (E) into two hemicords (F) that migrate laterally (G), passage of the bone spur (faintly seen at the white arrowheads in panels H and I) between the hemicords, and reunion of the hemicords below the bone spur (J). K–M: Three-dimensional computed tomography in anterior (K), posterior (L), and axial (M) views displays the characteristic short, squat vertebral bodies and hypoplastic discs, incomplete fusion of the posterior elements above and below the intersegmental fusion of laminae (T12–L1), and the origin of the bone spur from the laminae with residual synchondrosis (arrow) anteriorly between the spur and the centrum. In panel L,, note the relationship of the spur (white arrow) to the fused laminae.

In the series of Russell et al. (353), 62% of adult patients came to surgery. Immediate postoperative improvement was seen in 88%, and delayed improvement (after initial deterioration or requiring reoperation) was seen in 13%. The clinical course was stable and unchanged postoperatively in 4%. Gower et al. (354) reported less encouraging results: 14% immediate improvement, 14% delayed improvement, 57% unchanged postoperatively, and 5% progressive postoperative decline (but refusing potentially remediable re-operation). Reviewing 47 cases of pure split cord syndrome without other complicating dysraphisms, Andar et al. (370) reported that the neuro-orthopedic syndrome was an inevitable consequence of the abnormal functional anatomy of the split cord and therefore was not to be regarded as evidence of mechanical retethering requiring surgical release. True deterioration (defined as loss of a previously established neurologic or urologic function) did not occur in any children treated by prophylactic untethering of the spinal cord.

NORMAL EMBRYOGENESIS OF THE SPINAL COLUMN Development of the vertebral column begins during gastrulation when epiblastic cells migrate toward the primitive streak, ingress through the primitive groove, and then migrate laterally as the prospective paraxial presomitic mesoderm (Fig. 19.2). The epiblastic cells that enter the primitive groove from each 1505

side appear to distribute bilaterally and contribute to the somites on both sides of the embryo (32,371). Caudal somites develop from the caudal cell mass. By day 17, mesodermal cells at the cephalic end of the embryo form a thick mass of paraxial presomitic mesenchyme situated lateral to the notochord and ventrolateral to the neural plate. This paraxial presomitic mesoderm forms bilaterally symmetric longitudinal columns of solid mesoderm that begin to segment into paired blocks called somites (Figs. 19.100–19.102). Somites first form at about days 19 to 21 in the future cervical region and then continue to form as the embryo lengthens (32). Approximately five pairs of cranial somites have developed by the time the neural folds first approximate in the midline (32). Additional somites are then added caudally in time with neural tube closure, so that the caudal progression of somite formation keeps pace with the caudal progression of neural tube closure. Ultimately, 42 to 44 pairs are formed: 4 occipital, 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, and 8 to 10 coccygeal. The first occipital and the last five to seven coccygeal pairs later disappear. Somitomeres and Somites The somites first form as “presomites” called somitomeres. These form in strict, bilaterally symmetric, rostrocaudal order in relation to the rostral end of the primitive streak (Fig. 19.101). In avian embryos, as the primitive streak is forming, the first pair of somitomeres appears within the paraxial mesoderm, just to each side of the tip of the primitive streak (372). The prochordal plate forms in the midline just anterior to the rostral end of the primitive streak, partly between the first pairs of somitomeres (372). The primitive streak then elongates. As the streak reaches its greatest length, the second pair of somitomeres forms immediately caudal to the first pair. Thereafter, the primitive streak and Hensen’s node regress caudally. The notochord is laid down in the midline, and the paired somitomeres are laid down just to each side of the regressing Hensen’s node. Initially, seven somitomeres are formed. These are destined to disperse into the head. Thereafter, an additional species-specific number of somitomeres develop caudal to the first seven, at which time somitomere pair eight converts into the first pair of somites. From then on, in tandem, in a stepwise rostrocaudal pattern, additional pairs of somites condense from the somitomeres cranially, just as additional pairs of somitomeres are added caudally (372). The numbers of somitomeres between the most newly formed somite and the most newly formed somitomeres remain constant for a period of time, until formation of somitomeres ceases. The somites then “catch up,” and fill in the gap to reach the caudal end of the developing spine.

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FIGURE 19.99 Diastematomyelia with a teratogenous cyst, Pang type I, in a 1-year-old child with repaired myelomeningocele, diastematomyelia, and a mucoid cyst. A: Sagittal T2-weighted magnetic resonance image (MRI). B: Coronal T1-weighted MRI. C: Axial computed tomography through the spur. D: Axial T2-weighted MRI. The bone spur, malsegmentation anomalies of the vertebrae, and focal widening of the spinal canal indicate the presence and site of the diastematomyelia. The sharply marginated signal change surrounding the spur signifies the presence of the complicating cystic mass.

Axis Elongation Progressive elongation of the body axis requires a population of stem cells to fuel the addition of somites, neural elements, and related structures to the caudal end of the growing fetus. To that end, a complex interaction of retinoic acid, Fgf8, and Wnts maintains a population of stem cells in an epiblastic proliferation zone that surrounds the caudal end of the regressing Hensen’s node and neural plate (Fig. 19.103). This zone is designated the caudal neural plate and lateral epiblast (shortened to caudal lateral epiblast). Fgf8 secreted by the paraxial presomitic mesoderm stimulates the stem cells within the caudal lateral epiblast to proliferate without differentiating into neural or mesodermal fates. RA from the newly formed somites induces these stem cells to neuronal fates. The balance between RA and FGF8 keeps some cells proliferating in the caudal stem cell zone even as other cells differentiate further cranially. As axis elongation reaches completion, the balance between RA and FGF8 changes. Cell proliferation and the rate of axis elongation first slow and then cease, stopping further growth (14). Patterning the Somites Differentiation of the somites is regulated by many of the same inductive influences as is differentiation of the neural tube (373–377).

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FIGURE 19.100 Somitogenesis: overview. Diagrammatic representation of an embryo of 23 to 24 days. Paired blocks of somites have formed to each side of the closing neural tube. After seven pairs of somites have formed (sevensomite stage), the neural tube begins to close at the site of the third and fourth somite pairs (future occipital region). Closure may also occur at multiple other sites (46). The anterior neuropore closes at the lamina terminalis by day 23. The posterior neuropore closes at an unknown site by about day 25. (From Raybaud CA, Naidich TP, McLone DG. Développement de la moelle et du rachis. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

FIGURE 19.101 Somitogenesis. Details of the avian model, diagrammatic representation. The somitomeres and somites form in strict rostrocaudal order. The first pair of somitomeres and the prochordal plate form in relation to the developing primitive streak (not shown). The second pair of somitomeres forms when the primitive streak is longest (A). The notochord and additional somitomeres are laid down by Hensen’s node as the streak regresses caudally (B), until a species-specific number of somitomeres is made, at which time somitomere pair 8 condenses into the first pair of somites (C). Thereafter, in tandem, somitomeres are added caudally as the cranial somitomeres condense into somites, preserving a fixed number of intervening somitomeres (the segmental plate). In avians, the segmental plate numbers 10 to 12 somitomeres in length. When Hensen’s node is incorporated into the tail bud, the tail bud continues producing somitomere pairs until it “runs out.” Thereafter, continued condensation of residual somitomeres into somites fills in the gap, obliterating the segmental plate. The cells of the seven cranial somitomeres disperse to provide tissue to the head and neck without condensing into somites. (Redrawn from Jacobson AG. Somitomeres: mesodermal segments of vertebrate embryos. Development 1988;104(suppl):209–220, and reprinted from Carlson BM. Human Embryology and Developmental Biology. St. Louis, MO: Mosby; 1994, with permission.)

Dorsoventral Patterning The somites subdivide into a dorsolateral portion designated the dermomyotome, a ventromedial portion designated the sclerotome, and an intermediate portion designated the syndetome (Fig. 19.104). 1508

DERMOMYOTOMES. Wnt and neurotrophin-3 from the dorsal neural tube and BMP-4 from the early lateral plate mesoderm induce the dorsolateral portion of each somite to express Pax3, Pax7, and MyoD, and to differentiate into the dermomyotome (32,378). The dermomyotome will later parcellate into three regions: (i) a central region (the dermatome), (ii) a dorsomedial dermomyotomic lip (designated the primaxial lip) that lies closest to the neural tube, and (iii) a ventrolateral dermomyotomic lip (designated the abaxial lip) that lies farthest from the neural tube. The central dermatome will give rise to the dermis and subcutaneous tissue of the back. The dorsolateral primaxial lip will give rise to primaxial muscles, including the deep muscles of the back and the intercostal muscles between the proximal ribs. The ventromedial abaxial lip will give rise to the abaxial muscles of the body wall, limbs, and tongue (15).

FIGURE 19.102 Somitogenesis in the mouse embryo. In mice, the process of somitogenesis is highly analogous to that in the avian model, except that the segmental plate is called the presomitic mesoderm, the number of somitomeres in the presomitic mesoderm is six, and the tail bud is termed the caudal cell mass (375). The paired somites appear as segmented blocks of paramedian mesenchyme that curve along the dorsal surface of the embryo into the tailfold.

FIGURE 19.103 Axial extension of development. A dynamic balance of signaling by fibroblast growth factor 8 (FGF8), retinoic acid (RA) and Wnts maintains a population of proliferating stem cells within the “U”-shaped zone immediately caudolateral to the caudal end of the elongating neural plate and spine. Interaction between FGF-8 and RA in the developing spinal cord and paraxial mesoderm help to set the Hox code that determines segmental identity. (MODIFIED from Figure 6.5, page 97, of Carlson B. Human Embryology and Developmental Biology. 5th ed. Philadelphia, PA: Elsevier; 2014.)

SCLEROTOMES. SHH secreted by the notochord and floor plate induces the ventromedial portion of each somite to express the markers Pax1 and Pax9 and to differentiate into the sclerotome (32). The sclerotome will form the cartilage and bone of the vertebral column and medial portions of each rib. The medial and the lateral portions of the sclerotome have divergent fates. SHH induces surrounding 1509

mesenchymal cells to secrete epimorphin (15). Epimorphin attracts the medial sclerotomic cells to coalesce around the notochord, form a dense longitudinal column of perichordal mesenchyme, and differentiate into cartilage, ultimately forming the vertebral bodies and intervertebral disks of the spinal column (Fig. 19.4C) (15). Mice deficient in both Pax1 and Pax9 lack all of the medial derivatives of the sclerotomes: vertebral bodies, intervertebral disks, and the proximal portions of the ribs (378). After the neural tube closes and separates from the superficial ectoderm, the lateral portions of the sclerotomes will migrate about the neural tube, between the future spinal cord and the future skin, and form the perineural mesenchyme. The perineural mesenchyme will differentiate into the pedicles, the neural arches, and the lateral ribs. In the same doubly deficient Pax1 + Pax9 mutant mice, the neural arches that derive from the lateral portions of the sclerotomes remain unaffected (378).

FIGURE 19.104 Diagrammatic representation of somite parcellation. A: On each side of the midline neural tube (NT) and notochord (N), the paraxial somites (red shades) begin to differentiate into the dorsolateral dermomyotome (D) and the ventromedial sclerotome (S). E, epidermal ectoderm; central brown zone, somitocele. B: The sclerotomic cells (small mauve circles, S) lose cohesion and migrate toward the notochord. The dermomyotome (D) elongates, forming a dorsomedial primaxial dermomyotomic lip (PD) and a ventrolateral abaxial somitic bud (AS). Proliferating myoblasts (small red circles, M) begin to form a layer of precursor muscle cells deep to the dermomyotome. (Modified from Gilbert SF. Developmental Biology. 10th ed. Sunderland, MA: vSinauer Associates; 2014.) C: The scerotome (S) demonstrates dorsal (DS), ventral (VS) and lateral (LS) cell populations. D: Later in development, cells from the ventral (VS), central (CS) and dorsal (DS) portions form the early vertebra. Cells from the central and lateral portions of the sclerotome form ribs. Cells from the medial edge of the sclerotome (designated the meningotome, Mt) surround the developing spinal cord (NT) to form the meninges and their vasculature. Cells at the dorsolateral edge of the sclerotome form the syndetome (Sy) that will give rise to the tendons interconnecting the muscles and bone. Cells from the somitocele (arthrotome) join with ventral cells to form the intervertebral discs and the vertebral joint surfaces. (Modified from Carlson BM. Human Embryology and Developmental Biology. 5th ed. Philadelphia, PA: Elsevier Saunders; 2014.)

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FIGURE 19.105 Resegmentation of the sclerotomes into vertebrae. A: At the onset of resegmentation, each block of sclerotome consists of a denser, more-cellular caudal half-sclerotome (1) and a less-dense, less-cellular cranial halfsclerotome (2). The cylindrical notochord (N) passes vertically through these and is of relatively uniform diameter. The nerve roots (arrows) arise from the spinal cord (C) and pass out in relation to the midportion of each sclerotome to innervate the muscle. The muscles are arranged segmentally opposite each sclerotomic block. The vessels (arrowheads) pass between the sclerotomic blocks. B: Then the sclerotomic blocks divide and reunite (resegment), so each dense caudal half-sclerotome (1) unites with the next lower, less-dense cranial half-sclerotome (2) to make a new primitive precartilaginous vertebra. The old caudal half-sclerotome thus becomes the top half of the new primitive vertebra. The notochord cylinder constricts within the vertebrae and expands at the levels of the newly formed gaps between the primitive vertebrae. The nerve roots (arrows) still arise from the cord (C) and pass to the muscles, but the nerves now course in relation to the new gaps, and the muscles now bridge those gaps. The vessels (arrowheads) that ran between sclerotomes now course through the centers of the new primitive vertebrae. C: The portions of the notochord within the vertebrae degenerate to the mucoid streaks. The portions of the notochord within the gaps expand and undergo mucoid degeneration to help form the nuclei pulposi. Cells from the dense caudal half-sclerotome (1) (new top half of the primitive vertebra) supply the entire dorsal arch and migrate into the adjacent gap to form the annulus fibrosus. (Modified from Raybaud CA, Naidich TP, McLone DG. Développement de la moelle et du rachis. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

SYNDETOMES. By the geometry of the somite, the layer of cells immediately subjacent to the myotome is the most dorsal layer of the sclerotome. Fgf8 released by the myotome induces this cell layer to express the transcription factor scleraxis in two parallel stripes. These stripes become the syndetome that gives rise to the tendons and ligaments of the spine. SHH from the notochord and floor plate and other signals block the expression of scleraxis elsewhere in the sclerotome and promote the development of the cartilaginous vertebral elements. By this process, the tendons and ligaments developing from the syndetome are “pre-positioned” to link the muscles developing from the dorsolateral myotome with the vertebral elements developing from the underlying ventromedial sclerotome (15,379,380). Additional work is now identifying other portions of the sclerotome destined to form the meninges (meningotome) and the axial joints (arthrotome) among other divisions (381). Rostrocaudal Patterning and the Hox Code Rostrocaudal patterning of the somites appears to be controlled by the Hox code (Fig. 19.10). This code is actuated in the presomitic mesoderm prior to ingression into the primitive streak. Underexpression or overexpression of individual Hox genes (32,374) as well as shifts in the timing or concentration of the RA gradients (375) causes respecification of the numbers and fates of the somites and their costovertebral derivatives (Figs. 19.11 and 19.12). The system exhibits great redundancy because the embryo is able to generate normal numbers of somites of normal size after experimental extirpation of formed somites (32,376,377). 1511

Formation of the Vertebrae Following the patterning of the somites into sclerotomes, the vertebrae form by a series of steps arbitrarily categorized as membrane development, chondrification, and ossification (Figs. 19.105–19.112). Each vertebra goes through these steps sequentially (10–13). The process starts in the future occipital region and sweeps along the length of the spine, so different parts of the spine exhibit different stages of development at any one moment in time. This occurs as follows (15,378–391,392). Membrane Development (Fifth Week) Membrane development signifies the creation of a membranous template or anlage that will provide the scaffold for later chondrification and ossification. During the fifth week, cells from the sclerotomes migrate medially, surround the notochord, and form the dense longitudinal column of perichordal mesenchyme. This column will make the templates for the vertebral centra and disks (Fig. 19.4C). After the neural tube closes and the epidermal ectoderm disjoins from the neural ectoderm, cells from the sclerotomes also migrate dorsal to the neural tube to establish the templates for the neural arches of the vertebrae. These elements then undergo a complex resegmentation, discussed below, before they chondrify and ossify.

FIGURE 19.106 Relation of somites to cranial-spinal nerves and to spinal cord. In humans, 42 to 44 pairs of somites form. The most caudal five to seven pairs disappear during secondary neurulation (canalization and retrogressive differentiation). At term, the coccygeal vertebrae persist as vestiges without corresponding nerve roots. The conus medullaris probably represents somites 32 to 33, corresponding to the S3–S4 nerve level. The first pair of somites disappears in humans. The next three pairs form the portion of the skull designated the spondylocranium, that is, the basiocciput and the exoccipital bones. Portions of the fifth, sixth, and seventh somites constitute C1 and C2. (Modified from Raybaud CA, Naidich TP, McLone DG. Développement de la moelle et du rachis. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

Starting at about day 24, the membranous vertebral anlagen undergo a major division and resegmentation. Figure 19.105 illustrates the classic concept of resegmentation. In this view, the caudal and cephalic halves of each scerotome differentiate from each other to form (i) a cranial half-scerotome composed of loosely packed cells that express specific molecular markers, and (ii) a caudal halfsclerotome composed of densely packed cells that express other molecular markers. Hypocellular fissures of von Ebner form between the two half-sclerotomes, allowing the two halves to cleave from 1512

each other. These halves then unite with adjacent half segments (resegment), such that the lower, densely cellular half-sclerotome of one old segment joins with the upper, loosely cellular halfsclerotome of the old segment below forming a new structure designated the precartilaginous primitive vertebra. This entire process proceeds bilaterally and symmetrically. A fuller understanding of the complex molecular signaling involved in resegmenation is now beginning to emerge (14).

FIGURE 19.107 Stages of formation of the vertebra. Diagrammatic representation oriented like axial magnetic resonance imaging. A: Membranous stage (fourth to sixth weeks). The precartilaginous primitive vertebra (pink) contains a compressed degenerate remnant of the notochord designated the mucoid streak (purple). B: Chondrification to the cartilaginous vertebra (seventh to ninth weeks). Paired centers of chondrification (yellow with cross-marks) usually appear lateral to the mucoid streak (purple) in the centrum, in each half of the neural arch, and at the junctions of centrum with the neural arches. The centers for the centrum then merge together around the mucoid streak. The centers in the neural arch unite to form the cartilaginous neural arch and spinous process. The third pair of centers extends laterally into the transverse processes. C: Ossification (speckled gray) of the centrum begins as two centers, one anterior to and the second posterior to the mucoid streak. These coalesce to form one center that enlarges from the twentieth to the twenty-fourth week. Two additional pairs of ossification centers (speckled gray) arise in the neural arches, as shown. D: By term, these ossification centers (speckled gray) have enlarged to occupy a substantial portion of the cartilaginous vertebra (hatch lines). (Redrawn from Raybaud CA, Naidich TP, McLone DG. Développement de la moelle et du rachis. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

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FIGURE 19.108 Centers of ossification. A: Lumbar vertebra of a newborn. Axial anatomic section. The darker, marrow-containing central (C) and neural (N) ossification centers develop within the cartilaginous vertebra. Arrowheads indicate the zones designated neurocentral synchondroses. The neural ossifications and posterior cartilage arch medially to close the dorsal spinal canal. B: Thoracic vertebra of a 2-month-old boy. Three-dimensional computed tomography of bone shows the neural (N) and central (C) ossification centers, neurocentral synchondroses (white arrowheads), and costal ossification centers for the ribs (R).

FIGURE 19.109 Lumbar vertebra. Axial magnetic resonance imaging demonstrates the neural (N) ossification centers, the centrum (C), and the residual neurocentral synchondroses (white arrowheads). Note the paired ventral and dorsal nerve roots arising from the cord.

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FIGURE 19.110 Normal vertebra in an 11-year-old boy. A,B: Axial T1-weighted magnetic resonance imaging (MRI). C: Sagittal T1-weighted MRI. Nearly complete closure of central (C) and neural (N) ossification centers leaves the characteristic oblique low-signal fusion line (arrowheads) at the remnant neurocentral synchondroses. The vertebral body forms from both central and neural ossification centers.

As a result of this new division and fusion, the vessels situated between the two old segments become trapped within the middle of the new primitive vertebrae. Axons normally grow outward from the cord only in relation to the loosely packed cranial half-sclerotome, so that the spinal nerves and ganglia develop in relation to the cranial half segment (382) and the nerve exits through the neural foramina immediately inferior to the pedicles. The denser, caudal half-sclerotome gives rise to all of the dorsal vertebral arches (neural arch) (383). The less dense, upper half segments contribute substantially, possibly predominantly, to the formation of the future vertebral body. The precise contribution of the more dense, caudal half segment is still debated (382). The lower halves of the old segments now abut the gaps between the adjacent primitive vertebrae and contribute the cells that form the annuli fibrosi and the cartilaginous endplates. The dermatomyotomes that lay directly lateral to each old segment now lie lateral to the new disks and are able to attach to adjacent vertebrae across the disk. This provides mechanical advantage. Chondrification (Sixth Week) Under the inductive control of signals secreted from the adjacent notochord and ventral neural tube, the newly formed precartilaginous primitive vertebrae then begin to chondrify (Fig. 19.107). The derivatives of the medial sclerotome and of the lateral sclerotome continue to follow separate fates (38,90,383). Paired foci of chondrification appear just to each side of the midline within each precartilaginous centrum. Separate centers of chondrification also appear in each half of the neural arch and at the junction of each neural arch with the centrum. Chondrification begins in the cervicothoracic region and extends outward from there both cranially and caudally (32). During the chondrification phase, perinotochordal cells condense around the notochord to form the annulus fibrosus of the intervertebral disk. Phylsalipherous cells from the notochord form the central nucleus pulposus. Mesenchymal cells surrounding the cartilaginous vertebra begin to form the anterior and posterior longitudinal ligaments (32,384). With further chondrification, the notochord disappears from the centrum, except for a thin remnant of notochord called the mucoid streak. The posterior portions of the vertebrae (the pedicles and transverse processes) follow a different program. Mice with a specific mutation of the paired box gene Uncx4.1 form normal membranous anlagen for the pedicles, transverse processes, and proximal ribs, but cannot condense and chondrify these elements, leading to the loss of all pedicles, transverse processes, and proximal ribs over the full length of the spine (383).

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FIGURE 19.111 Formation of the vertebra. Regional differentiation. Diagrammatic representations oriented like axial magnetic resonance imaging. The centrum (polka dot), the neural ossification centers (light stipple), and the costal apophyses (circles) give rise to characteristic and homologous portions of each of the cervical (A), thoracic (B), lumbar (C), and sacral vertebrae (D). In panel A the uncinate processes derive from the neural arch, not the costal apophyses. The size and proportion of each component vary from level to level, but the costal apophyses vary most widely. (From Raybaud CA, Naidich TP, McLone DG. Développement de la moelle et du rachis. In: Manelfe C, ed. Imagerie du rachis et de la moelle. Paris: Editions Vigot; 1989, with permission.)

FIGURE 19.112 Normal coronal magnetic resonance image of a 22-year-old woman. The vertebral bodies (V) exhibit normal smoothly varying contour because the coronal section through the curved thoracic kyphosis intersects each vertebra at a slightly different portion of its sagittal dimension. This section through the greatest size of the upper and lower thoracic vertebrae includes only a smaller, more anterior component of the midthoracic vertebrae.

Ossification (Eighth Week Onward) Each centrum initially has two ossification centers: one anterior to and the other posterior to the mucoid streak (Fig. 19.107C,D). These usually coalesce rapidly into a single ossification center for each centrum. These central ossification centers for the centra first appear, simultaneously, at about 9 weeks gestation, in four sequential thoracolumbar vertebrae: T11, T12, and L1, plus either T10 or L2 (385). 1516

Additional ossification centers then arise within adjacent centra and extend, sequentially, in orderly fashion cranially toward C2 (rapidly) and caudally toward S3 or S4 (more slowly) (385). The C1, S4, and S5 centers ossify later. All fetuses show ossification in the centrum of C2 by 15 weeks gestation and in C1 by 18 weeks gestation (385). Caudally, all fetuses show ossification in the centrum of S2 by 11 to 12 weeks gestation, S3 by 13 to 14 weeks gestation, S4 by 17 weeks gestation, and S5 after 19 weeks gestation (385). Within each vertebra, enlargement of the ossification centers leaves residual plates of cartilage superior and inferior to the centrum. These plates become the cartilaginous endplates that face the intervertebral disks (Fig. 19.62). At approximately age 16 years, secondary centers of ossification form within the superior and inferior endplates of the vertebral bodies and at the tips of the spinous processes and transverse processes. These secondary ossification centers generally fuse with the adjacent bone by age 25 years. The vertebral arches ossify from distinct paired “neural” ossification centers, one within each hemiarch of each vertebra (390). Ossification of the neural arches is independent of ossification of the centra and indeed shows no regular order of appearance or specific sequence pattern (385,389). In general, the first cluster of neural arch ossifications appears at about 9 weeks gestation in a group of lower cervical–upper thoracic vertebrae. These ossifications tend to coincide with ossification in the superior nuchal line and squamous occipital bone and may reflect more active use of the attached musculature for head flexion and motion of the shoulder girdle (385). Shortly thereafter, a second cluster of neural ossifications appears in the upper cervical region. The remaining cervical arches may then “fill in,” and the ossifications may extend inferiorly toward the midthoracic region (385). A third cluster of neural ossifications may then appear in the lower thoracic–upper lumbar vertebrae and extend upward to meet those descending from the second cluster. In general, ossifications are seen histologically in all of the neural arches C2–T2 by 9 to 10 weeks gestation, T3–L2 by 10 to 11 weeks gestation, and L3–S1 by 12 weeks gestation (385,389). Ossification of the lower sacral arches does proceed sequentially, caudally from S2 (at 15 to 16 weeks gestation) toward S5 (19 weeks gestation) (389). By using ultrasound in vivo, Budorick et al. (391) actually displayed the sequential appearance of ossification within one new lumbosacral neural arch every 2 to 3 weeks gestation: Substantial ossification of the neural arch was evident by ultrasound in all fetuses at L5 at 16 weeks gestation, S1 at 19 weeks gestation, S2 at 22 weeks gestation, S3 at 24 weeks gestation, S4 at 25 weeks gestation, and S5 at 27 weeks gestation (391). The rate of ossification appears to be slightly more rapid in females. The cartilage between the neural and the central ossification centers on each side is designated the neurocentral synchondrosis. With growth of the centrum and the bony arches, the neurocentral synchondroses narrow and eventually fuse with the centra, well anterior to the sites of the pedicles (Figs. 19.108–19.110). Thus, the “ossified vertebral bodies” include bone contributed from both the centra and the neural arches. The terms centrum and body are not interchangeable. The laminae in the lumbar region fuse after birth, followed by the remainder of the spine. It should be noted that the laminae at the L5 level may normally remain unfused until age 5 or 6 years (12,13,392,393–404). The cervical spine exhibits several normal variations (Fig. 19.111). The atlas (C1) usually develops from one ossification center in the vertebral body and two centers in the neural arches. The center for the body is normally not ossified at birth but becomes visible during the first year of life. The neurocentral synchondroses usually fuse at about 7 years of age. If the ossification center in the body fails to develop, the ossification centers in the neural arches may grow forward to form the anterior portion of C1. If these do not fuse, a cleft may be visible in the anterior aspect of the vertebra. The axis (C2) usually develops from four primary ossification centers: one for the dens, one for the body, and two for the neural arches. These primary centers fuse by ages 3 to 6 years. A secondary ossification center for the tip of the dens normally appears at ages 3 to 6 years and fuses with the dens by age 12 years. Occasionally, the dens arises instead from two ossification centers that may fail to fuse in the midline, leaving a “bifid” dens. The typical cervical vertebrae C3–C6 develop one ossification center for the body and one for each half of the neural arch. The posterior synchondrosis between the two halves of the neural arches usually ossifies by ages 2 to 3 years. The neurocentral synchondroses unite by ages 3 to 6 years. The anterior portion of the transverse process may develop from a secondary center that arises in utero (sixth month) and unites with the neural arch by age 6 years. At C7, a similar ossification center may persist separately and elongate to form a cervical rib. Secondary ossification centers for the bifid spinous process and the superior and inferior epiphyseal rings appear at puberty and fuse to the vertebra by age 1517

25 years. Analysis of serial axial sections of embryos and fetuses has shown that the most rapid period for the growth of the lumbar spinal canal is from 18 to 36 weeks gestation (233). The size of the spinal canal at L1–L4 (interpediculate distance) is 70% of adult size at birth and reaches adult size in the first year of life (233). The L5 canal grows more slowly. It is only 50% of adult size at birth and only reaches adult size by age 5 years (233).

DERANGED EMBRYOGENESIS OF THE SPINAL COLUMN With variable cell migration, segmentation, and ossification, it is possible to anticipate the presence of numerous spinal variants in the population. Patients with myelomeningocele and unneurulated spinal cords will condense mesenchyme in abnormal position, making widely bifid posterior elements (Fig. 19.14C). Errors in the Hox code can lead to malsegmentation of the vertebrae, indeterminate vertebrae, and transitional vertebrae (Figs. 19.10–19.12) (394,405,406). Together, lumbarization of the most superior sacral segment and sacralization of the lowest lumbar vertebra are included within the category of lumbosacral transitional vertebrae. The prevalence of lumbosacral vertebrae has been variously reported, ranging from 4% to 30% in different populations (407). The T12 vertebra may lack ribs in 2% of patients, and the first lumbar vertebra may carry ribs, unilaterally or bilaterally, in 6% to 11% of cases. Defective ossification of the laminae of the low lumbar and sacral vertebrae is common (although reported incidences vary from 0.2% to 34% of cases) (408–410). Most such defects are midline; a few are paramedian at one or both sides of a well-formed spinous process. Persistence of separate ventral and dorsal ossification centers for each centrum produces coronal cleft vertebrae. Such vertebrae occur more frequently in the thoracolumbar region of males. They may be a normal variant that disappears within a few months after birth. However, coronal cleft vertebrae appear in increased frequency in patients with imperforate anus, myelodysplasia, and chondrodystrophia calcificans. Sagittal cleft vertebral bodies appear to develop when separate ossification centers form in each of the paired paramedian chondrification centers. These also may disappear within 6 months after birth or may persist as “butterfly” vertebra (Fig. 19.113). Hemivertebrae appear when the paramedian centers of chondrification fail to unite in the midline and the ossification center fails to develop on one side. These may lead to congenital mechanical scoliosis. Failure of bony union of the two neural arches posteriorly leads to spina bifida occulta, observed in 8.3% of women and 13.2% of men (411). In descending order of frequency, the most common sites of unfused spinous processes are L5 and S1, C1, C7, T1, and the lower thoracic region. Formation of a complete or incomplete cleft in the vertebral arch may lead to unilateral absence or hypoplasia of a pedicle (412,413). In such patients, affected vertebrae may exhibit posterior position of the lateral mass and absence of the posterior transverse process. The contralateral pedicle is usually thicker than normal. Block vertebrae may be single or multiple. They occur most commonly in the lumbar spine, then the cervical spine, and rarely in the thoracic spine. In larger series, the incidence of congenital fusion of the cervical spine is 0.71% (392). In block vertebrae, the intervertebral disk is absent or rudimentary. The combined vertebrae may be normal in height or tall. Deficient growth at the fusion site leads to narrow sagittal diameter and concave configuration of the block. Scalloping of the posterior surface may result from associated dural ectasia or (rarely) congenital mass. Disordered embryogenesis at adjacent levels may lead to hemivertebra or absent vertebra above or below the level of the block. Asymmetric malsegmentation may lead to hemivertebrae and/or tripediculate vertebrae, often as a series of jumbled mismatched half segments that extend along a substantial length of the spinal column. The posterior elements are also malsegmented in many patients with block vertebrae. These posterior fusions may lead to severe progressive kyphosis and scoliosis. In unusual cases, respiratory failure may result from thoracic lordosis created by the fused posterior elements. The craniovertebral region requires special discussion because the embryology of this region is complex. The base of the skull around the foramen magnum is designated the spondylocranium, because it forms from the union of “vertebral” elements derived from the occipital somites. The occipital condyles, superior facets of the atlas, and odontoid tip develop from the fourth occipital sclerotome. The rest of the dens and the lateral masses and neural arches of the atlas arise from the caudal part of the fourth occipital sclerotome plus the cranial part of the first cervical sclerotome. The body and neural arch of the axis derive from the caudal portion of the first cervical sclerotome plus the cranial portion of 1518

the second cervical sclerotome. Faulty segmentation may result in various degrees of atlanto-occipital assimilation, including unilateral or bilateral fusions of the occipital condyles with the lateral masses of the atlas, fusion of the anterior arch to the basion, and fusion of the posterior arch to the opisthion. Occipital vertebrae may form between the atlas and the occipital bone and present as unilateral or bilateral third occipital condyle(s) that project anteriorly form the tip of the clivus, or as single or multiple accessory ossicles in this region (414). Absence of the dens is rare. Ossiculum terminale results from failure to fuse the apical portion of the dens with the body of the dens. It is not usually associated with atlantoaxial instability, as the site of nonunion is above the level of the transverse atlantal ligament (415). Because the apical ossification center normally fuses with the base of the dens by age 12 years, a diagnosis of ossiculum terminale should not be made before this time. Os odontoideum results from failure to fuse the apical and basal portions of the odontoid process with the body of the axis. In any specific patient it may be impossible to differentiate congenital os odontoideum from an “acquired” or posttraumatic fragment that resembles os odontoideum. Because the site of nonunion lies below the transverse atlantal ligament, there is greater concern for atlantoaxial instability and the risk of neurovascular compromise after minor injury. While many patients with asymptomatic os odontoideum are managed conservatively with serial radiographs, some authors advocate surgical stabilization in young patients with dynamic instability on imaging studies and favorable anatomy. Symptomatic patients are treated surgically (415).

FIGURE 19.113 Butterfly vertebra with consequent molding of the adjacent endplates. A: Mild malsegmentation in a 55-year-old man. Coronal magnetic resonance imaging (MRI) of the lumbar spine shows paired hemivertebrae (v) with consequent constriction of the height of the midsagittal portion of the vertebra. The adjacent vertebrae grow to compensate for that defect. Intervening disks are hypoplastic. B: More severe malsegmentation in a 60-year-old woman with scoliosis. Coronal T1-weighted MRI demonstrates asymmetric separated hemivertebrae (v) at L4, partially united butterfly vertebra at L5, fusion between portions of L5 and S1, and molding of the inferior surface of L3 to conform to these changes.

Klippel–Feil Syndrome The Klippel–Feil syndrome is a congenital malformation characterized by failure in the segmentation of two or more cervical vertebrae (82,426–429). The condition occurs in approximately 1 in 40,000 births and demonstrates female predominance (F:M = 3:2). Clinically, 33% to 50% of patients may demonstrate the classic triad of short neck, low posterior hairline, and limited neck mobility (76,420). The syndrome presents heterogeneously with variable patterns of vertebral malsegmentation, leading to diverse classification schemes. As originally classified by Klipple–Feil,: type I shows massive fusion of most of the cervical and upper thoracic spine. Severe neurologic impairment and associated anomalies are most frequent in this group. Type II shows fusions of one or two interspaces, most often at C2–C3 and next most often at C5–C6. In 75% of cases, fusions occur from C3 cephalad. Type III shows fusions of the cervical vertebrae and lower thoracic or lumbar vertebrae. Of 57 cases of Klippel–Feil syndrome presenting to neurosurgery, Baba et al. (417) found type I in 5 (9%), type II in 48 (84%), and type III in 4 (7%). Klippel–Feil syndrome may be associated with a range of other skeletal and extraskeletal anomalies, including congenital scoliosis, ribab normalities, deafness, genitourinary abnormalities, and Sprengel’s deformity (420). Of note, Sprengel’s deformity (congenital failure of scapular descent) can present in association with or independent of Klippel–Feil syndrome. It is one of the most common congenital shoulder anomalies. A fibrous or osseous connection termed an omovertebral bar or bone may connect 1519

the cervical spine to the elevated scapula (421). In Ulmer’s series of patients with Klippel–Feil (76), hemivertebrae, butterfly vertebrae, or spina bifida were seen in one-third of cases; basilar impression or assimilation of C1 to the occiput in one-quarter; and Sprengel deformity in 15%. Diastematomyelia with partial or complete cord clefting was found in 20% and Chiari I malformation in 8%. Up to 65% of Klippel–Feil patients have genitourinary tract abnormalities, most frequently unilateral renal agenesis (76). David et al. (418) similarly reported seven cases of split cervical spinal cord in patients with Klippel–Feil syndrome. Patients with C2–C3 fusions often exhibit symptoms associated with odontoid dysplasia and occipitocervical instability (417). Most cases of Klippel–Feil syndrome are sporadic (422). However, numerous well-documented familial cases have identified genetic causes for the syndrome. The first gene to be implicated (SGM1) was found in a KF2–01 family and was localized to chromosome 8 (419). The expression of this gene overlaps with all three of the original Klippel–Feil subtypes I, II, and III. About 70% of this family have Klippel–Feil syndrome and an abnormal karyotype with an inversion of chromosome 8 (q22.2q23.3) affecting expression of the SGM1 gene. In this family, spinal fusion was restricted to the cervical region and occurred across alternate or skipped vertebral segments: C2–C3, C4–C5, and C6–C7, sparing C3–C4 and C5–C6. The fusions were always cumulative, adding additional levels from the most rostral C2–C3 fusion site. Of those with fusions, 100% showed involvement of C2–C3, 70% showed involvement of C2–C3 plus C4–C5, and 20% showed involvement of C2–C3, C4–C5, and C6–C7. This pattern of alternate involvement of segments strongly suggests a defect of the segment polarity genes affecting resegmentation of the parasegments, such as those induced by the Drosophila gene engrailed (419). Additional genetic loci have now been implicated in Klippel–Feil syndrome, including growth differentiation factor 6 (GDF6) (423); growth differentiation factor 3 (GDF3) (424); and mesenchyme homeobox 1 (MEOX1) (422). VATER Association, OEIS Complex, and Currarino Triad Other classifications of vertebral anomalies have been proposed, including the VATER association, the OEIS complex, and the Currarino triad. These overlap with Klippel–Feil syndrome and with each other. VATER Association The VATER association is a nonrandom occurrence of multisystem congenital malformations, specifically vertebral anomalies, anal atresia, esophageal atresia with tracheoesophageal fistula, and radial anomalies. Renal anomalies, a single umbilical artery, and cardiac malformations are commonly associated (425). Occult spinal dysraphism, especially filar–conal lipomas and lipomyelomeningoceles, are also associated (425). Uncommonly, occipital cephalocele, callosal dysgenesis, olfactory bulb hypoplasia, and aqueductal stenosis are reported (426). The VATER association overlaps in its features with hemifacial microsomia (HFM) and sirenomelia (427). Thirteen percent of patients with otherwise typical HFM also have three or more features of VATER and may be designated HFM–VATER phenotype (427). The HFM–VATER phenotype shows vertebral malformations in 97% versus 78% in VATER alone and versus 66% in sirenomelia (427). OEIS Complex The OEIS complex is a nonrandom combination of omphalocele, exstrophy of the cloaca, imperforate anus, and spinal defects, occurs sporadically in 1 per 200,000 to 400,000 births. Ribs are rarely affected (428). Karyotypes are normal. The OEIS complex may be the most severe end of the exstrophy– epispadias sequence that includes epispadias, pubic diastasis, bladder exstrophy, cloacal exstrophy, and OEIS—in order of increasing severity and complexity (428). Posterior meningoceles may be associated (428). Of seven cases of OEIS, five (71%) had terminal myelocystocele, one a spinal lipoma, and one a myelomeningocele (429). Conversely, in nine cases of terminal myelocystocele, seven (78%) had OEIS complex (302). Currarino Triad The Currarino syndrome (Currarino Triad) is an association of three major features: (partial) sacral agenesis, anorectal stenosis (or other low anorectal malformation), and presacral masses, including meningocele, teratoma, enteric cyst, or a combination of these (Fig. 19.114) (263,430). The sacrum is partially deficient and often assumes a scimitar shape that results from unilateral deficiency of S2–S5 inferior to a bilaterally intact left and right S1 (431). The full Currarino triad may be one extreme of a 1520

spectrum of pathology inherited as an autosomal dominant trait with phenotypic variability and low penetrance (343,431). In practice, the triad is often incomplete and manifests as only one or two of the three major features. The cause for most cases of Currarino syndrome is haploinsufficiency of the gene MNX1 (Motor neuron and pancreas homeobox 1; formerly termed HLXB9) on 7q36 (431). The defect may be sporadic or inherited. When inherited it is most frequently transmitted in the female line (431).

FIGURE 19.114 Currarino triad in a 4-year-old child. (A) Sagittal and (B) axial T1-weighted magnetic resonance images show a low-lying tethered spinal cord (c) with hydromyelia, a filar lipoma, a short sickled sacrum, and a presacral mass (arrow).

Of 40 reports of the complete triad, 21 (53%) had meningocele alone, 17 (43%) had benign teratoma, and 2 (5%) had enteric cysts, and 3 (7.5%) had a combination of anterior sacral meningocele and presacral teratoma (432). The major features of a recent series of 28 patients with Currarino syndrome are summarized in Table 19.15 (441). Goldenhar Complex Vertebral segmentation anomalies are also observed in a large number of other conditions, including Goldenhar complex (433). In Goldenhar complex, 19% of cases have cervical anomalies such as vertebral fusion, hemivertebrae, spina bifida occulta, and craniovertebral base anomalies. Less than 1% have vertebral anomalies below the cervical spine or rib anomalies (433). Other Vertebral Abnormalities Congenital Vertebral Dislocation Congenital vertebral dislocation is a translatory and/or a rotatory displacement of the entire upper vertebral column on the lower vertebral column at a single level, causing an abrupt angulation of the neural canal (32,434). This is proposed to arise by early embryonic buckling between the fourth and the sixth embryonic weeks, so the neural tube has already closed and the spatial relationships among the notochord, the neural tube, and the somites are relatively preserved. As a result, there are only minor developmental deformities of the vertebral elements, with mild hypoplasia of the vertebral bodies, elongated pedicles, widened canal, and bifid neural arches at the affected level (32,434). There are no concurrent bony malformations elsewhere. At the affected level, the spinal cord is deviated posteriorly with possible aplasia of the segmental nerve roots. The cord and roots are intact both cranial and caudal to the offset, but the conus typically lies in low position at L3 or L34 (32,434). SEGMENTAL SPINAL DYSGENESIS. Segmental spinal dysgenesis is a rare congenital malformation in which an isolated segment of the spinal column and cord fail to develop normally (Fig. 19.115) (435). Tortori-Donati et al. (436) advanced the theory that segmental spinal dysgenesis results from improper imprinting of future identity and location of a group of cells entering the primitive pit at a specific time. Such misspecification of future identity leads to later massive apoptosis of these cells and segmental agenesis–hypogenesis (436,437,438,439). In avians, removal of a notochordal segment causes massive death of sclerotomal cells, whereas the myotome and dermatotome remain nearly unaffected, similar to 1521

the changes observed with segmental spinal dysgenesis (436,440). These authors time the malformation to the third gestational week, because at least some of these segmental dysgeneses are associated with neurenteric fistulas (436,441). Patients with segmental spinal dysgenesis show thoracic or lumbar gibbus with stenosis or interruption of the spinal canal in 100%. Scoliosis is frequent (442). The worst cases show complete disconnection of the upper from the lower spine (436,440). The pedicles, transverse processes, and spinous processes are not identified at the level of dysgenesis (442,443). Half of the cases show additional vertebral anomalies affecting a single level distant from the major site. All thoracic lesions have concurrent costal (rib) abnormalities. The spinal cord is abnormal in 100% of cases: thin at the gibbus in 60% and undetectable in 40%. The cord distal to the gibbus is bulky and thick in 80%. The tip of the conus lies at or below L3 in 100% (436). Concurrent open spinal dysraphism is not present in any case, but 50% show occult spinal dysraphism: diastematomyelia without a septum (10%), a tethering intradural lipoma (10%), a neurenteric fistula draining into the retroperitoneum (10%), and tight filum terminale (20%). Twenty percent of patients with segmental spinal dysgenesis also show hydromyelia of the upper cord (436). TABLE 19.15 Features of 28 Patients with Currarino Syndrome

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FIGURE 19.115 Segmental spinal dysgenesis in a 3-year-old child. (A) Sagittal and (B) axial T1-weighted magnetic resonance images show a segmental hypoplasia of the spinal cord and the spinal canal.

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Multiple Vertebral Segmentation Disorders Disordered segmentation of multiple vertebrae is also observed in other conditions. Jarcho–Levin syndrome is an autosomal recessive condition that leads to death from respiratory infections before age 2 years (436,444,445). The vertebral segmentation defects typically involve the entire spine, producing a symmetric, crablike thorax (436). Spondylothoracic dysostosis is an autosomal recessive condition that also leads to early infantile death from respiratory infections (436). The segmentation defects involve the entire spine, especially the thoracic spine, and are associated with rib anomalies (436,446). Spondylocostal dysostosis is an autosomal dominant condition associated with a normal life span (436). It manifests as severe kyphoscoliosis, milder segmentation abnormalities, and invariable rib abnormalities. The degree to which these truly constitute distinct separable entities is not yet established.

ACKNOWLEDGMENTS We thank Mr. Antonio Chirinos and Ms. Mabel Rodriguez for their superb work in preparing images for publication. We gratefully commend Ms. Elba Colman of Mt. Sinai Medical Center, New York, for her invaluable assistance in overseeing the production of this newly revised chapter. We remember with sadness and deep gratitude the tireless dedication of Ms. Susan DeBusk in preparing the original manuscript for publication.

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AJR Am J Roentgenol 1946;55:292–298. 410. Hadley HG. Frequency of spina bifida. VA Med Monthly 1941;68:43–46. 411. Eubanks JD, Cheruvu VK. Prevalence of sacral spina bifida occulta and its relationship to age, sex, race, and the sacral table angle: an anatomic, osteologic study of three thousand one hundred specimens. Spine (Phila Pa 1976) 2009;34(15):1539–1543. 412. Sutow WW, Pryde AW. Incidence of spina bifida occulta in relation to age. AMA J Dis Child 1956;91:211–217. 413. Bardsley JL, Hanelin LG. The unilateral hypoplastic lumbar pedicle. Radiology 1971;101:315–317. 414. Smoker WR. Craniovertebral junction: normal anatomy, craniometry, and congenital anomalies. Radiographics 1994;14(2):255–277. 415. Klimo P Jr, Coon V, Brockmeyer D. Incidental os odontoideum: current management strategies. Neurosurg Focus 2011;31(6):E10. 416. Yousefzadeh D, El-Khoury GY, Lupetin AR. Congenital aplastic-hypoplastic lumbar pedicle in infants and young children. Skeletal Radiol 1982;7:259–265. 417. Baba H, Maezawa Y, Furusawa N, et al. The cervical spine in the Klippel-Feil syndrome: a report of 57 cases. Int Orthop (SICOT) 1995;19:204–208. 418. David KM, Copp AJ, Stevens JM, et al. Split cervical spinal cord with Klippel-Feil syndrome: seven cases. Brain 1996;119:1859–1872. 419. Clarke RA, Kearsley JH, Walsh DA. Patterned expression in familial Klippel-Feil syndrome. Teratology 1996;53:152–157. 420. Tracy MR, Dormans JP, Kusumi K. Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin Orthop Relat Res 2004;(424):183–190. 421. Bindoudi A, Kariki EP, Vasiliadis K, et al. The rare sprengel deformity: our experience with three cases. J Clin Imaging Sci 2014;4:55. 422. Mohamed JY, Faqeih E, Alsiddiky A, et al. Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly. Am J Hum Genet 2013;92(1):157–161. 423. Tassabehji M, Fang ZM, Hilton EN, et al. Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome. Hum Mutat 2008;29(8):1017–1027. 424. Ye M, Berry-Wynne KM, Asai-Coakwell M, et al. Mutation of the bone morphogenetic protein GDF3 causes ocular and skeletal anomalies. Hum Mol Genet 2010;19(2):287–298. 425. Michie I, Clark M. Neurological syndromes associated with cervical and craniocervical anomalies. Arch Neurol 1968;18:241–247.

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426. Chestnut R, James JE, Jones KL. The VATER association and spinal dysraphia. Pediatr Neurosurg 1992;18:144–148. 427. Duncan PA, Shapiro LR. Interrelationships of the hemifacial microsomia-VATER, VATER, and sirenomelia phenotypes. Am J Med Genet 1993;47:75–84. 428. Raffel C, Litofsky S, McComb JG. Central nervous system malformations and the VATER association. Pediatr Neurosurg 1990–1991;16:170–173. 429. Choi S, McComb JG. Long-term outcome of terminal myelocystocele patients. Pediatr Neurosurg 2000;32(2):86–91. 430. Dias MS, Azizkhan RG. A novel embryogenetic mechanism for Currarino’s triad: inadequate dorsoventral separation of the caudal eminence from hindgut endoderm. Pediatr Neurosurg 1998;28:223–229. 431. Merello E, De Marco P, Ravegnani M, et al. Novel MNX1 mutations and clinical analysis of familial and sporadic Currarino cases. Eur J Med Genet 2013;56(12):648–654. 432. Smith NM, Chambers HM, Furness ME, et al. The OEIS complex omphalocele-exstrophy-imperforate anus-spinal defects: recurrence in sibs. J Med Genet 1992;29:730–732. 433. O’Riordain DS, O’Connell PR, Kirwan WO. Hereditary sacral agenesis with presacral mass and anorectal stenosis: the Currarino triad. Br J Surg 1991;78:536–538. 434. Dias MS, Li V, Landy M, et al. The embryogenesis of congenital vertebral dislocation: early embryonic buckling? Pediatr Neurosurg 1998;29:281–289. 435. Scott RM, Wolpert SM, Bartoshesky LF, et al. Segmental spinal dysgenesis. Neurosurgery 1988;22:739–744. 436. Tortori-Donati P, Fondelli MP, Rossi A, et al. Segmental spinal dysgenesis: neuroradiologic findings with clinical and embryologic correlation. AJNR Am J Neuroradiol 1999;20:445–456. 437. Maden M, Graham A, Gale E, et al. Positional apoptosis during vertebrate CNS development in the absence of endogenous retinoids. Development 1997;124:2799–2805. 438. Maden M, Gale E, Zile M. The role of vitamin A in the development of the central nervous system. J Nutr 1998;128(suppl 2):471S–457S. 439. Yaginuma H, Tomita M, Takashita N, et al. A novel type of programmed neuronal death in the cervical and spinal cord of the chick embryo. J Neurosci 1996;16:3685–3703. 440. Hirano S, Hirako R, Kajita N, et al. Morphological analysis of the role of the neural tube and notochord in the development of somites. Anat Embryol (Berlin) 1995;192:445–457. 441. Rastogi H, Behari S, Phadke RV, et al. Spinal segmental maldevelopment with a dermal sinus. Neuroradiology 1996;38:658–660. 442. Faciszewski T, Winter RB, Lonstein JE, et al. Segmental spinal dysgenesis: a disorder different from spinal agenesis. J Bone Joint Surg Am 1995;77A:530–537. 443. Hughes LO, McCarthy RE, Glasier CM. Spinal segmental dysgenesis: a report of three cases. J Pediatr Orthop 1998;18:227–232. 444. Jarcho S, Levin PM. Hereditary malformation of the vertebral bodies. Bull Johns Hopkins Hosp 1938;62:216–226. 445. Reyes MG, Morales A, Harris V, et al. Neural defects in Jarcho-Levin syndrome. J Child Neurol 1989;4:51–54. 446. Giacoia GP, Say B. Spondylocostal dysplasia and neural tube defects. J Med Genet 1991;28:51–53.

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20 Degenerative Disease of the Spine Richard T. Kaplan, Leo F. Czervionke, and Victor M. Haughton

Magnetic resonance (MR) has become the primary imaging modality for evaluation of degenerative disorders of the cervical, thoracic, and lumbosacral spine. The intervertebral disc, vertebrae, ligaments, spinal canal, and neural foramen may all be evaluated using MR techniques. Paramagnetic contrast agents are valuable for differentiating scar and recurrent disc herniation in the postoperative setting and occasionally are used preoperatively for detecting inflammatory processes that may accompany acute disc herniation, facet joint synovitis, and radiculitis. This chapter deals with the spectrum of degenerative disease of the spine, including disc herniation, disc degeneration, spinal stenosis, spondylosis deformans, and osteoarthritis, and other degenerative disorders affecting the spinal column. The MR techniques used to image the spine are discussed. In addition, the significance of descriptive radiology terminology is noted, with the goal of stressing clinically significant imaging findings and reducing extraneous or irrelevant pseudo-quantification in radiology reports.

MAGNETIC RESONANCE PULSE SEQUENCE CONSIDERATIONS It is important to be aware of the MR pulse sequences available when designing protocols for examining the spine because the optimal MR technique will vary considerably, depending on the region of interest and on the pathologic process being studied. In the lumbar spine, spin-echo (SE) and fast spin-echo (FSE) imaging sequences are optimal for evaluating degenerative spine disorders (Fig. 20.1). The major reason for the success of SE imaging in this region is that epidural and foraminal fat is abundant and stands out as high intensity on T1weighted SE images compared with the relatively lower intensity of the adjacent thecal sac, herniated disc, or other tissue. On most T2-weighted gradient-recalled echo (GRE) and FSE images, the intensity of the epidural fat is similar to or less than that of CSF and does not always provide adequate contrast between the other tissues in the spinal canal. This is especially true in the lumbar neural foramen, where lateral herniated may be very difficult to visualize on T2-weighted FSE images and the same disc fragment is obvious on the T1-weighted SE image (Fig. 20.2). Compared with the lumbar spine, the epidural space in the cervical and thoracic spine has little epidural fat. In the cervical spine, contrast is provided by the signal intensity differences related to the presence of prominent epidural veins and from CSF in the thecal sac. Therefore, GRE imaging is an important tool in the cervical spine for defining epidural disease. Furthermore, on conventional SE and FSE images, it is difficult to differentiate osteophytes from disc material. On GRE images, these can usually be easily differentiated because bone is markedly hypointense and disc is hyperintense, regardless of flip angle (Figs. 20.3 and 20.4) (1). T2-weighted FSE images are routinely obtained in the sagittal and axial planes to evaluate the lumbar spine. These can be obtained in one-third to one-half of the acquisition time required for conventional T2-weighted SE sequences. FSE images are typically obtained using a multiple-echo pulse sequence with an effective echo time (TE) of approximately 100 ms. The relaxation time (TR) interval (determined by the patient’s heart rate) is generally in the range of 3,500 to 4,500 seconds. Axial T2-weighted FSE images are useful in the lumbar region to evaluate spinal canal size and particularly to evaluate the nerve roots of the cauda equina and the facet joints (Fig. 20.2). A major disadvantage of axial FSE imaging is the difficulty in differentiating disc from bone (Fig. 20.5). For this reason, GRE axial images are preferable to axial FSE images in the cervical spine. However, sagittal T2-weighted FSE techniques 1537

can produce images with exquisite spinal cord detail (Fig. 20.6) and are not nearly as sensitive to magnetic susceptibility artifacts as are GRE sequences. The use of fat-saturation techniques with FSE imaging can render active inflammatory conditions of the disc or facet joints more obvious. Anatomic considerations also have an impact on the choice of MR pulse sequence. First, there is less of a need for ultrathin section, very high-resolution scans in the lumbar spine because disc spaces are relatively thick and foramina are large. In the cervical and thoracic spine, disc spaces are thinner and the neural foramina are smaller, so thinner slice thicknesses are necessary. Cervical spine imaging requires the use of contiguous slices, a factor that also favors GRE sequences, because contiguously acquired conventional SE scans may be degraded by cross-excitation artifacts (“cross-talk”) or necessitate very long scan times. The sagittal plane is often adequate for demonstrating lumbar spine neural foramina because of the anatomic orientation of these canals, whereas the cervical foramina are obliquely oriented and require either oblique sectioning or three-dimensional (3D) reformatted images for optimal visualization. Although computed tomography (CT) using thin sections (1 mm or less) and three-dimensional (3D) reformatting remains the gold standard for evaluation of the cervical neural foraminal stenosis, 3D FT GRE MR of the cervical neural foramen has become an acceptable alternative (Fig. 20.7). The 3D images are acquired using either T2*-weighted GRE or T1-weighted GRE (spoiled grass) sequences. The 3D spoiled grass (SPGR, GRE Medical Systems, Milwaukee, WI) sequence with intravenous gadolinium is especially valuable for evaluating the foramen because the epidural veins, prevalent in the cervical foramen, enhance with paramagnetic contrast agents, whereas normal nerve roots do not enhance. However, the dorsal root ganglia do enhance with contrast because they lack a “blood–nerve barrier.” The size of the cervical neural foramina can be accurately evaluated, and any impinging osteophytes can be detected by using the 3D GRE technique (Fig. 20.8).

FIGURE 20.1 Appearance of an intervertebral disc on sagittal T1 spin-echo (A), T2 fast spin-echo (B), and fatsaturated T2 fast spin-echo images (C). The intervertebral disc has uniform intensity on the T1 spin-echo image. The nucleus (N) and inner annulus have relatively high intensity, whereas the outer annulus (O) has low intensity on T2 fast spin-echo images in panels B and C and on the axial T2 fast spin-echo image (D). The nucleus is brighter relative to the vertebral body on the fat-saturated image in panel C.

Imaging Strategies When imaging the lumbar spine with MR, SE/FSE sequences are generally the most useful for depicting 1538

the relevant anatomy. All patients evaluated for spinal disease should first be scanned with T1-weighted and T2-weighted (F)SE sequences. In MR, one should capitalize on the ability to image the spine in multiple planes, which allows us to see the nerve roots in the foramina, the cephalocaudad extent of herniated disc material, and any changes in the disc architecture itself. In the lumbar spine, a 3- to 4mm slice thickness is preferable for adequate resolution of the disc and neural foramen in the sagittal and axial planes. In the cervical and thoracic spine, a 2- to 3-mm slice thickness is necessary for routine sagittal and axial imaging. By virtue of more powerful gradients in state-of-the-art scanners as well as available 3-T systems, either very thin-section 2D GRE images or 3D volume reformatted images can optimally evaluate the cervical neural foramen.

FIGURE 20.2 Lateral disc protrusion (arrow) at the L2–L3 level is easier to see on the T1-weighted image (A) but less conspicuous on the T2-weighted fast spin-echo image (B).

FIGURE 20.3 Axial images through the cervical spine (three-dimensional Fourier transform gradient-echo magnetic resonance; 50/15/60, 30, 10, and 5 degrees) show that at a high flip angle, the cord is hyperintense and cerebrospinal fluid (CSF) is of low intensity. At 10 degrees the cord and surrounding CSF are isointense, and at 5 degrees the CSF is hyperintense to low-intensity cord. Note that neural foramina are clearly depicted on the 5-degree flip-angle image. Also note that bone is always of low intensity, whereas disc material is always of high intensity, regardless of flip angle.

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FIGURE 20.4 A,B: Cervical spondylosis with osteophytes and bulging discs noted at multiple levels in gradient-echo images (panel A, echo time 9 ms; panel B, echo time 27 ms). Note that the osteophyte (white arrows) appears larger in panel B because of accentuation of its size by magnetic susceptibility artifact. This makes the spinal canal appear narrower in panel B than in panel A. Black arrows in panel A refer to posterior longitudinal ligament.

FIGURE 20.5 Cervical disc bulging shown on sagittal gradient echo (A) obtained with 30-degree flip angle and on corresponding sagittal T2-weighted fast spin echo (B). Because the intervertebral disc (white arrow) has high signal intensity in panel A compared with panel B, it is easier to differentiate the vertebral body from the disc material in panel A on the gradient echo. The spinal cord is visualized better in panel B, as is the thickened ligamentum flavum (black arrow).

Coverage on the sagittal images should include the neural foramen bilaterally, and the conus medullaris must always be imaged because it is not rare for a conus mass to present as radiculopathy or low back pain (Fig. 20.1). In the axial plane, the lumbar spine must be imaged with angled slices oriented parallel to each respective disc, and axial images should cover pedicle to pedicle through all lower lumbar intervertebral discs. However, nonangled contiguous axial image acquisition is preferable to angled sections for evaluation of the vertebrae, for spinal stenosis and pars interarticularis defects, and generally to avoid inadvertent omission of regions of the spine when selecting angled slices.

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FIGURE 20.6 Comparison of sagittal T2-weighted fast spin-echo image (A) and gradient-echo image (B). The intervertebral discs have higher signal intensity relative to bone on the gradient-echo image. However, the spinal cord and ligaments are better visualized in panel A.

T2-weighted FSE sequences are excellent for evaluating the spinal cord and cauda equina and for measuring the spinal canal. However, T2-weighted FSE sequences are less effective for evaluating bone marrow edema or marrow-infiltrating disease unless they are acquired with a fat-suppression technique or supplemented with STIR (short inversion-time inversion recovery) imaging. In the cervical spine, GRE images are more useful than FSE images in evaluating disc disease in axial plane. After cervical spine fusion or laminectomy, GRE images may be less useful due to their greater sensitivity to magnetic susceptibility artifact from metallic material. Using minimum TE and higher receiver bandwidth (e.g., 32 kHz), particularly with FSE acquisitions, one can minimize these artifacts. In cervical and thoracic spine imaging, the initial sequence should include thin-section (3 mm), sagittal, T1-weighted, and T2-weighted scans with minimal or no interslice interval. Axial images should be performed using either 2D or 3D GRE techniques in the cervical spine, where a low flip angle is selected to generate high-intensity CSF (5-degree flip angle for 3D FT and 30-degree flip angle for 2D FT techniques). Aside from slice thickness, the benefit of GRE imaging in the cervical spine is more accurate distinction of disc material from osteophyte. Thoracic spine imaging often is accomplished by the use of sagittal thin-section FSE images and is optimized with the concomitant use of saturation pulses and gradient moment nulling, as already discussed. In imaging for thoracic disc and spinal cord disease, T1-weighted SE and T2-weighted FSE sequences are obtained routinely. Axial images are optionally obtained if the sagittal scans show an abnormality. Herniated thoracic discs can be shown in axial plane on T1-weighted SE or T2-weighted FSE images. It is important not only to evaluate the spinal column and associated structures, but also carefully to evaluate the paraspinal musculature for inflammation, localized muscle enlargement, or atrophy. Because the posterior paraspinal muscles are often partially obscured by the bright signal intensity related to the nearby surface coil, there is a tendency to overlook the paraspinal muscles in routine evaluation of MR spine images. Axial T2-weighted FSE images with fat saturation, inversion recovery with STIR, or contrast-enhanced T1-weighted images of the spine with fat saturation can be very helpful in revealing posterior paraspinal muscular abnormalities or facet joint synovitis (Fig. 20.9). Obtaining these sequences is strongly recommended when patients have localized back pain or spinal instability and conventional MR imaging (MRI) of the spinal column structures fails to reveal the source of the pain. In cases of low back pain and normal or minor abnormal imaging findings on the lumbar spine MR study, one should consider evaluation of the lower thoracic spine, sacrum or the pelvic bone, and soft tissues. Care must be taken not to overlook occult sacral insufficiency fractures or a tumor of the lower pelvis or conus medullaris, which could be the source of the patient’s symptoms.

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FIGURE 20.7 Three-dimensional Fourier transform images showing a herniated disc (large arrow) at the C5–C6 level to the left of midline. Note that the cervical neural foramen is well shown on two image slices. The site of annular tear (small arrow) is also well shown. However, there is poor differentiation between the cervical spinal cord and the cerebrospinal fluid despite the 5-degree flip angle used.

FIGURE 20.8 Evaluation of cervical neural foramen using three-dimensional (3D) Fourier transform imaging in axial 3D gradient-echo image (A) with a 1-mm slice thickness and 5-degree flip angle. The neural foramen (between arrows) is well demonstrated, and there is adequate contrast between the cerebrospinal fluid and the spinal cord. In axial 3D spoiled grass (B) after administration of intravenous gadolinium-diethylenetriamine penta-acetic acid, the epidural venous network and other connective tissues enhance, surrounding the nerve root and nerve root sheath in the neural foramen (arrows). C: Reformatted 45-degree oblique coronal image with gadolinium enhancement demonstrates the size of the neural foramen and indicates the presence of mild neural foraminal narrowing (arrows) at the C5–C6 level on the left due to uncinate and facet hypertrophy.

FIGURE 20.9 Facet synovitis, C4–C5 left. Unenhanced axial T2 fast spin-echo image with fat saturation (A) shows hyperintense signal in the lamina (wavy arrow), articular facets, and surrounding soft tissues (arrows). The same areas enhance (arrows) on gadolinium-enhanced T1 spin-echo image (B) obtained with fat saturation. The findings could be seen in sterile or infectious synovitis.

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ANATOMY OF THE INTERVERTEBRAL DISC The intervertebral disc is a complex structure consisting of several highly specialized connective tissues (2). A combination of hyaline cartilage, fibrocartilage, mucopolysaccharide, and dense collagenous fibrous tissue gives the discs the properties that confer flexibility and stability to the spine (3). The disc structure is usually described in terms of three components: the cartilaginous endplate, nucleus pulposus, and annulus fibrosus. The cartilaginous endplate is a layer of hyaline cartilage that covers most of the vertebral endplate (Fig. 20.10). Surrounding the cartilaginous endplate is a ring of dense bone—the ring apophysis—that fuses to the vertebra in the second decade of life. The cartilaginous endplate attaches firmly to the osseous endplate by means of numerous collagenous fibers and strengthens the osseous endplate, which contains multiple perforations. Because of the perforations, Schmorl suggested that it should be classified with cancellous bone. Within the pores of the vertebral endplate are numerous vascular channels, which are the major source for the nutrients and, during imaging studies, the contrast medium, which diffuses into the disc (Fig. 20.11) (4,5). With degeneration of the disc, the perforations become less well defined and less conspicuous. One of the theories of disc degeneration is that endplate changes that impair diffusion into and out of the disc hinder the function of chondrocytes and fibroblasts in the disc. The annulus fibrosus is a complex fibrous and fibrocartilaginous structure that consists of 12 to 15 layers, each with well-developed dense parallel fibrous bands (6) (Fig. 20.10). For descriptive purposes, it can be divided into outer and inner rings. The outer ring contains the densest fibrous lamellae. The fibers in this portion of the annulus originate and insert in the compact cortical bone in the ring apophysis (Fig. 20.12). These fibers, because of their osseous attachments, may be described as Sharpey fibers after the English anatomist who described the collagenous structure of bone. The lamellae consist almost exclusively of dense type I collagen with little ground substance, unlike other portions of the disc. This portion of the disc on T2- or T1-weighted images has a low signal intensity (Fig. 20.13). The approximately 8,000 cells in each cubic millimeter of tissue within the outer ring of the annulus are almost exclusively fibroblasts. The outer annulus is thicker anteriorly than posteriorly.

FIGURE 20.10 Sagittal anatomic section through a normal lumbar intervertebral disc illustrating the cartilaginous endplate (arrowheads), the annulus fibrosus (A), nucleus pulposus (N), ring apophysis (white arrows), anterior longitudinal ligament (black arrows), and adjacent vertebral bodies.

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FIGURE 20.11 Sagittal magnetic resonance images of a rabbit spine obtained before (A) and at 30 (B) and 120 (C) minutes after intravenous administration of gadoteridol, 0.3 mmol/kg. Note that contrast enhancement is evident first at the endplate (arrows, B) and then throughout the intervertebral disc (C).

FIGURE 20.12 Sagittal anatomic section of the L5–S1 intervertebral disc illustrating a dense collagenous lamellar structure in the peripheral annulus fibrosus (arrows). These dense fibers originate and insert in the ring apophysis. Medial to this dense collagenous structure is the central portion of the annulus fibrosus with a less well-defined lamellar structure and fibrocartilage. The nucleus pulposus occupies a small portion of the intervertebral disc. The dark pigment (P) stains part of the nucleus and the inner annulus.

The inner ring of the annulus fibrosus contains fibrocartilage. Unlike the outer ring of the annulus, the inner ring contains predominantly chondrocytes and has plentiful ground substance. The collagen in the inner ring is less plentiful than in the outer ring. Because of the ground substance, the inner ring has a high signal intensity like the nucleus pulposus on T2-weighted images (Fig. 20.13) (7). The lamellae are less well defined and less fibrous than in the peripheral ring. The lamellae become less and less well defined toward the center of the disc. As the lamellar structure changes, the annulus becomes gradually less and less distinguishable from the nucleus pulposus (Fig. 20.14). The fibers in each layer of the inner 1544

or outer annulus run radially at an angle of about 30 degrees with respect to the endplates. Fibers in adjacent lamellae are nearly perpendicular to each other.

FIGURE 20.13 Comparison of a sagittal anatomic section (A) with the exact corresponding magnetic resonance image (B) (repetition time 2,000 seconds, echo time 80 ms, spin echo). Note that the peripheral annulus has a low signal intensity (arrows), whereas the inner annulus and the nucleus pulposus, which have a mucopolysaccharide matrix, have a higher signal intensity. The lower signal intensity in the equator of the nucleus and annulus (arrowheads) is due to a higher concentration of collagen.

FIGURE 20.14 Axial cryomicrotome section through the L3–L4 intervertebral disc. No clear distinction exists between the inner annulus and nucleus pulposus. Concentric fiber bundles make up the outer annulus. The posterior disc margin is concave and does not deform the thecal sac. 1, Inner annulus; 2, outer annulus; 3, ligamentum flavum; 4, nucleus pulposus; 5, thecal sac containing cauda equina nerve rootlets; 6, epidural fat.

The nucleus pulposus is also composed of fibrocartilage. It has approximately the same amount of ground substance as the inner annulus and approximately the same signal intensity as the inner annulus on T2-weighted images (Fig. 20.13). The collagen present in the nucleus is type II, which is stronger in compression and weaker in tension than type I. The collagen in the nucleus is less well structured than in the annulus, giving it an amorphous appearance rather than a lamellar structure. The equator of the disc contains a higher collagen concentration than the remainder of the disc. The region of greater collagen concentration has a lower signal intensity than the remainder of the disc on T2-weighted images (Fig. 20.12) (7). The ground substance in the nucleus pulposus consists of hyaluronic acid and glycosaminoglycans, which contain the polysaccharides keratin and chondroitin sulfate. These substances have a high concentration of fixed negative charges that cause the disc to absorb water even in the presence of a high-pressure gradient (8). The mucopolysaccharide gel in the nucleus pulposus gives the disc its high intrinsic pressure, which allows it to resist compressive forces. When the nucleus is removed from the disc, it readily absorbs water and expands. Water in the disc is normally determined by the intradiscal pressure and the capacity of the disc to absorb water. When the load on the disc increases, water leaves the disc, and when the intradiscal pressure diminishes, water returns (9). These changes in water content result in a diurnal variation in height. The glycosaminoglycans are 1545

synthesized by the chondrocytes present in the nucleus pulposus. Diffusion through the vertebral endplates provides the nutrients necessary for the metabolism and function of these cells (5). The composition of the fibrocartilage in the intervertebral disc explains the observed phenomenon of contrast enhancement. Normally, with doses of contrast medium in the range of 0.1 mmol/kg and images obtained promptly after intravenous injection of contrast medium, enhancement is not observed in the intervertebral disc. With larger doses of contrast medium and with longer elapsed times before imaging, enhancement may be observed because of the slow accumulation of contrast medium by diffusion (4). The enhancement is observed first near the periphery of the disc and subsequently near the center (Fig. 20.11). Enhancement is greater when nonionic contrast media such as gadoteridol or gadodiamide are used because diffusion of the ionic medium is hindered by the fixed negative charges in the intervertebral disc (Fig. 20.15) (10). The anterior longitudinal ligament (ALL) and posterior longitudinal ligament (PLL), although not normally considered part of the disc, are not easily distinguished from the disc (Fig. 20.14). The ALL, consisting of fibroblasts and collagen, forms a thin layer over the anterior and lateral surfaces of the disc (Fig. 20.10). Its fibers are in contact with the outermost layer of the annulus fibrosus. It contains some fibers that originate and insert in the compact cortical bone in the vertical portion of the vertebrae. The low signal intensity of the PLL is difficult to distinguish from the low signal intensity of the peripheral annulus fibrosus in either T1- or T2-weighted MR. The PLL has a similar composition and signal intensity. The thin band of collagenous fibers in the PLL is difficult to distinguish from the annulus fibrosus along the posterior aspect of the disc (Fig. 20.10). At the intervertebral disc level the fibers of the PLL diverge, have a horizontal orientation, and merge with the fibers of the annulus fibrosus. Between disc spaces, the PLL has mostly longitudinally oriented fibers. It forms a band approximately 1 mm thick and 3 mm wide between intervertebral discs, posterior to the retrovertebral plexus and ventral to the dural sac.

FIGURE 20.15 Contrast enhancement of normal rabbit intervertebral discs after the administration of a nonionic or ionic gadolinium-containing chelate (0.3 mmol/kg). Contrast enhancement is greater from nonionic ProHance or Omniscan than for the ionic Magnevist.

The disc normally lacks innervation and vascularity. Nerves, which may be nociceptors, have been identified in the ALL and PLL, in the facet joints, in the vertebral endplates, and arguably in the peripheral layer of the annulus fibrosus (3). Therefore, the disc is not normally a source of pain, although degeneration in the disc may lead to pain by means of stretching of nociceptor and nerve compression of the production of inflammation. Blood vessels are not normally found in cartilage. The nutrition of the intervertebral disc, as in other cartilaginous structures, is provided by diffusion.

AGE-RELATED CHANGES IN THE INTERVERTEBRAL DISC The intervertebral disc undergoes marked changes with aging, which should be distinguished from the changes due to degeneration of the intervertebral disc (9,11–14). When age-related and degenerative changes are not distinguished, the incidence of degeneration is grossly exaggerated. The incidence of intervertebral disc degeneration increases with age, but most intervertebral discs in normal individuals do not show the changes in height, signal intensity, and morphology that characterize degenerating intervertebral discs. Despite increasing numbers of small tears and amount of pigment and collagen and decreasing amounts of glycosaminoglycans in the nucleus pulposus, most discs retain normal 1546

biomechanical function into the seventh and eighth decades of life (6,13). The magnitude of the agerelated changes in the intervertebral disc can be illustrated by comparing the appearance of the neonatal, transitional and young-adult, and older-adult intervertebral discs. In the neonate, with an incompletely ossified vertebral body, the space between vertebrae appears large. A portion of that space consists of unossified cartilaginous vertebral body. The disc itself contains a thin peripheral rim with a distinct lamellar structure, which corresponds to the peripheral annulus fibrosus (Fig. 20.16). This annular rim and the ossification centers in the vertebrae have low signal intensity on T1- and T2-weighted images. The remainder of the disc has moderately high signal intensity (15). Medial to the peripheral annulus is a thin layer of tissue with little lamellar structure that grossly has the same appearance as vertebral cartilage. It represents the inner portion of the annulus fibrosus. The remainder of the disc consists of a translucent substance—the nucleus pulposus. In the equator of the disc are thin streaks of tissue with syncytial cells that are remnants of the primitive notochord (13). The nucleus and annulus are sharply demarcated in the newborn. On gross inspection, vessels are evident in the vertebral cartilage near the future ring apophysis and in the ossifying center of the vertebra (Fig. 20.16). Otherwise, the disc appears avascular as in the adult.

FIGURE 20.16 In the cryomicrotome (A) and magnetic resonance image (B) of the neonatal intervertebral disc, the unossified portion, small vascular channels can be identified (arrows). The annulus and nucleus are sharply demarcated. In the peripheral annulus, a lamellar structure is evident.

During the first two decades of life, the disc develops the fibrous structure that characterizes the adult disc (16). During the second decade of life, the intervertebral disc can be characterized as transitional between the newborn and the adult disc. The transitional disc has lamellae of fibrocartilage with a distinct fibrous structure. The nucleus pulposus, which has an ill-defined border within the annulus, has become opaque rather than translucent because of the development of collagen fibers within it. The collagen content of the inner annulus and the equator of the disc has increased to the degree that these regions are less translucent and lower in signal intensity on T2-weighted MR (Fig. 20.17). The vertebral body and the ring apophysis have not yet ossified completely. On MR, the marked difference in signal intensity between the fibrous and fibrocartilaginous portions of the disc is evident. Once the adult intervertebral disc has appeared, it continues to change with age. With aging, small concentric and transverse tears develop in the annulus (Fig. 20.18) (14,16). The former is characterized as delamination of the lamellae in the annulus fibrosus with the development of a mucoid substance or fluid in the space. These tears may be visualized on MR as a narrow band of higher-intensity signal, indicating the location of the mucoid substance or fluid. The latter are short disruptions in the annulus near the insertion of Sharpey fibers into the ring apophysis. These may be visualized on MR or CT as small collections of fluid. Rarely, gas may be identified in these tears. Both types of tears are common in adult discs with or without other signs of degeneration. These are, therefore, aging changes rather than degenerative changes.

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FIGURE 20.17 Sagittal anatomic image of the spine of a 13-year-old child. Note the decreased translucency of the nucleus pulposus.

With aging, the composition of the intervertebral disc changes (8,17). Collagen increases and glycosaminoglycans decrease in the disc. These changes result in a lower affinity of the disc for water and therefore a decrease in the water content of the disc. The water content of the disc may diminish by 10% or 15% over five decades. Therefore, with aging the signal intensity of the disc diminishes by a few percent. Loss of the normal high signal intensity on T2-weighted images or loss of the normal intervertebral disc height is, however, not explained entirely by aging.

ANATOMY OF THE ARTICULAR FACETS The facet joint is a true synovial-lined joint that allows the spine to bend. The plane of the facet joint varies from a near-sagittal plane in the cervical spine to an oblique coronal orientation in the thoracic and lumbar spine. The facet is the surface of the inferior or superior articular process. Each apposing facet is composed of a thin uniform layer of dense cortical bone and an overlying layer of cartilage. The facet joint in young normal persons contains a meniscus that usually disappears after the age of 40 years. The facet joint is lined by synovium. Anteriorly, the facet joint has no capsule and is bound only by the ligamentum flavum (18). The synovium anteriorly extends a variable distance posterior to the ligamentum flavum. In fact, the space posterior to the ligamentum flavum should be considered an extension of the facet joint. When the ligamentum flavum degenerates, the synovial-lined space posterior to the ligamentum flavum may distend and form a discrete synovial-lined cyst that can impinge on the thecal sac. Posteriorly, the facet joint is lined by a broad, thick, fibrous capsule.

FIGURE 20.18 Sagittal anatomic and magnetic resonance images. A: Sagittal cryomicrotome section of lower lumbar spine in an adult. With advancing age, the disc loses water and becomes fibrotic (1). A more normal disc is seen at the L5–S1 level. There are early degenerative changes seen in the nucleus pulposus at this level. The normal annulus fibrosus has 12 to 15 concentric lamellae (5). 1, Degenerated L4–5 disc; 2, L% vertebral body; 3, anterior longitudinal ligament; 4, Sharpey fibers; 5, anterior annulus; 6, posterior longitudinal ligament; 7, cartilaginous endplate; 8, nucleus pulposus. B: Sagittal anatomic sections illustrating transverse (arrow) and concentric tears (arrowheads) that develop in many older intervertebral discs. For comparison, a radial tear is illustrated (open arrows) at levels where disc degeneration is present.

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DEGENERATION OF THE INTERVERTEBRAL DISC The pathogenesis of intervertebral disc degeneration is not well understood. Trauma is not likely the major factor in disc degeneration. Epidemiologic studies show that a history of trauma is obtained in some patients with herniated intervertebral discs. Biomechanical studies show that the disc is less likely than the vertebral body to fail as the result of trauma (19). Repetitive cyclical loading of the disc may result in failure of annular fibers (20). Decreasing permeability of the vertebral endplates has been suggested as a cause for disc degeneration. Despite the lack of consensus on the cause of disc degeneration, one morphologic feature characterizes discs with herniations, bulging, loss of height, and loss of signal intensity (21,22). The annular fissure (formerly tear), which is found consistently with the other degenerative changes in the intervertebral disc, is characterized in the biomechanical engineering studies of the disc as a primary failure of the annulus (23,24). Annular fissures are sometimes classified by their orientation (Fig. 20.19). The radial fissure involves all layers of the annulus fibrosus in its anterior, posterior, or possibly lateral portion (Figs. 20.18 and 20.20). The annular fissure can be seen effectively with precise anatomic sectioning techniques such as cryomicrotomy. It may be detected by MR as a band of high– signal-intensity tissue in the region of the disc normally characterized by low signal intensity (Fig. 20.21). It may also be visualized on contrast-enhanced MR as a strip of enhancement in the normally nonenhancing disc (Figs. 20.22 and 20.23). The annular fissure may, therefore, be a marker of disc degeneration. MR is less sensitive than cryomicrotomy or discography in detecting radial fissures (Fig. 20.24).

FIGURE 20.19 Fissures of the annulus fibrosus. Fissures of the annulus fibrosus occur as radial (R), transverse (T), and/or concentric (C) separations of fibers of the annulus. The transverse fissure depicted is a fully developed, horizontally oriented radial fissure; the term “transverse fissure” is often applied to a less extensive separation limited to the peripheral annulus and its bony attachments. (From Fardon DF, Williams AL, Dohring EJ, et al. Lumbar disc nomenclature: version 2.0. Recommendations of the combined task forces of the North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology. Spine J 2014;14:2525–2545 with permission.)

FIGURE 20.20 Sagittal cryomicrotome section through the lumbar intervertebral disc. The nucleus (1) is desiccated, and there is a type 2 tear (3) in the outer annulus (2). The posterior disc margin (4) bulges into the spinal canal. A tiny type 1 tear (5) is seen in the posterior annulus.

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FIGURE 20.21 A: Annular fissures posteriorly (arrows) at L4–L5 and L5–S1 levels in sagittal T2 fast spin-echo image. B: L4–L5 (arrow annular fissure) shown on axial gradient-echo image.

FIGURE 20.22 Sagittal T1-weighted spin-echo image after intravenous administration of gadolinium demonstrates enhancement in a posterior annular fissure (arrows) at the L4–L5 level.

FIGURE 20.23 A composite of a T1-weighted spin-echo image (A), a contrast-enhanced and fat-suppressed T1weighted image (B), and a T2-weighted image (C) illustrating an annular fissure at L4–L5 characterized by contrast enhancement and high signal intensity in T2-weighted images.

FIGURE 20.24 Discogram (A) shows extravasation of contrast (arrow) through a posterior annular tear.

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Postdiscogram axial CT (B) shows a posterior annular tear (arrows) with extravasation along the posterior disc margin.

Magnetic Resonance of Disc Degeneration As a disc degenerates it loses water, fissures develop in the annulus, and the structural integrity of the annulus becomes compromised (Fig. 20.25). On MR, these changes are manifested as a decrease in disc space height and decreased signal intensity on T2-weighted image (Fig. 20.26) which may or may not be associated with disc bulging. It has been proposed that intervertebral disks that have diminished T2 signal intensity without evidence of disk collapse, herniation, or bulging differ from normal disks not only in water content but also in gross morphology, biochemistry, and biomechanics, and have the potential to cause low back or leg pain (25). In severe disc degeneration, the disc is collapsed and often contains gas (believed to be nitrogen), which is low intensity on T1- and T2-weighted images. Intradiscal gas is more obvious on T2*-weighted GRE images because of signal intensity loss related to magnetic susceptibility effects. CT is more sensitive than MR for detecting gas in a severely degenerating facet or intervertebral disc (Fig. 20.27). Another characteristic of disc degeneration (intervertebral osteochondrosis) is alterations of the adjacent vertebral body architecture (Fig. 20.28). Affected vertebrae show increased density (“discogenic sclerosis”) on radiographs and CT. The MR appearance of degenerative discogenic vertebral changes has been classified (see Table 20.1) (Fig. 20.29 and 20.30) (14). While there is no consensus as to the clinical significance of the described “types” of marrow change within such a classification, type 1 changes have been reported as being associated with active low back symptoms and segmental instability (26). As vertebral endplates in type I or II may enhance with gadolinium contrast, it is most important to avoid confusion with less benign diseases like infection or metastases (Table 20.1). Intervertebral Disc Infection Intervertebral discitis is an inflammatory condition resulting in disc and vertebral endplate destruction and usually osteomyelitis in the adjacent vertebral bodies. In adults, the process is caused by infection that initially involves the cancellous bone adjacent to the vertebral endplate, as the endplate is destroyed, the disc is destroyed, and fluid accumulates in the disc space. A paraspinal mass is often present at the affected level, but 25% also have other disc levels involved.

FIGURE 20.25 Anatomic (A) and exactly correlating magnetic resonance (B) illustrating degenerative changes associated with a radial tear of the annulus fibrosus in a cadaver. At L4–L5, the intervertebral disc has diminished height, diminished signal intensity, and slight bulging of the posterior annulus. The radial tear (arrow) is evident on the anatomic sections as a dark band extending through the annulus.

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FIGURE 20.26 Sagittal T2-weighted spin-echo image showing early degenerative disc disease at L4–L5 and marked signal intensity loss in the intervertebral disc at L5–S1 indicating advanced disc degeneration at this level. A posterior radial tear (arrows) has high signal intensity relative to adjacent bone and degenerating disc.

On T1-weighted images, the vertebral body endplates in discitis are hypointense and sometimes slightly hyperintense, and the endplate cortex is ill defined or destroyed. The signal intensity within the disc is decreased on T1-weighted images but is almost always increased on T2-weighted images with discitis (Fig. 20.31). This is an important differential diagnostic point because in uncomplicated degenerative discogenic disease, the intervertebral disc has low signal intensity (27). Rudimentary or underdeveloped discs also appear to be slightly hyperintense on T2-weighted images, but the endplates are intact in this situation. Vertebral osteomyelitis, seen as high signal intensity on T2-weighted images, often enhances intensely with paramagnetic contrast (Fig. 20.32). Endplate enhancement due to degenerative disease tends to be subtler unless a fat suppression technique is used. The intervertebral disc itself typically enhances intensely in discitis unless the disc space contains fluid sequestered from the contrast agent (Figs. 20.33 and 20.34). An inflammatory paraspinal and peridiscal mass usually accompanies discitis, and the paraspinal mass enhances with paramagnetic contrast. In chronic osteomyelitis and discitis, the disc space can be totally obliterated.

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FIGURE 20.27 Vacuum disc, vertebral subluxation at L4–L5, and degenerative discogenic vertebral disease. A: Computed tomography demonstrates gas in the L4–L5 intervertebral disc. Sagittal T1-weighted spin-echo image (B) and gradient-echo image (C) demonstrate gas (long arrow) in the L4–L5 disc, which has low signal intensity. Type I degenerative vertebral disease (small arrows) is seen in the adjacent vertebrae. Note anterior subluxation of L4 on L5.

FIGURE 20.28 Vertebral marrow and endplate changes associated with degenerative disc disease. In the vertebrae adjacent to a degenerating L4–L5 disc (A), fatty degeneration (arrows) is noted in the marrow. A different type of reaction characterized by fibrosis and hyperemia of the marrow (arrows) is noted adjacent to another degenerating intervertebral disc with a radial tear (B). Sclerosis of the adjacent vertebral endplates (arrows) is illustrated by this anatomic section through the cervical spine (C).

TABLE 20.1 Modic Classification of Vertebral End Plate Bone Marrow Degenerative Changes 1553

FIGURE 20.29 Type II discogenic vertebral disease. The distorted vertebral architecture (arrows) has high intensity on T1-weighted (A) and T2-weighted (B) spin-echo images. Loss of signal intensity in the intervertebral disc at L4– L5 and L5–S1 indicates disc degeneration.

FIGURE 20.30 Modic type 2 endplate bone marrow signal changes (black arrowheads). L5–S1 disc extrusion compressing thecal sac (white arrows). Mixed areas of low signal with the disc herniation may reflect annular material and possibly bone.

FIGURE 20.31 L2–L3 disc space infection and osteomyelitis. The vertebral endplates are destroyed and the adjacent vertebral bodies have abnormal signal intensity secondary to osteomyelitis on T1-weighted sagittal spin-echo image (A) and T2-weighted fast spin-echo image (B). The infected disc space (small arrows) has higher intensity than

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normal intervertebral disc.

FIGURE 20.32 Enhancing degenerative endplate disease. Unenhanced image (A) shows low signal intensity (arrow) in the vertebral bodies adjacent to the degenerating L5–S1 disc. Gadolinium-enhanced image (B) shows subtle enhancement in the adjacent endplates and vertebral body but no appreciable enhancement of the intervertebral disc itself.

FIGURE 20.33 Intense enhancement of vertebral endplates and vertebral bodies adjacent to degenerating disc at C5–C6. A: Unenhanced image shows low signal intensity in the vertebral bodies adjacent to the C5–C6 disc. B: Intense enhancement (arrows) in C5 and C6 vertebral bodies adjacent to the disc is accentuated by the fat suppression technique. The intervertebral disc endplates appear intact.

CLASSIFICATION OF LUMBAR DISC PATHOLOGY The terms used to describe bulging and herniated discs have historically been somewhat confusing and widely misused. It is important to understand first the morphologic classification of the various degrees of disc displacement and then to adopt a practical working classification for reporting purposes. In 2001 and more recently revised in 2014, combined task forces of North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology published recommendations to standardize nomenclature and classification of lumbar disc pathology (28). The main nomenclature and classification recommendations are as follows (Figs. 20.35 and 20.36): 1. Disc bulge. A disc bulge represents a disc in which the contour of the outer annulus extends, or appears to extend, in the horizontal (axial) plane beyond the edges of the disc space, usually greater than 25% (90 degrees) of the circumference of the disc and usually less than 3 mm beyond the edges of the vertebral body apophyses (Fig. 20.2). This occurs due to tears in the oblique collagen bridges between the concentric annular fibers (Fig. 20.37), producing diffuse laxity of the annulus. The concentric annular fibers remain intact (Fig. 20.38). The MR appearance of disc bulging is symmetric uniform extension of the outer disc margin circumferentially (Fig. 20.39). An asymmetric disc bulge is the presence of more than 25% of the outer annulus beyond the perimeter of the adjacent vertebrae, 1555

more evident in one section of the periphery of the disc than another, but not sufficiently focal to be characterized as a protrusion (Fig. 20.2). A disc bulge by definition is not a herniation.

FIGURE 20.34 A: Disc space infection, osteomyelitis, and epidural abscess (arrows) at T12–L1 level compresses the conus medullaris. B: Note intense enhancement of the vertebral bodies and vertebral endplates. A thin, dark band of nonenhancement at the disc space level in panel B probably represents fluid in the disc space that is sequestered from the blood supply.

FIGURE 20.35 Graphical depiction of a normal lubar disc. Axial (left) and sagittal (right) images demonstrate that the normal disc, composed of central nucleus pulposus (NP) and peripheral annulus fibrosis (AF), is wholly within the boundaries of the disc space, as defined craniad and caudad by the vertebral body end plates and peripherally by the planes of the outer edges of the vertebral apophyses, exclusive of ostephytes. (From Fardon DF, Williams AL, Dohring EJ, et al. Lumbar disc nomenclature: version 2.0. Recommendations of the combined task forces of the North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology. Spine J 2014;14:2525–2545, with permission.)

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FIGURE 20.36 (Left) Normal disc for comparison; no disc material extends beyond the periphery of the disc space, depicted here by the broken line. (Middle) Symmetric bulging disc; annular tissue extends, usually by less than 3 mm, beyond the edges of the vertebral apophyses symmetrically throughout the circumference of the disc. (Bottom) Asymmetric bulging disc; annular tissue extends beyond the edges of the vertebral apophysis, asymmetrically greater than 25% of the circumference of the disc. (From Fardon DF, Williams AL, Dohring EJ, et al. Lumbar disc nomenclature: version 2.0. Recommendations of the combined task forces of the North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology. Spine J 2014;14:2525–2545, with permission.)

FIGURE 20.37 Sagittal cryomicrotome image through the anterior portion of the L4–L5 intervertebral disc demonstrating nucleus pulposus (N), inner annulus (IA), and cartilaginous endplate (CE); vertically oriented annular fibers are called concentric fibers. These are joined by oblique and transverse collagen bridges (cb). Densely compacted outer collagen fibers (cf) are called Sharpey fibers (S). ALL, anterior longitudinal ligament; BE, vertebral body endplate.

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FIGURE 20.38 Axial cryomicrotome section through the L3–L4 disc. The disc bulges diffusely in all directions and has a flattened or slightly convex posterior margin (1). 2, Anterior epidural venous space; 3, superior articular process of L4; 4, inferior articular cartilage of L3; 5, nerve root; 6, superior articular cartilage L4; 7, inferior articular process; 8, ligamentum flavum.

2. Disc herniation. A disc herniation is localized or focal displacement of disc material beyond the normal margin of the intervertebral disc space. Localized by definition refers to less than 25% (90 degrees) of the circumference of the disc. Disc material may include nucleus pulposis, cartilage, bone, or annular tissue (Fig. 20.40). The term “herniated nucleus pulposus,” is a misnomer because the herniated disc material often contains not only nuclear material but other disc components as well (Fig. 20.30). Herniated discs may be classified as either a protrusion or an extrusion, based on the shape of displaced material. 3. Disc protrusion. A disc protrusion is a herniated disc in which the greatest distance, between the edges of the disc material presenting outside the disc space is less than the distance between the edges of the base of that disc material extending outside the disc space. The base is defined as the width of the disc material at the outer margin of the disc space of origin, where disc material displaced beyond the disc space is continuous with the disc material within the disc space (Fig. 20.41). Anatomic classifications refer specifically to “intra-annular disc protrusions” (29), which may be considered as two subcategories. Inner annular disruption (Fig. 20.42) is similar to the anatomic term “intradiscal mass displacement,” which represents a shift in the location of nuclear material within the disc due to ruptures in the innermost fibers of the annulus. This causes no appreciable focal contour abnormality of the disc margin on MR. In the second subcategory, subtotal annular disruption, there is displacement of nuclear and inner annular material through a defect (radial fissure or tear) involving the inner annular fibers and some outer annular fibers. However, a few overlying outer annular fibers remain intact. On MR images, this causes a small focal abnormality of the disc margin where the protruding disc is cone shaped with a wide waist. This appearance is widely referred to as a disc protrusion in routine clinical practice. However, it is important to keep in mind that with MR or CT, it is difficult or impossible to differentiate a small herniated disc that has extended through the inner annulus from a small herniated disc that has penetrated all layers of the annulus, because either may produce a focal contour abnormality along the posterior disc margin (Figs. 20.43 and 20.44).

FIGURE 20.39 Diffusely bulging disc and central spinal canal stenosis. The disc margin (small white arrows) bulges in all directions symmetrically. Bilateral facet hypertrophy (small black arrows) and thickening of the ligamentum flavum (larger black arrow) all contribute to produce moderate central canal stenosis.

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FIGURE 20.40 Sagittal T1-weighted images (left) and sagittal T2-weighted images (right) demonstrate L4–L5 disc extrusion (white arrows). Notice the low-signal components (black arrow) of the disc herniation, which may represent fragments of annulus and/or apophyseal bone in addition to the nuclear material.

4. Disc extrusion. This is a herniated disc in which, in at least one plane, any one distance between the edges of the disc material beyond the disc space is greater than the distance between the edges of the base of the disc material beyond the disc space in the same plane or when no continuity exists between the disc material beyond the disc space and that within the disc space (Fig. 20.45). This is usually the result of extension through all layers of the annulus and appears as a focal epidural mass obscuring the epidural fat. In this situation, the disc herniation has a narrow waist at its site of its origin from the annulus where the disc material has extended through the outer annulus. Extruded discs may lie anterior or posterior to the PLL or both. Extruded discs that lie anterior to the PLL are often termed “subligamentous.” Extruded discs may lie anterior or posterior to the PLL or both. Extruded discs that lie anterior to the PLL are often termed “subligamentous.” When the distinction between the outer annulus and PLL is unclear or cannot be made, the term subligamentous is appropriate. The term “extruded disc” is sometimes erroneously used to indicate a free disc fragment because an extruded disc may extend above or below the disc space level and still be in continuity with the parent disc (Figs. 20.30 and 20.46). Extruded disc material that has no continuity with the disc of origin may be further characterized as sequestered or “sequestrated” (Fig. 20.47). The sequestrated disc fragment may lie at the disc level, either anterior or posterior to the PLL, or can migrate inferior or, less commonly, superior to the parent disc level. Free disc fragments may extend over two disc levels. Rarely, free disc fragments may extend into the thecal sac, i.e., through the dura, where they are properly referred to as “intradural disc herniations.”

FIGURE 20.41 Disc protrusion. Axial (left) and sagittal (right) images demonstrate displaced disc material extending beyond less than 25% of the disc space, with the greatest measure, in any plane, of the displaced disc material being less than the measure of the base of displaced disc material at the disc space of origin, measured in the same plane. (From Fardon DF, Williams AL, Dohring EJ, et al. Lumbar disc nomenclature: version 2.0. Recommendations of the combined task forces of the North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology. Spine J 2014;14:2525–2545, with permission.)

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FIGURE 20.42 Anatomic section, disc protrusion. The nuclear material (large arrow) protrudes through a defect in the inner annulus (small arrows) but does not extend through the outer annular fibers.

FIGURE 20.43 L4–L5 disc protrusion (black arrows). It is difficult to say whether this represents a protruding disc with some outer annular fibers intact or if it has extended through all layers of the annulus.

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FIGURE 20.44 Anatomic section (A) and axial MRI (B) showing partial annular disruption. Nuclear material (N) extends through a radial tear (T) in the posterior annulus on the right. Some overlying Sharpey fibers (S) remain intact in axial cryomicrotome.

Although the concepts and framework that resulted from the work of the joint task forces are beneficial for all physicians involved in the treatment of patients with lumbar disc disease, there are a few points that require clarification. First, there is no precise method for measuring a disc bulge, protrusion, or extrusion. In their definition, a disc bulge and herniation are described as abnormal discs that extensor appear to extend beyond the outer edges of the vertebral body apophyses. Although these are acceptable descriptions for the purposes of a definition, assigning the actual points on an image or pixels at which the disc space ends is subjective and prone to interobserver variability. Second, when one considers the inherent accuracy of measurement related to technical parameters commonly used in routine MR spine imaging protocols, it becomes clear that there is no method for accurately measuring a disc bulge or herniation. Any number provided by an interpreting physician is at best an estimate and of questionable value without considering the relative size of the spinal canal and neural foramen and the impact on adjacent neural structures. Given the above, there is little point in assigning a quantitative measurement for a disc bulge or herniation; moreover, it is misleading to put imprecise and nonreproducible numbers into a medical record.

FIGURE 20.45 Disc extrusion. Axial (left) and sagittal (right) sagittal images demonstrate that the greatest measure of the displaced disc material is greater than the base of the displaced disc material at the disc space of origin, when measured in the same plane. (From Fardon DF, Williams AL, Dohring EJ, et al. Lumbar disc nomenclature: version 2.0. Recommendations of the combined task forces of the North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology. Spine J 2014;14:2525–2545, with permission.)

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FIGURE 20.46 Huge extruded herniated disc fragment (arrows) continuous with the parent L4–L5 intervertebral disc has migrated inferiorly to the mid-S1 level in sagittal T2 fast spin-echo image (A). The disc fragment causes severe compression of the anterolateral aspect of the thecal sac at L4–L5 (B: axial T1 spin-echo image) and at L5–S1 (C: axial T1 spin-echo image).

The single, most essential role of the radiology report is to convey meaningful information to the referring doctor. Regardless of journal articles or society declarations that pronounce “official” terminology, therefore, it is critical that the MRI report utilizes terminology that the particular patient’s physician will understand. A bulging disc refers to generalized or diffuse disc bulging and can be modified by the terms mild, moderate, or severe, depending on the degree of disc bulging. A herniated disc (protrusion or extrusion) by convention is localized, involving less than 25% of the circumference of the disc margin, and causes a focal contour abnormality along the disc margin. The disc material or fragment size should be further characterized as small, medium, or large relative to adjacent anatomy as well as the disc material location. The location and relationship of the disc herniation to surrounding structures including nerve root compression if present should also be described. Wiltse proposed a location classification based on anatomic zones and levels primarily defined by the relationship of the disc herniation to medial margin of the articular facets and margins of the pedicles (20-48A) (30). Using axial images, one then classifies disc herniations into “central,” “subarticular,” “(intra)foraminal,” and “extraforaminal (lateral)” zones (20-48B). Location classification based on axial imaging is the most frequently used, in part relating to the ability to visualize the relationship of the disc to adjacent to exiting nerves.

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FIGURE 20.47 Sequestration. Axial (left) and sagittal (right) images show that a sequestrated disc is an extruded disc in which the displaced disc material has lost all connection with the disc of origin. (From Fardon DF, Williams AL, Dohring EJ, et al. Lumbar disc nomenclature: version 2.0. Recommendations of the combined task forces of the North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology. Spine J 2014;14:2525–2545, with permission.)

FIGURE 20.48 Vertebral body drawing demonstrating anatomic boundaries as proposed by Wiltse. A: Anatomic levels depicted in sagittal and coronal projections. B: Anatomic zones depicted in axial and coronal projections. (From Fardon DF, Williams AL, Dohring EJ, et al. Lumbar disc nomenclature: version 2.0. Recommendations of the combined task forces of the North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology. Spine J 2014;14:2525–2545, with permission.)

LUMBAR DISC HERNIATION The etiology of disc herniation in the lumbar spine is unknown, but degenerative disc disease, repeated trauma, and genetic factors have been implicated. Even more obscure is the etiology of the pain associated with disc herniation. Although mechanical pressure of the herniated disc on the nerves is certainly an important factor, this does not explain all symptoms in every case (31,32). Lindahl (33) showed that pressure on normal nerves is insufficient to cause pain unless the nerves are already hypersensitive to pain. Inflammation caused by release of histamine, bradykinin, or prostaglandins can sensitize the nerves to pain by activating pain receptors (nociceptors) when the disc herniates (33–35). Phospholipase A2 is another substance that may contribute to low back pain. Phospholipase A2 in increased amounts is found in synovial fluid, in facet synovitis, and in herniated disc fragments (36). Because the disc is an avascular substance (the largest in the body), the body may regard the herniated disc material as a foreign substance and mount an autoimmune response to it in some cases (37). Nerve endings exist in the periphery of the annulus, and when cracks develop in the annulus, these nerve endings may be irritated, causing low back pain (38). Stretching of the PLL by bulging or herniated discs has been implicated as a cause of low back pain and referred pain. Instability of the 1563

spine due to abnormal movement at the facet joints eventually develops either secondary to or concomitant with degenerative disc disease and undoubtedly plays a major role in causing low back pain and sciatica (39). Paraspinal muscle spasm, inflammation, and eventually muscular atrophy may also occur secondary to facet osteoarthritis. Paraspinal muscular imbalance may further accentuate the spine instability (Fig. 20.49). MRI of Herniated Lumbar Discs Herniated discs are uncommon in children. Approximately 90% of lumbar herniated discs occur at L4–L5 or L5–S1 levels; 7% occur at the L3–L4 level; and 3% at the L1–L2 or L2–L3 level (40). Most lumbar disc herniations extend through defects in the posterior annulus posterolaterally or in the midline. Herniations through the anterior annulus also occur but usually do not compress vital structures and are less common, probably because the annulus is thicker anteriorly. Lumbar disc herniations are usually associated with degeneration of the intervertebral portion of the disc on T1-weighted images. However, most degenerating discs are not associated with disc herniation (41). Normal signal intensity on T2weighted images is uncommonly seen with disc herniation (this is not necessarily true in the cervical region). This signal intensity loss reflecting disc degeneration is more apparent on T2-weighted (F)SE images than on T2*-weighted GRE images (42).

FIGURE 20.49 Dystrophic muscular disease (type unknown) in a patient with generalized low back pain. Note complete fatty replacement (F) of posterior paraspinal muscles in the lumbar region on T2 fast spin-echo sagittal image (A) and axial image (B). The spared psoas muscles (P) have normal signal intensity. Note vertebral osteochondrosis at the L3–L4 level.

There has been much interest in recent years from patients, employers, insurers, attorneys, and clinicians in using imaging studies to determine the acuity of a disc bulge or herniation. Although the presence of other findings of acute trauma (Fig. 20.50), calcification/ossification or prior imaging studies may be helpful, in their absence, there are no accepted imaging criteria for “dating” a disc bulge or herniation. Specifically, it is nonfactual and without scientific basis for an interpreting physician to assign a specific temporal relationship to a disc bulge or herniation. The hallmark of a herniated disc is a focal contour abnormality along the posterior disc margin with a soft tissue mass displacing the epidural fat, nerve root, epidural veins, or thecal sac. The herniated disc material is usually contiguous with the intervertebral portion of the disc, which is the site of an annular fissure (Fig. 20.51). Central, intraforaminal, and lateral disc herniations are well seen on T1-weighted images because of displacement of high–signal-intensity fat in the epidural space or foramen (Fig. 20.52). Fat displacement is an especially important sign in the evaluation of small disc herniations (Fig. 20.53).

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FIGURE 20.50 Traumatic disc herniation. C5–C6 disc extrusion (black arrows) with spinal cord compression a spinal cord contusion (white arrows). Posterior paraspinal/interspinous edema (white asterisk) suspicious for ligamentous injury.

MR not only provides morphologic information, but it also improves visualization of disc herniations because of better soft tissue contrast of MR relative to CT. On T1-weighted images, a disc herniation appears isointense or slightly hyperintense relative to the intervertebral portion of the disc (Fig. 20.52). On T2-weighted FSE images, the herniated portion may be relatively hyperintense or more hypointense than the degenerating intervertebral disc (Figs. 20.52 and 20.53). This may be due to increased water content or granulation tissue infiltrating the disc. On GRE images, it is difficult to visualize the herniated disc in the epidural space because the signal intensity of fat and disc material is similar. However, annular fissures may be better seen with T2-weighted FSE or GRE sequences (Fig. 20.54). GRE images show bone abnormalities better than do conventional SE images because normal bone is very dark relative to disc material on T2*-weighted GRE images. FSE sequences are routinely used to evaluate lumbar disc degeneration. Herniated discs typically have very low signal intensity on sagittal and axial T2-weighted FSE images (Figs. 20.52 and 20.55). In some cases, small herniated discs are easier to detect on T1-weighted SE images (Fig. 20.56). Nerve root and thecal sac compression are well shown on T1-weighted SE images, particularly in the axial plane, which is necessary to show the side of the disc displacement. Occasionally, the nerve root sleeve will have slightly higher signal intensity than normal, possibly indicating an inflammatory response to the disc material (Fig. 20.57). The nerve root adjacent to the herniated disc may enhance with gadolinium. MR is very sensitive for detecting sequestered disc fragments (43). Sequestered fragments (free fragments) at the disc level in the spinal canal often have the appearance of two or three distinct fragments (Fig. 20.58). Herniated discs that penetrate the PLL often represent sequestered fragments (free fragments) and can be diagnosed by a thin dark line between the free fragment and the parent disc, which implies a breach in the PLL (Fig. 20.59). Not all free disc fragments represent nuclear material; a fragment of the annulus may also be separated from the parent disc and may lie adjacent to the nuclear material (Fig. 20.60). Free fragments more commonly migrate inferiorly than superiorly, can be found anterior or posterior to the PLL, and are best seen on sagittal MR (Figs. 20.61 and 20.62). The intradural herniated disc represents a rare type of free fragment that penetrates the dura to reside in the subarachnoid space and is seen as a vague region of increased signal intensity in the spinal canal or within the thecal sac on T1-weighted images (Fig. 20.63) (44).

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FIGURE 20.51 Herniated disc (disc extrusion) at the L5–S1 level. A: Herniated disc material (white arrow) obscures the epidural fat on sagittal T1- and T2-weighted FSE images. B: Axial T1- and T2-weighted FSE images demonstrate disc material (white arrow) compressing the thecal sac and left S1 nerve root sleeve. For comparison, normal right S1 nerve root sleeve surrounded by epidural fat (black arrow).

FIGURE 20.52 Large midline disc herniation (arrow) at the L4–L5 level is hypointense on sagittal and axial T2 fast

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spin-echo images (A,B) and is slightly hyperintense relative to the thecal sac on T1 spin-echo axial image (C).

FIGURE 20.53 Herniated disc at L5–S1 on the right. The herniated disc (large arrow) is slightly hyperintense with respect to the intervertebral portion of the disc, and the disc fragment displaces the right S1 nerve root (small arrow) posteriorly. The disc material obscures the epidural fat normally seen anterior to the nerve root.

FIGURE 20.54 Lateral disc herniation, axial plane at L3–L4. A: In unenhanced axial image the herniated disc (arrow) is seen as a soft tissue mass in the neural foramen on the left, which does not enhance with gadolinium (B, arrow). C: T2-weighted gradient-echo image at the same level demonstrates a defect (small arrows) in annulus and a disc fragment (large arrow), which has high signal intensity similar to the intervertebral portion of the disc (dot).

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FIGURE 20.55 Large herniated disc at L4–L5 causing cauda equina syndrome. A: A large midline herniated disc fragment compresses the thecal sac at the L4–L5 level, obscuring the epidural fat in the T1-weighted spin-echo image. B: The herniated disc fragment has a very low signal intensity on the fast spin-echo image (TR 4,000 seconds, effective TE 102 ms).

FIGURE 20.56 Herniated disc (arrow) in lateral recess on the right at the L4 level is easier to visualize on T1weighted axial spin-echo image (A) than on fast spin-echo image (B).

FIGURE 20.57 A: The herniated disc at L4–L5 on the left has a higher signal intensity (long arrow) than the intervertebral portion of the disc. The disc fragment displaces the left L5 nerve root (small arrow) posteriorly. B: Below the disc level, the L5 nerve root (arrow) is enlarged and slightly hyperintense relative to the right nerve root and sheath.

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FIGURE 20.58 Multiple extruded disc fragments (arrows) on sagittal T1 spin-echo image (A) and T2 fast spin-echo image (B). On axial T2 fast spin-echo image (C), disc fragments (arrows) are shown compressing the anterolateral aspect of the thecal sac on the left.

FIGURE 20.59 Free disc fragment in the spinal canal at the L3–L4 level shown in sagittal gradient-echo image. The posterior longitudinal ligament (small black arrows) is displaced posteriorly by the herniated disc. A thin, dark line (small white arrow) separates the protruding disc fragment from the free fragment more posteriorly (long white arrow). A small subligamentous herniation (curved arrow) is seen at the L4–L5 level.

FIGURE 20.60 A,B: Parasagittal spin-echo images of a herniated disc at the L4–L5 level with an inferiorly migrated fragment (B, arrow). The fragment has extended to a radial tear (A, long arrow). A small annular fragment (A, white arrow) is positioned superior to the annular tear.

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FIGURE 20.61 A herniated disc with inferior migration of a disc fragment behind the L5 vertebral body. A: On sagittal T2-weighted fast spin-echo image, a small tear (small arrow) is seen in the posterior annulus of the L4–L5 disc. The disc fragment (large arrow) is seen behind the L5 vertebral body within the spinal canal. B: In axial image, the herniated disc (h) is located on the left and deforms the left ventral aspect of the thecal sac. v, Epidural veins; n, right L5 nerve root/nerve root pouch.

Acute traumatic disc herniations can occur anywhere along the spine and are often associated with spine fracture or subluxation. A migrated disc fragment is typically seen posterior to the subluxed vertebrae (Fig. 20.64). The limbus vertebra (Fig. 20.65) probably represents the sequela of a traumatic herniated disc that extended beneath the ring apophysis early in life.

FIGURE 20.62 Sequestered disc fragment at the L5 level from herniation at L4–L5. The inferiorly migrated free fragment (white arrow) is nearly isointense relative to cerebrospinal fluid on T1 spin-echo image (A) and hypointense relative to cerebrospinal fluid on T2 fast spin-echo image (B). Note synovial cyst (A,B, black arrow) embedded in the ligamentum flavum at the L4 level. C,D: In axial T1 spin-echo and T2 fast spin-echo images, the free fragment (arrow) deforms the thecal sac.

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FIGURE 20.63 Intradural disc herniation at the L3–L4 level. A: A small disc bulge or herniation (black arrow) in sagittal T1-weighted image extends from the intervertebral disc. A vague soft tissue mass in the thecal sac at this level represents an intradural disc herniation (white arrows). B,C: The intradural fragment (long arrows) has higher intensity than the cerebrospinal fluid (dot) and occupies most of the spinal canal, displacing the thecal sac (C, small arrow) into the right lateral recess. (Case contributed by Brian S. Puglisi, Phoenix, AZ.)

FIGURE 20.64 Traumatic disc herniation, vertebral fracture. The ruptured disc and L3 vertebral body fracture (arrows) are difficult to differentiate on T1-weighted spin-echo image (A). In gradient-echo image (B) obtained with 30-degree flip angle, the bone fragment has low signal intensity compared with the cerebrospinal fluid and herniated disc fragment (long arrow). Computed tomography (C) confirms the displaced fragment of bone (white arrows) and correlates well with panel B. Black arrows denote the site of bone avulsion from the right apophysis.

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FIGURE 20.65 Sagittal T1-weighted and sagittal T2-weighted images demonstrate an L4 limbus vertebra (white arrows).

Lateral disc herniations are best evaluated by MR. Lateral disc fragments compress the exiting nerve roots as they course below the pedicle at a given lumbar disc level. For example, a far lateral disc herniation at the L4–L5 level will produce L4 radiculopathy, whereas a posterolateral disc herniation compressing the thecal sac at the same level causes L5 radiculopathy. MR has advantages over CT for detection of lateral disc herniation (Figs. 20.54 and 20.66). In addition to the axial T1-weighted images, which show excellent contrast between the disc material and the fat, sagittal MR T1-weighted SE images through the foramen are valuable for defining the amount of nerve root compression. TABLE 20.2 Indications for Contrast-Enhanced Spine Magnetic Resonance

With herniated disc involution, if herniated discs were imaged sequentially for weeks or months, it is possible that a large number of these herniated disc fragments would be seen to involute, but the incidence of spontaneous regression of disc fragments is unknown. Herniated discs anywhere in the spine may involute (Fig. 20.67). Paramagnetic Contrast in Routine Spine MRI It is difficult to justify the routine use of paramagnetic contrast agents in routine lumbar spine MRI. However, situations exist in which contrast enhancement is very valuable in spine MRI and should be considered in the following situations (Table 20.2). 1. Foraminal herniated disc versus tumor. Contrast-enhanced scans are helpful for differentiating lateral disc herniation from a nerve sheath tumor (e.g., schwannoma) in the neural foramen (Figs. 20.68 and 20.69) or in the lateral recess. Lateral disc herniations may cause minimal or no root pouch deformity on myelography and are often difficult to distinguish from a nerve sheath tumor by CT. Lateral disc fragments compress the exiting nerve roots in the lateral recess or beneath the pedicle. The neural foramen in the lumbar region is optimally evaluated on sagittal and axial T1-weighted MR scans before and after administration of intravenous paramagnetic contrast (Fig. 20.70). The herniated disc fragment generally does not enhance, although there often is subtle enhancement at the periphery of the disc fragment (Fig. 20.66).

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FIGURE 20.66 Herniated disc into the medial neural foramen. A: Axial computed tomography (CT) at L3–L4 demonstrates herniated disc material (black arrow) obscuring the epidural fat in the medial portion of the neural foramen compared with the normal epidural fat (white arrow) on the left. B: Unenhanced axial T1-weighted image shows the herniated disc (arrow) obscuring epidural fat. C: The disc fragment (large white arrow) does not enhance, but there is enhancing tissue (small black arrow) posterior to the disc fragment. The thecal sac is compressed (small white arrow). A Schmorl node (dot) is sclerotic on the CT and has low intensity on the magnetic resonance image.

FIGURE 20.67 Disc extrusion, spontaneous resolution. Large extruded disc fragment at L5–S1 (A) spontaneously resolved on MRI performed three years later (B) without any surgical intervention.

2. Herniated disc inflammatory component. A herniated disc may incite an intense inflammatory response that may mimic an epidural abscess or tumor ventral to the thecal sac but centered at the intervertebral disc level (Fig. 20.71). 3. Herniated disc versus disc space infection versus tumor. Contrast-enhanced MR scans are useful for differentiating a herniated disc from a disc space infection or tumor. If one performs contrastenhanced scans routinely on patients with herniated discs, peripheral enhancement around the nonenhancing disc fragment is commonly seen (Fig. 20.72). A herniated disc fragment will rarely enhance centrally, attributed to vascular granulation tissue infiltrating the fragment.

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FIGURE 20.68 Herniated disc material causing widening of the right lateral recess (arrows) of L5. This appearance may be mistaken for a nerve sheath tumor.

4. Radiculitis or cauda equina neuritis. Nerve rootlets in the thecal sac near a herniated disc may enhance either because of compression or from an inflammatory response caused by the disc herniation (Fig. 20.73) (45). Occasionally, a patient will have symptoms only on the side opposite to a large herniated disc. Gadolinium-enhanced scans may be useful in this situation to determine whether there is an enhancing nerve root on the opposite side of the herniated disc (46). 5. Facet joint synovitis. Paramagnetic contrast-enhanced T1-weighted images with fat saturation show enhancement of the facet joint and perifacetal soft tissues in infectious or sterile synovitis of the facets (Figs. 20.74 and 20.75). 6. Paraspinal myositis. Disc herniation or facet disease can result in paraspinal muscle atrophy, spasm, or inflammation; active myositis will enhance with paramagnetic contrast. Schmorl Node Herniations that extend into the vertebral endplates are called Schmorl nodes and are exceedingly common. These are usually asymptomatic but are well seen on MR adjacent to the endplate and should not be confused with vertebral metastases. Typically, Schmorl nodes have low signal intensity on T1weighted images and high signal intensity on T2-weighted images with respect to cancellous vertebral bone. Schmorl nodes can enhance with gadolinium contrast because there is a rich vascular supply in the endplates capable of infiltrating the herniated disc (Fig. 20.76). Schmorl nodes may enhance homogeneously, in a ringlike fashion, or not at all (Fig. 20.66). Conditions that Mimic Lumbar Disc Herniation It is usually not difficult with MR techniques to differentiate lumbar disc herniation from other conditions. Epidural metastasis will occasionally resemble a herniated disc on axial images, but the distinction is usually made with ease on sagittal images. The epicenter of the epidural tumor in the spinal canal tends to be located away from the disc level, whereas herniated discs generally are located at the disc level unless the fragment has migrated. A free disc fragment that has migrated away from the disc level may mimic epidural neoplasm. Contrast-enhanced scans are needed to differentiate a tumor from a sequestered disc in this situation (Fig. 20.77).

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FIGURE 20.69 Schwannoma in the lateral recess of L3 on the right. Unenhanced image (A) and enhanced image (B) demonstrate a homogeneously enhancing mass (arrow) in the lateral recess of L3 on the right causing widening of the lateral recess and neural foramen.

FIGURE 20.70 Herniated disc in the neural foramen at the L3–L4 level. Right parasagittal unenhanced image (A) and enhanced image (B) demonstrate a nonenhancing soft tissue mass (arrows) in the neural foramen. p, Pedicle of L3 and L4, respectively.

FIGURE 20.71 Herniated disc at the L4–L5 level with a prominent enhancing component. A: Unenhanced sagittal image shows a vague soft tissue mass (arrows) ventral to the thecal sac at L4 and L5. B: Most of this tissue is seen to enhance with contrast material, except for the disc fragment (large arrow). Small arrows indicate the site of radial tears in the posterior annulus at L3–L4 and L4–L5. C: In axial image the herniated disc fragment (larger arrow) is surrounded by a rim of enhancing tissue. The small arrow indicates a thin, dark linear structure representing a midline septum that limits the migration of the disc fragment across the midline.

FIGURE 20.72 Preoperative rim enhancement of a herniated disc fragment. A: The unenhanced image shows a prominent soft tissue mass (arrows) obscuring the epidural fat in the spinal canal on the right. B: In the enhanced image, the herniated disc fragment (H) is surrounded by a rim of enhancing tissue. The thecal sac (ts) is markedly compressed. F, Epidural fat posterior to thecal sac.

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FIGURE 20.73 Enhancing nerve root located above a herniated disc at L4–L5. The T2-weighted fast spin-echo image (A) shows a herniated disc at L4–L5 compressing nerve roots of the cauda equina (arrows) in the thecal sac. The unenhanced axial image (B) and enhanced image (C) obtained at the same level above the herniated disc demonstrate an enhancing nerve root (arrow) on the left within the thecal sac.

FIGURE 20.74 Facet synovitis, L4–L5 right. Fat suppression, contrast-enhanced, T1-weighted image. Abnormal enhancing tissue (small arrows) surrounds the facets on the right, and there is abnormal enhancement in the adjacent lamina (long arrow). Infectious or sterile synovitis may produce this appearance.

FIGURE 20.75 Facet synovitis, right L4–L5. There is a small amount of fluid within a degenerated facet joint (white arrow) with associated enhancement (black arrows) on T1-weighted fat suppression postcontrast images.

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FIGURE 20.76 A Schmorl node is seen extending into the L4 vertebral body on unenhanced (A) and enhanced (B) images. The Schmorl node has a slightly hyperintense rim (arrows) in panel A, and there is ring enhancement shown in panel B.

Conjoined root pouches (Fig. 20.78) or synovial cysts (Fig. 20.79) are sometimes difficult to distinguish from disc herniation by plain CT but are readily differentiated on MR because they have the same signal intensity as the thecal sac on T1- and T2-weighted images. Enlarged root pouches, or Tarlov cysts, also have similar signal intensity as CSF (Fig. 20.80). It is rarely if ever a problem to distinguish epidural hematoma or abscess from a herniated disc because of their typical signal intensity characteristics and patterns of enhancement. Postoperative Lumbar Spine, MRI, and Gadolinium MR is an extremely valuable tool in the postoperative setting; indeed it is an essential part of the imaging protocol in every postoperative back. The value of MRI in such cases is underscored by the relatively high incidence of “failed back” after lumbar disc surgery, although they differ among different surgical procedures. In the estimated 10% to 40% of patients with recurrent or residual back pain, a number that has not significantly changed for decades despite advances in technology and surgical techniques (47), a number of very different diagnoses can be clearly defined on postoperative MRI, including residual or recurrent disc herniation, spinal stenosis, foraminal stenosis, scarring, or arachnoiditis. The importance of high-quality imaging in defining these entities should not be questioned, given that only some are treated with success and their treatment varies considerably. In addition, the likelihood of recurrent or persistent low back pain after surgery is considered higher after repeated surgery. In more general terms, the importance of persistent or recurrent back pain cannot be overestimated. The impact of failed back syndrome on an individual’s quality of life and functional status are even more disabling than other common chronic pain conditions, and the costs to society are enormous. In cases with metallic hardware in the vicinity, or even sometimes when metallic residual is left that obscures conventional imaging, newer methods of artifact suppression can be employed. One such method in clinical use is called IDEAL (48), in which separate water and fat images are acquired. In this technique, the increase in scan time can be partly offset by parallel imaging. The use of gadoliniumbased paramagnetic contrast agents for MR has dramatically improved the evaluation of the postoperative spine for recurrent disc herniation. Contrast-enhanced MR scanning is the most valuable imaging method for differentiating scar and recurrent or residual herniated disc. Contrast-enhanced CT has not been proven as effective as MR for differentiating scar and disc (49–52). On unenhanced images, epidural scar is isointense with respect to disc on T1-weighted images and relatively hypointense on T2-weighted images, but the distinction can be difficult (Fig. 20.81) (53).

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FIGURE 20.77 Sequestered disc fragment mimicking an epidural tumor. The unenhanced image (A) reveals a vague soft tissue mass (arrows) posterior to the L5 vertebral body. In the enhanced image (B), a free disc fragment (black arrow) is seen posterior to the vertebral body. A rim of enhancement surrounds the disc fragment. A tear (small white arrow) is seen in the posterior annulus of the L4–L5 disc.

FIGURE 20.78 A conjoined root mimics a herniated disc on computed tomography. A: Axial CT reveals soft tissue density obscuring epidural fat on the right (black arrow). The epidural fat on the left (open arrow) is seen as a region of low density. B: In the axial T1-weighted image the conjoined root pouch (arrows) has the same signal intensity as the thecal sac and is clearly delineated by adjacent high-intensity fat.

Most herniated discs detected postoperatively at the site of surgery do not enhance significantly or are clearly separable from adjacent enhancement (Fig. 20.82) (54). Scar tissue within the laminectomy defect and posterior paraspinal soft tissue may or may not enhance, but scar in the epidural space enhances homogeneously (Fig. 20.83). Normal tissues in the epidural space or foramen that also enhance include epidural fat, connective tissue, dura, root sleeves, and the dorsal root ganglia. The nerve roots and spinal cord do not enhance because a blood–neural barrier exists for these tissues.

FIGURE 20.79 Axial computed tomography of a synovial cyst (long arrow) at L4–L5 on the left associated with gaseous degeneration of the facet joint (short arrow). The synovial cyst causes lateral deformity of thecal sac on the left.

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It is important to obtain sagittal and axial images before and after paramagnetic contrast is given. Scanning should be performed immediately after the contrast material is administered. If scanning is delayed after contrast injection, the disc fragment may enhance, making it very difficult to differentiate scar from disc material. It is extremely useful to evaluate precontrast and postcontrast images side by side to detect subtle differences in the enhancement pattern (Fig. 20.84). Focal scarring in the epidural space can mimic disc herniation on precontrast MR or CT (Fig. 20.83). Diffuse scarring in the epidural space often masks all normal anatomic detail in the spinal canal (Fig. 20.85). The most common pattern we observe in patients with low back pain or radiculopathy after surgery for disc disease is the presence of both scar and recurrent herniated disc material in the epidural space (Figs. 20.82 and 20.86). Enhancement of the posterior disc margin is a common postoperative finding, but the clinical significance of this is unknown. This probably represents scar or granulation tissue infiltrating the disc through a defect in the posterior annulus (Fig. 20.87) (53). Herniated discs can enhance with gadolinium contrast, but this enhancement is generally along the margins of the disc (Fig. 20.88), although rarely the entire disc fragment will enhance (Fig. 20.89). In these cases it is usually possible to make the diagnosis because of nerve root or thecal sac displacement, which is usually not seen to any significant degree in scarring alone. Preoperative or postoperative enhancement of the vertebral body endplates is occasionally seen and can be confused with discitis, as already mentioned.

FIGURE 20.80 A Tarlov cyst has low signal intensity (arrow) similar to that of the cerebrospinal fluid in the thecal sac on this T1-weighted spin-echo image.

FIGURE 20.81 Postoperative herniated disc at the L5–S1 level with extensive scarring. A: In the T1-weighted spinecho image the herniated disc (large straight arrow) can be distinguished from the surrounding scar tissue (small arrows) by a dark rim of annular fibers. B: The scar tissue has inhomogeneous low signal intensity relative to the bright cerebrospinal fluid.

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FIGURE 20.82 Large herniated disc and enhancing scar at L5–S1. A: Unenhanced image shows a herniated disc (black arrow) poorly distinguished from an adjacent scar (small white arrows). B: In the enhanced image, the herniated disc (black arrow) is clearly demarcated by enhancing scar above and below (small black arrows). The S1 root is posteriorly displaced. C: The unenhanced image reveals the herniated disc (arrow) lateral to the thecal sac. D: In the enhanced image, the disc fragment (arrow) does not enhance, which is typical of most recurrent disc herniations.

FIGURE 20.83 A: Scar tissue (arrow) mimics a herniated disc in the axial image. B: This tissue enhances almost homogeneously in the gadolinium-enhanced image.

The role of paramagnetic contrast in the evaluation of postoperative arachnoiditis is routinely part of clinical protocols. The pathogenesis of arachnoiditis is poorly understood, and the clinical diagnosis can be difficult, usually presenting with vague nonspecific back pain with radiation into the lower extremities. Arachnoiditis is an inflammatory process that causes cauda equina nerve rootlets to adhere to the thecal sac and to each other. The most common finding is the clumping of nerve rootlets in the thecal sac (Fig. 20.90); this finding is seen on myelography, postmyelogram CT, or MR, particularly T21580

weighted FSE images. The pattern of enhancement in arachnoiditis is variable, from no enhancement to minimal or even pronounced enhancement of the nerve rootlets. The nerve roots may be clumped centrally or peripherally (Fig. 20.91) (56). Another common pattern with arachnoiditis is the so-called vacant thecal appearance due to adherence of the nerve rootlets to the thecal sac peripherally (Fig. 20.92).

FIGURE 20.84 Postoperative disc herniation, L4–L5 left. A: The herniated disc (arrow) is slightly hypointense centrally, with peripheral darker rim on axial T2 fast spin-echo image. The disc fragment deforms the ventral aspect of the thecal sac on the left and displaces the left S1 root posterolaterally. B: The disc fragment (arrow) is difficult to distinguish from the nerve root (white arrowhead) on the unenhanced axial T1 spin-echo image. C: In the enhanced T1 spin-echo image, a peripheral rim of enhancement surrounds the nonenhancing central portion of the disc fragment. The hemilaminectomy defect (black arrowhead) is well shown on all images.

FIGURE 20.85 Scar tissue encases the thecal sac. Unenhanced axial image (A) and enhanced image (B) at the L4– L5 level demonstrate extensive scar tissue surrounding the thecal sac, which enhances in panel B. Small arrows in panel A represent scar tissue in the laminectomy defect. Focal-enhancing scar tissue (B, arrow) might be mistaken for a recurrent disc herniation in the unenhanced image in panel A.

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FIGURE 20.86 Postoperative recurrent disc herniation and scar tissue at L5–S1. A: In the axial unenhanced image the soft tissue mass obscures the epidural fat between the thecal sac and nerve root. B: The gadolinium-enhanced image reveals enhancing scar tissue (small black arrow) between the disc fragment (longer white arrow) and the S1 root (smaller white arrow).

FIGURE 20.87 A: Postoperative posterior intervertebral disc enhancement (arrow) in sagittal T1 spin-echo image. B: Unenhanced axial T1 spin-echo image shows nonspecific low-intensity soft tissue (wavy arrow) that could represent a herniated disc or a scar adjacent to the left S1 nerve root. C: Gadolinium-enhanced axial T1 spin-echo image confirms the scar (wavy arrow) adjacent to the left S1 root. A posterior annular tear (straight arrow) also enhances in the axial image in panel C.

FIGURE 20.88 Postoperative herniated disc with surrounding scar tissue in the lateral recess of L5. A: In the

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unenhanced image, soft tissue (arrow) obscures the epidural fat on the right. B: In the enhanced image, there is enhancing scar tissue (arrows) surrounding a nonenhancing recurrent disc fragment.

FIGURE 20.89 Postoperative enhancing disc herniations at L4–L5 and L5–S1. Compared with the unenhanced sagittal T1-weighted image (A) and the enhanced image (B), the herniated disc (arrows) at L4–L5 and L5–S1 enhances (black arrows). C: The axial unenhanced image reveals a focal herniated disc (large arrow) and posterior S1 root displacement (small arrow). D: The herniated disc at L5–S1 (arrow) enhances.

A common cause of postoperative low back pain is abnormal mobility of the vertebra due to incomplete fusion after laminectomy. MR is useful for excluding a disc herniation, but plain radiographs and CT are best for showing any associated bone abnormalities. Paraspinal muscle imbalance may also contribute to the preoperative or postoperative back pain, and MRI is useful in evaluating muscle asymmetry (Fig. 20.93).

THORACIC DISC HERNIATION Degenerative disc disease of the thoracic spine is extremely common in older age groups as manifested by multilevel osteophytosis (spondylosis deformans) and degenerating discs seen as narrowed discs having low signal intensity on T2-weighted images. Herniated discs in the thoracic region are not uncommon and are being increasingly recognized because of the ease of screening the thoracic spine with MR (Fig. 20.94) (57). A thoracic herniated disc usually presents with myelopathy or referred back pain rather than a radiculopathy. Because of the normal dorsal kyphotic curvature, the thoracic cord is positioned in the subarachnoid space anteriorly, close to the vertebral bodies. Therefore, a small disc herniation in the thoracic region can produce significant myelopathy. Even minimal deformity of the cord anteriorly suggests significant cord compression (Fig. 20.95). Large herniations also occur in the thoracic region but are uncommon (Fig. 20.96). A thoracic disc herniation may calcify and mimic a calcified tumor in the spinal canal on CT (58).

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The morphologic characteristics of cervical disc herniations are similar to those seen in the lumbar spine (Fig. 20.97). A focal protuberance of the disc margin is the hallmark of disc herniation (Fig. 20.98), whereas bulging of the disc is seen as a broad, convex posterior disc margin extending between uncinate processes (Fig. 20.99). It may not be possible to differentiate a bulging cervical disc from a small herniated disc based on the sagittal images alone, and therefore axial images are essential (59). In addition, large, bulging cervical discs can produce significant myelopathy and even cord edema. MR is very sensitive to cervical degenerative disc disease and spondylosis deformans (60,61).

FIGURE 20.90 A: Arachnoiditis showing a thickened cord of matted-together nerve rootlets (arrows) with thecal sac in sagittal T2 fast spin-echo image. B: Axial T2 fast spin-echo image shows the matted nerve rootlets within the thecal sac posterolaterally on the right at the L2–L3 level.

FIGURE 20.91 Postoperative arachnoiditis. The thickened and clumped nerve roots of the cauda equina in the unenhanced image (A) shows subtle enhancement (arrows) (B). In both the axial unenhanced image (C) and the enhanced image (D), there is a region of hyperintensity (white arrow) in the posterior portion of the disc. This

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probably represents granulation tissue infiltrating the disc. There is enhancement of a thickened cluster of nerve roots in the thecal sac on the left (large black arrow), and there is a crescentic band of enhancing tissue along the right lateral margin of the thecal sac, which probably represents thickened dura with adherent nerve roots (D, small black arrow).

FIGURE 20.92 Arachnoiditis. Sagittal T2 fast spin-echo image (A) demonstrates thickened nerve rootlets that are matted together (short arrows), a “vacant” thecal sac (T) due to rootlets adherent to the thecal sac, and pantopaque at the S1 level. The pantopaque (arrow) is dark on the T2 fast spin-echo image in panel A and bright on the T1 spinecho image (B).

FIGURE 20.93 Sagittal T2 fast spin-echo image (A) and (B) axial T2 fast spin-echo image of erector spinae muscle atrophy (arrowheads) on the right in a patient with right leg pain and a herniated disc (arrows). A disc fragment has migrated below the L4–L5 level.

FIGURE 20.94 Sagittal T1, sagittal T2, and axial T2 FSE images demonstrate T9–T10 (black arrows) and T11–T12 (white arrows) right central disc protrusions.

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FIGURE 20.95 Herniated disc at the T10–T11 level. A: The herniated disc (arrow) extends into the ventral aspect of the spinal canal in the T1-weighted sagittal spin-echo image. B: In the T2-weighted fast spin-echo image, the herniated disc fragment has low signal intensity relative to the cerebrospinal fluid. C: In the axial image, the herniated disc fragment is positioned to the right of midline and the spinal cord is deformed slightly on the right.

FIGURE 20.96 A T11–T12 herniated disc (arrowhead) has low signal intensity on sagittal T1 spin-echo image (A), T2 fast spin-echo image (B), and axial gradient-echo image (C).

FIGURE 20.97 Sagittal anatomic section of the cervical spine demonstrates a bulging disc (B) at C3–C4 contacting the posterior longitudinal ligament (PLL). The spinal cord containing gray (G) and white (W) matter does not appear to be deformed. Degenerating discs (DD) are present at lower cervical levels.

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FIGURE 20.98 Magnetic resonance scan of a herniated disc in a cadaver on sagittal (A) and axial (B) spin-echo images. The herniated disc (HD) displaces the posterior longitudinal ligament (PLL) posteriorly. A, Normal annulus; N, normal nucleus at level above; G, cord gray matter stripe; D, dorsal root ganglion; F, neural foramen; S, superior articular process; W, white matter of posterior columns.

FIGURE 20.99 C6–C7 small disc bulge (arrows) in (A) sagittal and (B) axial T2 fast spin-echo images.

Small herniated discs are often difficult to detect on standard T1-weighted SE images. They are easier to detect in 2D or 3D GRE images (Fig. 20.7) than on T1-weighted SE images because there is a paucity of epidural fat and foraminal fat in the cervical region. Instead, a rich venous plexus surrounds the thecal sac and nerve root sheaths. Because GRE images display fluid-containing structures with very high signal intensity and bone has very low signal intensity relative to the disc, disc herniations are very obvious on GRE sequences in the cervical region and can be differentiated from osteophytes (Fig. 20.100). Cervical herniated disc fragments have very low signal intensity on T2-weighted FSE images (Fig. 20.101).

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FIGURE 20.100 C5–C6 disc herniation. Sagittal T1-weighted spin-echo (A) and gradient-echo image (B) demonstrate disc herniation (white arrow) displacing the posterior longitudinal ligament (black arrow) and indenting the thecal sac. The disc herniation (arrow) is located to the left of the midline in the axial gradient-echo image (C).

FIGURE 20.101 Cervical spondylosis, herniated disc, and cord compression. Generalized disc bulging, disc degeneration, and osteophyte formation is seen on sagittal T1-weighted spin-echo image (A) and T2-weighted fast spin-echo image (B). C: The herniated disc (arrow) has higher intensity than the bone. D: This image, obtained adjacent to the herniated disc, shows an osteophytic ridge (arrows) encroaching on the spinal canal more on the

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right.

Asymptomatic cervical disc herniations are common (60), and therefore the significance of a disc herniation seen on MR must be judged based on associated clinical findings. The most common symptoms found with cervical disc herniation are neck pain, radiculopathy, and myelopathy if the cord is compressed. Cervical herniations most commonly (90%) occur at the C5–C6 or C6–C7 level (Fig. 20.102). Midline cervical disc herniations are more common than in the lumbar region, but posterolateral herniations are also common (Fig. 20.103). Far lateral herniated discs are rare, probably because of buttressing by the uncinate processes (Fig. 20.104). Herniated disc fragments may migrate inferiorly or superiorly and are best seen on T2*-weighted GRE images (Fig. 20.105). If the disc fragment penetrates the PLL, a thin, dark band is sometimes seen between the parent disc and the free fragment similar to that seen in the lumbar region (Fig. 20.106). If the PLL appears to be thinned or diminished in signal intensity on the sagittal T2*-weighted images, this is a sign of disc herniation and is more commonly seen in the acute stage after disc herniation. In chronic cervical disc disease, the PLL may be thickened or heavily calcified, which can contribute to spinal cord compression. A compressed spinal cord may show areas of increased signal intensity, representing edema in the acute stage and myelomalacia or gliosis in the case of chronic cord compression (Fig. 20.101). Herniated disc fragments may calcify (so-called hard disc), and these are found anywhere in the spine. CT can be misleading because calcified herniated discs resemble osteophytes (Fig. 20.107). Calcified herniated discs on MR have the typical appearance of a herniated disc, except that the periphery of the disc is often more hypointense on GRE images. The role of gadolinium-enhanced MR in the cervical region is unclear. Normal structures that enhance include the dural sac, epidural veins, fat, connective tissue, and dorsal root ganglia (62). Because the epidural venous network is so extensive, contrastenhanced CT or MR has been suggested to aid in diagnosis of cervical herniated discs (Fig. 20.108). Although this technique is a useful adjunct in the diagnosis of cervical disc herniation, contrast-enhanced scans are usually not required to make the diagnosis; in fact, midline and paramidline cervical herniated discs are often seen better on T2*-weighted GRE images (Fig. 20.109). Cervical disc herniations are less well seen on axial T2-weighted FSE images because the hypointensity of the disc fragment mimics osteophyte (Fig. 20.110).

FIGURE 20.102 C6–C7 disc extrusion. Sagittal and axial T2-weighted FSE images demonstrate extension of disc material (white arrows) superiorly compressing the thecal sac and mildly compressing the spinal cord.

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FIGURE 20.103 Herniated disc at the C6–C7 level on the left. A: Axial computed tomography shows the disc fragment as a soft tissue mass (arrow) compressing the contrast-filled thecal sac on the left. B: The herniated disc (arrow) has high signal intensity on a gradient-echo image obtained with a 30-degree flip angle, and the bone is relatively dark compared to the disc fragment.

FIGURE 20.104 Axial cryomicrotome section in a cadaver. A lateral herniated disc (HD) extends into the medial aspect of the left neural foramen posterior to the uncinate process (U) and compresses the ventral root (V). ID, Intervertebral disc; HD, dorsal root ganglion; S, superior articular process; F, facet joint; I, inferior articular process; L, ligamentum flavum. The white arrow indicates articular cartilage of the inferior facet of C5 on the left.

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FIGURE 20.105 Herniated disc, C5–C6 level with inferior migration. A: Sagittal T1-weighted spin-echo image reveals disc material extending from the intervertebral disc level inferiorly (white arrow) and causing mild deformity of the cervical cord anteriorly (black arrow). B: The disc fragment is best seen on parasagittal gradient-echo image, where the fragment (black arrows) extends inferiorly from the C5–C6 level to the C6–C7 level. C: Axial gradient-echo image obtained with 30-degree flip angle at the C5–C6 level demonstrates that the disc herniation (large white arrow) has higher intensity than adjacent bone. D: The dark band (small white arrows) between the disc fragment and the cord represents posteriorly displaced posterior longitudinal ligament and dura.

FIGURE 20.106 A: Large herniated disc, C3–C4 level, “double fragment sign.” A large herniated disc compresses the spinal cord ventrally. B: Sagittal gradient-echo image demonstrates a thin, dark line (white arrow) separating two apparent disc fragments at the C3–C4 level. A dark line is also located behind the second aberrant disc fragment (black arrow). C: In axial gradient-echo image the herniated disc (large white arrow) has high signal intensity relative to bone. Small white arrows point to the defect in the annulus and the posterior longitudinal ligament. The black arrow points to the dark line between the disc fragment and the spinal cord, representing thickened posterior longitudinal ligament fragment and dura.

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FIGURE 20.107 A calcified herniated disc (H) resembles an osteophyte on axial computed tomography (A) but has the typical appearance of a herniated disc on two-dimensional gradient-echo image (B). The small white arrow indicates the dark medial margin of a disc fragment due to a remnant of the annulus, the posterior longitudinal ligament, or dural thickening.

SPINAL STENOSIS, OSTEOARTHRITIS, AND SPONDYLOSIS The changes seen in spinal stenosis are best evaluated with a combination of T1-weighted SE, FSE, and 3D reformatted images. The most common degenerative process of the spine is spondylosis deformans. Osteophytes probably arise secondary to degenerative disc disease. When Sharpey fibers are torn from their attachments along the vertebral body margins, stress is placed on the bone as the disc moves and osteophytes form in reaction to this stress (63).

FIGURE 20.108 Postoperative enhancement of the tissue surrounding a herniated disc fragment at the C5–C6 level. The herniated disc (arrow) does not enhance with gadolinium, similar to that seen in unoperated lumbar disc herniations.

FIGURE 20.109 Herniated cervical disc gradient echo versus gadolinium-enhanced spin echo. A: The herniated disc

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(arrow) has high signal intensity on axial gradient-echo image obtained with 30-degree flip angle. B: Enhancement of foraminal structures including foraminal veins is seen in axial T1-weighted spin-echo image, but the herniated disc does not enhance and is more difficult to visualize in this panel compared with panel A.

Osteoarthritis refers to a degenerative arthritis involving synovial joints, so the affected joints in the spine are the apophyseal (facet) joints (Fig. 20.111) (64). Spondylosis and osteoarthritis are terms often used synonymously because they often coexist and have similar predisposing factors. Both conditions result in bone proliferation and enlargement, which narrow either the spinal canal or neural foramen, producing spinal stenosis.

LUMBAR SPINAL STENOSIS Lumbar spinal stenosis includes central spinal canal stenosis, lateral recess stenosis, and foraminal stenosis. These conditions may coexist or occur independently in any given patient. Central canal stenosis is most common at the L2–L3, L3–L4, and L4–L5 levels (65), and patients present with symptoms of radiculopathy or myelopathy, often with bilateral lower-extremity claudication on exertion. The degenerative complex in acquired spinal stenosis includes diffuse disc bulging, facet hypertrophy and ligamentous thickening, and redundancy (66). In patients who have “short pedicles” on a developmental basis, minimal degenerative disease will result in symptoms of spinal stenosis at an earlier age than in those patients with purely acquired spinal stenosis. Lumbar central stenosis is characterized by circumferential (“napkin-ring”) narrowing of the central canal to an area less than 1.5 cm2 or an anteroposterior diameter of less than 11.5 mm (67). The thecal sac narrowing is well seen on myelography, CT, or MR in the sagittal and axial planes (Fig. 20.112). The nerve rootlets of the cauda equina are compressed by this process, resulting in neurogenic claudication. The affected nerve roots and engorged veins may enhance with paramagnetic contrast (46). Fardon et al. suggested a simple method for grading stenosis using 2D measurements taken from an axial section at the site of the most severe compromise. Canal compromise of less than one-third of the canal at that section is “mild,” between one and two-thirds is “moderate,” and greater than twothirds is “severe.” The same grading can be applied for foraminal involvement (28). Osteoarthritic disease of the facets is a contributing factor producing facet hypertrophy, cartilage destruction, and bone erosions. The degenerating facet joints may contain effusions or gas (vacuum facets), and erosions are present in advanced disease. The facet joint space is widened when acute inflammatory effusions are present but is often narrowed in chronic facet disease. The bone abnormalities and vacuum discs are easiest to visualize with CT (68), but can be detected with T2*-weighted sequences, which depict bone as low signal intensity, and fluid, erosions, and bone defects as high signal intensity (Fig. 20.113). It is important to keep the TE delay short to minimize magnetic susceptibility artifacts from bone or ferromagnetic material, which can simulate spinal stenosis or make the facets appear larger than they are (Fig. 20.114). The obliteration of the epidural fat that accompanies spinal stenosis is easier to see on T1-weighted SE images. However, bone detail is poorly seen on T1-weighted SE images, and this is a disadvantage in visualizing calcified discs or ligaments.

FIGURE 20.110 A herniated disc (arrow) at C5–C6 on the left has higher intensity relative to bone in the axial gradient-echo image (A) than in the axial T2 fast spin-echo image (B). An osteophyte or disc could have the same appearance in panel B.

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FIGURE 20.111 Anatomic sections comparing normal and degenerating facets in the lumbar region. Normal axial cryomicrotome image (A) from a cadaver demonstrates a normal facet joint (FJ) between the superior (S) and the inferior (I) articular processes. The inferior facet (IF) and the superior facet (SF) cartilage are clearly distinguished from the adjacent bone. C, Cauda equina; F, epidural fat posterior to thecal sac; L, ligamentum flavum. Severely degenerating facets shown in axial cryomicrotome image (B) have loss of articular cartilage (arrows) and multiple small erosions (E). The facets are hypertrophic bilaterally, and the facet joints are widened. The disc bulges diffusely, and the spinal canal is narrowed significantly.

FIGURE 20.112 Severe multilevel spinal stenosis in the lumbar region. Sagittal T1-weighted image (A) and T2weighted fast spin-echo image (B) reveal multiple bulging and degenerating discs along with thickening of the ligamentum flavum, causing circumferential narrowing of the thecal sac, more pronounced at L3–L4 and L4–L5. Central canal stenosis is more apparent on the T2-weighted axial fast spin-echo image (D) than on the T1-weighted spin-echo image (C).

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FIGURE 20.113 Severe lumbar spinal stenosis and facet disease, magnetic resonance (MR) versus computed tomography (CT). A: A diffusely bulging disc (small arrows) narrows the spinal canal anteriorly on the T1-weighted spin-echo image. Epidural fat (dot) is located posterior to the thecal sac. The facets are bilaterally enlarged and the facet joints irregular. The long arrows indicate facet erosions. L, Ligamentum flavum. B: In the T2-weighted spinecho image, the erosions (long arrows) have high signal intensity and probably contain fluid. Facet joint effusions are seen bilaterally (dots). The spinal canal (small arrows) is markedly narrowed and triangular in shape. C: CT obtained 1 year later with soft tissue (A) and bone (B) windows reveal vacuum facet (long arrows). At the site of previous joint effusions, the disc bulges diffusely (small arrows). The facets are enlarged (open arrows). D: Erosions in the superior and inferior facet (arrows) on CT correlate well with erosion seen on MR 1 year earlier (B).

Synovial cysts arise at the L4–L5 or L5–S1 level more commonly on the right and are probably related to facet degeneration of trauma (Fig. 20.115). Synovial cysts are not infrequently easier to visualize on CT because they are sometimes peripherally calcified (Fig. 20.116). Others are difficult to differentiate from disc herniation by CT (Fig. 20.79). On MR the cysts are isointense or slightly hyperintense with respect to CSF on T1-weighted SE images and hyperintense on T2-weighted images (68,70). Sometimes, synovial cysts contain blood, and these are seen as low intensity on T2-weighted images (Fig. 20.117). Synovial cysts are important because they can produce thecal sac compression and contribute to central canal stenosis, especially if they are bilateral. The periphery of the cyst often enhances with paramagnetic contrast (Fig. 20.118).

FIGURE 20.114 Artifact mimicking facet hypertrophy and stenosis, incidental Schmorl node. A: Unenhanced T1weighted axial image at L3–L4 demonstrates a metallic object (large arrow) that might be confused with facet

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hypertrophy. B: This does not enhance in the gadolinium-enhanced image. There is enhancement of the Schmorl node (A,B, small arrow). C: In the gradient-echo image, the apparent increased size of the metallic clip is due to a magnetic susceptibility artifact, which might be confused with severe facet hypertrophy causing central stenosis. The Schmorl node (small arrow) has high intensity in panel C.

Lateral recess stenosis is present when the distance between the superior facet anteromedially and the posterior vertebral body margin is less than 4 mm. Lateral recess stenosis is caused by the hypertrophic superior facet encroaching on the lateral recess and produces symptoms by compressing the nerve root before it exits the neural foramen. Hypertrophic inferior facets narrow the lateral recess by reducing the interlaminar angle (Fig. 20.119) (71). Foraminal stenosis occurs when a bulging disc, hypertrophic facet, or vertebral body osteophyte encroaches on the neural foramen (Figs. 20.120 and 20.121). Foraminal size is best assessed on sagittal unenhanced or gadolinium-enhanced T1-weighted SE images because fat normally outlines the nerve root and dorsal root ganglia in the foramen. A bulging or herniated disc first encroaches on the lower portion of the neural foramen, which is largely composed of fat and veins. The lumbar nerve roots are located in the superior portion of the foramen (Fig. 20.122). Facet synovitis is being recognized with increasing frequency on spine MR studies when fat saturation techniques are included in the standard spine protocol. Sagittal or axial T2-weighted FSE images with fat saturation are most useful for screening of synovitis. If these show abnormal hyperintensity in the joint or around the facets, then contrast-enhanced T1-weighted images with fat saturation should be obtained in axial plane (Figs. 20.9, 20.74, and 20.123). If the bone of the articular processes or lamina is also involved, osteomyelitis should be considered, but biopsy may be necessary to help differentiate sterile from infectious synovitis.

CERVICAL SPINAL STENOSIS Central canal stenosis in the cervical spine is most often secondary to spondylosis deformans (osteophytosis) and ligamentous thickening (Figs. 20.123 and 20.124). Foraminal stenosis is usually caused by uncinate process hypertrophy and enlargement of the superior articular facet. MR is well suited for screening the cervical spine for cervical stenosis. Patients generally experience symptoms of myelopathy or radiculopathy if the anteroposterior diameter of the cervical canal is less than 11 mm (Fig. 20.125).

FIGURE 20.115 Typical magnetic resonance appearance of a facet joint synovial cyst. Sagittal T1-weighted (A) and sagittal T2-weighted (B) images demonstrate a small ovoid complex cyst (black arrows) arising from the posterior margin of a right L4–L5 facet joint. Note the small amount of fluid within the joint space (white arrrow). C: With contrast, the sagittal fat suppression T1-weighted image shows enhancement (white arrow).

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FIGURE 20.116 Lumbar spinal stenosis and synovial cyst L4–L5. A: Axial computed tomography shows a diffusely bulging disc (short arrows) and a calcified synovial cyst (long arrow) on the right encroaching on the spinal canal. B: In T1-weighted spin-echo image, the synovial cyst (long arrow) is difficult to distinguish from adjacent bone. C: The synovial cyst has high signal intensity as a fluid (long arrow) in gradient-echo image. A facet joint effusion (open arrow) is present on the right. The bulging disc has low intensity along its margins (B,C, small arrows).

Assuming magnetic susceptibility artifact can be minimized, T2*-weighted GRE images are well suited for evaluating cervical spondylosis because osteophytes are clearly distinguished from discs. However, the most accurate assessment of spinal canal size is obtained from T2-weighted sagittal FSE image. Osteophytes have low signal intensity relative to higher–signal-intensity disc material on GRE images. The constellation of findings in spinal stenosis includes bulging discs, osteophytic ridging (spondylosis deformans), and thickening or redundancy of the ligaments (PLL and ligamentum flavum) (Fig. 20.126). If the spinal cord is compressed over a long period, irreversible changes in the spinal cord architecture occur manifested by gliosis and myelomalacia. These changes are seen as focal areas of increased signal intensity in the cord on T2-weighted images and are indicative of a poor prognosis (Figs. 20.101 and 20.125) (72).

FIGURE 20.117 Epidural tumor simulating a herniated disc in an axial plane. A: In T1-weighted spin-echo magnetic resonance image, abnormal soft tissue (arrows) compresses the thecal sac ventrally, obliterates the epidural fat on the left, and extends into the left neural foramen. This may be confused with a large extruded disc. B: In sagittal T2weighted scan, the epidural mass (long arrow) is centered above the disc space level, typical of epidural metastasis.

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The tumor is seen in multiple vertebral bodies (dots) as low–signal-intensity material replacing the normally highintensity fatty marrow. The epidural tumor is also present in the spinal canal at the T12 level (short arrow).

FIGURE 20.118 A: Bilateral synovial cysts (arrows) in axial T2 fast spin-echo image. The cyst shown on parasagittal T2 fast spin-echo image (B) enhances peripherally in gadolinium-enhanced T1 spin-echo image (C).

FIGURE 20.119 Lateral recessed stenosis on the left at L4 obscures the epidural fat (arrow) at the L4 level on the left on this T2-weighted axial fast spin-echo image. Central canal stenosis is also present due to facet hypertrophy bilaterally.

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FIGURE 20.120 Parasagittal anatomic images of cadaver lumbar neural foramen showing bulging disc (BD) encroaching on the inferior aspect of the upper foramen. The normal disc annulus at the lower level does not encroach on the epidural fat (F) of the lower foramen. D, Dorsal root ganglion; V, ventral root; S, superior articular process; I, inferior articular process; PARS, pars interarticularis; PED, pedicle.

FIGURE 20.121 Severe foraminal stenosis in an anatomic parasagittal section through the lumbar neural foramina obtained with a cryomicrotome. A vertebral body osteophyte (O) and bulging disc encroach on the inferior portion of the upper neural foramen. A hypertrophied superior articular process (S) compresses the nerve roots in the foramen. F, Foraminal fat; FJ, facet joint; PARS, pars interarticularis; PED, pedicle.

Cervical vertebral osteochondrosis causes similar signal intensity alterations in the cervical vertebral endplates, as already described in the lumbar spine, and often accompanies advanced cervical spondylosis deformans. Degenerative disease of the vertebral endplates should not be confused with cervical discitis, in which the infected disc space has high signal intensity and vertebral endplate destruction is present (Fig. 20.121). CT previously had been considered the procedure of choice for diagnosing foraminal stenosis because the margins of the normal foramen, spinal canal, and osteophytes are so well demonstrated. Assuming that motion and magnetic susceptibility artifacts can be controlled, MRI is now generally preferred for the evaluation of cervical radiculopathy. Using volume 3D GRE techniques, thin sections (1 mm or less) can be obtained, which is ideal for evaluating the cervical neural foramen (73). Contrast-enhanced MR scanning with gadolinium enhancement using 3D or 2D pulse sequences represents an important adjunct to CT in evaluating foraminal disease of all types, including cervical radiculopathy (Fig. 20.127). Although CT is a viable option, MR can be used to screen for neural foraminal narrowing on axial GRE or contrast-enhanced MR. 3D volume imaging with oblique reformatting is reserved for difficult cases to minimize examination time (Fig. 20.8).

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FIGURE 20.122 Disc bulging into the foramen shown in parasagittal T1-weighted lumbar spin-echo images. A: A slightly bulging disc encroaches on the L4–L5 foramen inferiorly. nr, Nerve root in foramen; vn, foraminal. B: In a different patient, a bulging disc (bd) abuts the nerve root (nr) in the L4–L5 foramen.

FIGURE 20.123 Spinal stenosis at the C4–C5 and C5–C6 levels demonstrated on sagittal T2-weighted fast spinecho image. In addition to disc bulging at these levels, there is thickening of the posterior longitudinal ligament (arrows), which contributes to the spinal stenosis.

Rheumatoid arthritis is typically associated with spondylosis and central canal narrowing (Fig. 20.128) (74,75). In rheumatoid arthritis, pannus formation, odontoid erosion, and cord compression, if present, are well shown with MR. Because plain radiographs are fine for assessing the degree of atlantoaxial subluxation, MR is most valuable for assessing the degree of cord compression. Atlantoaxial subluxation can be diagnosed on T1-weighted images obtained in neck flexion and extension. Ankylosing spondylitis causes multilevel fusion of the facet joints without bone sclerosis, giving the vertebral column the classic “bamboo spine” appearance. On CT, the intervertebral disc can appear denser than the adjacent vertebra (76). On MR, alternating bands of low and high signals in the intervertebral discs are characteristic (Fig. 20.129). These patients can develop arachnoiditis, resulting in characteristic arachnoid diverticula that erode the adjacent lamina (77).

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FIGURE 20.124 Sagittal cryomicrotome section of a cadaver. Cervical spine with osteophytes (O) displacing dura (DU) and posterior longitudinal ligament (PLL) posteriorly. DD, Degenerating disc; VB, vertebral body; VN, anterior epidural veins; black dots, sclerotic vertebral endplates; DR, dorsal rootlets; VR, ventral rootlets; C, spinal cord.

FIGURE 20.125 Severe central canal stenosis, C3–C4 level. A: Significant (less than 11 mm) anteroposterior diameter narrowing (arrows) in sagittal T2 fast spin-echo image. The cord is compressed, and subtle hyperintense signal is noted in the cord at the C3–C4 level. B: Axial gradient-echo image shows the anteroposterior diameter narrowing (short arrows) and severe right foraminal stenosis (long arrows).

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FIGURE 20.126 Herniated disc, osteophyte, and ligamentous thickening, causing cord compression at the C5–C6 level. A: The herniated disc is seen to cause cord compression on the T1-weighted sagittal spin-echo image. B: In gradient-echo image obtained with a 30-degree flip angle, the bulging disc has high signal intensity relative to the adjacent osteophyte (small white arrow). Below the herniated disc, there is thickening of the posterior longitudinal ligament (long arrow). The normal posterior longitudinal ligament (small black arrows) is seen above the disc level.

FIGURE 20.127 Foraminal stenosis (arrows) is shown at the C5–C6 level on the right because of uncinate hypertrophy and facet hypertrophy on this axial two-dimensional gradient-echo image with 30-degree flip angle and 3-mm slice thickness.

FIGURE 20.128 Rheumatoid arthritis. Sagittal T1-weighted (A) and T2-weighted (B) spin-echo images show separation of the dens (d) and anterior arch of C1 by pannus (P). The spinal canal (B, arrows) is narrowed because of dens displacement, resulting in spinal cord compromise.

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FIGURE 20.129 Ankylosing spondylitis. Sagittal T1-weighted spin-echo image (A) and T2-weighted image (B) demonstrating alternating bands of low and high signal intensity in the disc. The nucleus pulposus (N) is dark and the inner annulus (A) is bright on both sequences. Syndesmophyte (arrow) has similar intensity to marrow. C: Axial T1weighted image shows alternating intensity band producing a “target” appearance to the disc with nucleus (N) dark, the inner annulus (i) bright, and the outer annulus (O) dark. The syndesmophytic ridge (white arrows) has bright signal intensity like marrow. Facet joints are fused (black arrows). D: Oblique coronal image shows fusion of the synovial portions of the sacroiliac joints.

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FIGURE 20.130 Ossified ligaments. A: In the sagittal computed tomography reformatted image, the anterior longitudinal ligament (large arrowheads) is ossified. The transverse ligament (wavy arrow) of the dens (D) and posterior longitudinal ligament (PLL) (open arrows) are also ossified. B: On the T2 fast spin-echo sagittal image, ossification of the PLL (open arrows) is demonstrated and cord compression (solid arrow) is evident at the C3–C4 level. Axial computed tomography (C) and gradient-echo (D) images display the central canal stenosis and ossification of the PLL (open arrows).

Ossification of the PLL generally produces significant myelopathy because of severe spinal canal stenosis (78). In this condition, segmental or diffuse ossification of the PLL is responsible for the cord compression. The ossified ligaments have high or low signal intensity, depending on whether or not they contain bone marrow elements (79,80). Diffuse idiopathic skeletal hyperostosis is manifested by exuberant calcification of the ALL in the absence of apophyseal joint ankylosis, and relatively minimal degenerative disc disease is present (81). Diffuse idiopathic skeletal hyperostosis and ossification of the PLL often coexist (Fig. 20.130). Spondylolisthesis Spondylolisthesis (vertebral subluxation) may arise secondary to congenital or acquired defects in the pars interarticularis (spondylolysis). Acquired defects probably represent stress fractures. A degenerative form of spondylolisthesis occurs secondary to degenerative disease of the facet joints and most commonly occurs at the L4–L5 level. Spondylolisthesis is typically graded as I, II, or III, depending on the degree of subluxation. If the vertebra has subluxed 25% or less, this is considered grade I, 25% to 50% as grade II, and 50% to 75% as grade III. A subluxation greater than 25% is almost always associated with bilateral spondylolysis. A grade I spondylolisthesis may be associated with either spondylolysis or severe degenerative disease of the facet joints (82).

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FIGURE 20.131 Computed tomography of spondylolisthesis, L5–S1, and spondylolysis, L5. Horizontal undulating defects (white arrows) in the pars interarticularis. Sclerotic, 45-degree obliquely oriented facet joints (black arrows).

FIGURE 20.132 Grade I spondylolisthesis, L5–S1, and bilateral spondylolysis, L5. A: Anterior subluxation of L5 results in disc bulging/pseudobulging (arrows) on midsagittal T2 fast spin-echo image. The horizontally oriented pars defect is seen as a low-intensity band (black arrow), whereas facet joints (white arrows) are oriented obliquesagittally above and below. B: The nerve root (open arrow) is compromised by a narrow neural foramen on parasagittal spin-echo image. Axial T1 spin-echo image (C) and T2 fast spin-echo image (D) show horizontal undulating pars defects (large arrows) and 45-degree obliquely oriented facet joints (small arrows) more posteriorly. Note the characteristic elongation of the central spinal canal in the anteroposterior direction.

Retrolisthesis or reverse spondylolisthesis is characterized by posterior subluxation of a given vertebral body relative to the vertebral body below and is secondary to degenerative disc disease (intervertebral osteochondrosis). CT is the procedure of choice for evaluating pars interarticularis defects (83) and associated degenerative disease (bone sclerosis and overgrowth) often seen at the margin of old pars defects or adjacent facets (Fig. 20.131). Pars defects are more difficult to see on MR images but can usually be recognized if the pars interarticularis is carefully examined on axial and parasagittal images at L4 and L5 (Fig. 20.2). GRE images often display the pars defects well, with the bright pars defects contrasted against the adjacent dark bone. 1605

Disc bulging or “pseudobulging” of the disc usually accompanies spondylolisthesis (Fig. 20.132). The foraminal nerve roots may be compromised in the foramen at the subluxation level related to elongation of the foramen in the anteroposterior direction and disc bulging into the foramen (84). Herniated discs rarely occur at the level of the spondylolisthesis.

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The anatomic basis of vertebrogenic pain and the autonomic syndrome associated with lumbar disc extrusion. AJR Am J Roentgenol 1989;152:1277–1289. 41. Cavanaugh JM, Ozaktay AC, Yamashita HT, et al. Lumbar facet pain: biomechanics, neuroanatomy and neurophysiology. J Biomech 1996;19:1117–1129. 42. Shapiro R. Myelography. Chicago, IL: Year Book; 1975. 43. Sylven B. On the biology of the nucleus pulposus. Acta Orthop 1951;20:275–279. 44. Murayama S, Numaguchi Y, Robinson AE. The diagnosis of herniated intervertebral discs with MR imaging: a comparison of gradient-refocused-echo and spin-echo pulse sequences. AJR Am J Roentgenol 1990;11:17–22. 45. Holtas S, Nordström CH, Larsson EM, et al. MR imaging of intradural disc herniation. J Comput Assist Tomgr 1987;11:353–356. 46. Jinkins JR. MR of enhancing nerve roots in the unoperated lumbosacral spine. AJNR Am J Neuroradiol 1993;14:193–202. 47. Chan CW, Peng P. Failed back surgery syndrome. Pain Med 2011;12:577–606. 48. Reeder SB, Pineda AR, Wen Z, et al. Iterative decomposition of water and fat with echo asymmetry and leastsquares estimation (IDEAL): application with fast spin-echo imaging. Magn Reson Med 2005;54:636–644. 49. Jinkins JR. Magnetic resonance imaging of benign nerve root enhancement in the unoperated and postoperative lumbosacral spine. Neuroimag Clin N Am 1993;3:525–541. 50. Teplick JG, Haskin ME. Intravenous contrast-enhanced CT of the postoperative lumbar spine: improved identification of recurrent disc herniation, scar, arachnoiditis, and discitis. AJNR Am J Neuroradiol 1984;5:373–383. 51. Braun IF, Hoffman JC, Davis PC, et al. Contrast enhancement in CT differentiation between recurrent disc herniation and postoperative scar: prospective study. AJR Am J Roentgenol 1985;6:607–612. 52. Yang PJ, Seeger JF, Dzioba RB, et al. High-dose i.v. contrast in CT scanning of the postoperative lumbar spine. AJNR Am J Neuroradiol 1986;7:703–707. 53. Bundschuh CV. Imaging of the postoperative lumbosacral spine. Neuroimag Clin N Am 1993;3:499–516. 54. Bundschuh CV, Modic MT, Ross JS, et al. Epidural fibrosis and recurrent disc herniation in the lumbar spine: MR imaging assessment. AJNR Am J Neuroradiol 1988;9:169–178. 55. Hueftle MG, Modic MT, Ross JS, et al. Lumbar spine: postoperative MR imaging with Gd-DTPA. Radiology 1988;167:817–824. 56. Bangert BA, Ross JS. Arachnoiditis affecting the lumbosacral spine. Neuroimag Clin N Am 1993;3:517–524. 57. Ross JS, Perez-Reyes N, Masaryk TJ, et al. Thoracic disc herniation: MR imaging. Radiology 1987;165:511–515. 58. Roosen N, Uwe D, Nicola N, et al. MR imaging of calcified herniated thoracic disc. J Comput Assist Tomogr 1987;11:733–735. 59. Czervionke LF, Daniels DL. Cervical spine anatomy and pathologic processes. Radiol Clin N Am 1988;26:921–947. 60. Teresi LM, Lufkin RB, Reicher MA, et al. Asymptomatic degenerative disc disease and spondylosis of the cervical spine: MR imaging. Radiology 1987;164:83–88. 61. Hedberg MC, Drayer BP, Flom RA, et al. Gradient echo (grass) MR imaging in cervical radiculopathy. AJNR Am J Neuroradiol 1988;150:683–689. 62. Czervionke LF, Daniels DL, Ho PS, et al. The cervical neural foramina: a correlative anatomic and MR study. Radiology 1988;1:753–759. 63. McRae DL. Asymptomatic intervertebral disc protrusions. Acta Radiol 1956;46:9–27. 64. Resnick D, Niwayama G. Degenerative diseases of the spine. In: Resnick D, ed. Bone and Joint Imaging. Philadelphia, PA: WB Saunders; 1989:413–439. 65. Newton TH, Potts DG. Computed Tomography of the Spine and Spinal Cord. San Anselmo, CA: Clavadel Press; 1983. 66. Major NM, Helms CA. Central and foraminal stenosis of the lumbar spine. Neuroimag Clin N Am 1993;3:557–566. 67. Ullrich CG, Binet EF, Sanecki MG, et al. Quantitative assessment of the lumbar spinal canal by computed tomography. Radiology 1980;134:137–143. 68. Grenier N, Grossman RI, Schiebler ML, et al. Degenerative lumbar disc disease: pitfalls and usefulness of MR imaging in detection of vacuum phenomenon. Radiology 1987;164:861–865. 69. Jackson DE, Atlas SW, Mani JR, et al. Intraspinal synovial cysts: MR imaging. Radiology 1989;170:527–530. 70. Liu SS, Williams KD, Drayer BP, et al. Synovial cyst of the lumbosacral spine: diagnosis by MR imaging. AJNR Am J Neuroradiol 1989;10:163–166. 71. Mikhael MA, Ciric I, Tarkington JA, et al. Neuroradiological evaluation of lateral recess syndrome. Radiology 1981;140:97–107. 72. Takahashi M, Yasuyuki Y, Yuji S, et al. Chronic cervical cord compression: clinical significance of increased signal

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intensity on MR images. Radiology 1989;173:219–224. 73. Tsuruda JS, Norman D, Dillon W, et al. Three-dimensional gradient-recalled MR imaging as a screening tool for the diagnosis of cervical radiculopathy. AJNR Am J Neuroradiol 1989;10:1263–1271. 74. Pettersson H, Larsson EM, Holtas S, et al. MR imaging of the cervical spine in rheumatoid arthritis. AJNR Am J Neuroradiol 1988;9:573–577. 75. Bundschuh CV, Modic MT, Kearney F, et al. Rheumatoid arthritis of the cervical spine: surface-coil MR imaging. AJNR Am J Neuroradiol 1988;9:565–571. 76. Kenny JB, Hughes PL, Whitehouse GH. Discovertebral destruction in ankylosing spondylitis: the role of computed tomography and magnetic resonance imaging. Br J Radiol 1990;63:448–455. 77. Ginsburg WW, Cohen MD, Miller GM, et al. Posterior vertebral body erosion by arachnoid diverticula in cauda equina syndrome: an unusual manifestation of ankylosing spondylitis. J Rheumatol 1997;24:1417–1420. 78. Resnick D. Calcification and ossification of the posterior spinal ligaments and tissues. In: Resnick D, ed. Bone and Joint Imaging. Philadelphia, PA: WB Saunders; 1989:452–457. 79. Luetkehans TJ, Coughlin BF, Weinstein MA. Ossification of the posterior longitudinal ligament diagnosed by MR. AJNR Am J Neuroradiol 1987;8:924–925. 80. Widder DJ. MR imaging of ossification of the posterior longitudinal ligament. AJR Am J Roentgenol 1989;153:194– 195. 81. Resnick D, Niwayama G. Diffuse idiopathic skeletal hyperostosis (DISH). In: Resnick D, ed. Bone and Joint Imaging. Philadelphia, PA: WB Saunders; 1989:440–451. 82. Teplick JG, Laffey PA, Berman A, et al. Diagnosis and evaluation of spondylolisthesis and/or spondylolysis on axial CT. AJNR Am J Neuroradiol 1986;7:479–481. 83. Ulmer JL, Mathews VP, Elster AD, et al. MR imaging of lumbar spondylolysis: the importance of ancillary observations. AJR Am J Roentgenol 1997;169:233–239. 84. Jinkins JR, Matthes JC, Sener RN, et al. Spondylolysis, spondylolisthesis, and associated nerve root entrapment in the lumbosacral spine: MR evaluation. AJR Am J Roentgenol 1992;159:799–803.

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21 Neoplastic Disease of the Spine and Spinal Cord Puneet S. Pawha, Gerard M. Reddy, and Gordon Sze

Of all areas of spinal pathology, it may be in the field of spinal tumors that magnetic resonance imaging (MRI) has had the most impact. Almost immediately after its inception, even with the poor quality of early scans, the potential of MR in the evaluation of suspected neoplasms of the cord was recognized (1). Today, MR is always considered the essential procedure of choice for the workup of all spinal tumors (2), in the absence of contraindications to its use. Spinal tumors should virtually always initially be assessed by the radiologist asking “within what compartment is the lesion situated?” that is, is it extradural, intradural, extramedullary, or intramedullary. This classification scheme has stood the test of time, over decades of radiologic diagnosis of spinal mass lesions, as well as over the entirety of the dramatic evolution of imaging methodology up to and including the current state-of-the art MRI techniques. The key to answering this essential question in the diagnostic approach to spinal lesions lies in inspection of the edge of the lesion at its interface with the subarachnoid space. In extradural lesions, the subarachnoid space is at the interface of the mass lesion and the spinal cord (Fig. 21.1). In intradural extramedullary masses, the subarachnoid space is widened and caps the lesion (Fig. 21.2). In intramedullary masses, the lesion is part of the expanded spinal cord; hence, the subarachnoid space around the lesion–spinal cord complex is narrowed (Fig. 21.3). That said, there are cases in which the categorization of mass lesions into a single compartment either cannot be accomplished or is less helpful than in most cases. First, a given lesion may reside in two compartments simultaneously. The most common diagnosis in the scenario of a lesion occupying two compartments is a neurofibroma extending into both the extradural and the intradural extramedullary spaces (Fig. 21.4). Second, two lesions with identical pathology may occur in different compartments. For example, metastases obviously may occur in any of the three compartments, including the intramedullary space. Third, a lesion that is plaquelike, instead of spherical, will not necessarily demonstrate the above-described effects on the appearance of the cerebrospinal fluid (CSF) column. The typical example would be a plaquelike meningioma that, although an intradural extramedullary lesion, would not necessarily widen the CSF space. Nevertheless, this classification scheme serves well as the basis for localization and ultimately the appropriate differential diagnosis of spinal tumors.

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FIGURE 21.1 Extradural mass (lymphoma). Sagittal T1-weighted (A) and sagittal T2-weighted (B) images demonstrate an ovoid mass dorsal to the canal at the L1–L2 level that narrows the subarachnoid space. Note the tapering of the dorsal CSF column as it approaches the L1 mass, both superiorly and inferiorly. Vertebral marrow infiltration with smaller anterior and posterior epidural components are also noted at the L3 level.

FIGURE 21.2 Intradural extramedullary masses (metastases). Note the widening of the subarachnoid space as the cerebrospinal fluid caps the mass, indicating its intradural (subarachnoid space) location. Multiple smaller lesions are identified along nerve roots in the subarachnoid space.

In the extradural space, numerous primary bone tumors can occur. However, with few exceptions, such as hemangioma, most of the primary bone tumors are comparatively unusual. Secondary tumors, including metastases, are far more common in the extradural space. In the intradural extramedullary space, primary tumors, such as neurofibroma and meningioma, are relatively common. Secondary tumors or leptomeningeal metastases were formerly considered quite rare. This entity is now seen more frequently because of several factors. First, clinicians have a higher awareness of leptomeningeal tumor and greater suspicion of it under the appropriate clinical circumstances. Second, laboratory tests are more precise in identifying tumor cells in the CSF. Third, as patients live longer with their tumors, they have more opportunity to develop ancillary complications of their disease, such as leptomeningeal tumor. Therefore, the increase seen in leptomeningeal tumor is due to both better diagnosis and an actual increase in its incidence. Finally, in the intramedullary space, primary tumors are far more common than secondary tumors or metastases. Metastases to the cord itself are comparatively unusual.

EXTRADURAL TUMORS Technique

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When evaluating spinal tumors involving the epidural space with MR, it is important to keep two goals in mind: (a) the detection of vertebral body lesions, even if there is no suspicion of epidural impingement; and (b) the delineation of possible nerve root or spinal cord compression. Unenhanced MR scans are generally superb at delineating extradural tumors, whether they are primary or secondary (1–3). Vertebral body lesions are usually well visualized as low-intensity lesions surrounded by the higher intensity of normal fat-containing marrow on T1-weighted images. Before the development of MR, bone scans were considered the most sensitive means of detecting suspected tumors of the vertebral body. MR, however, has been found to be more sensitive to marrow abnormalities (2). For example, active lesions that might not be visible on a bone scan are generally detectable on MR (2).

FIGURE 21.3 Intramedullary mass (Ependymoma). Sagittal (A) and axial (B) T2 FSE images demonstrate a round and mildly hyperintense lesion within the substance of the cord. There is localized cord expansion and circumferential narrowing of the subarachnoid space. Axial T2 GRE image (C) demonstrates greater contrast between the central hyperintense lesion and the peripheral rim of surrounding cord parenchyma.

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FIGURE 21.4 Neurofibromas occupying multiple compartments in sagittal T2 (A, B) and axial postcontrast images (C).

The standard MR parameters for the detection of vertebral body lesions generally consist of short– repetition time (TR)/short–echo time (TE) (T1-weighted) spin-echo (SE) sequences (2). These acquisitions are very sensitive to the high intensity of normal fat-containing marrow and show morphology in great detail. Tumors usually are of low signal intensity on T1-weighted sequences and of high signal intensity on long–TR/TE (T2-weighted) sequences. Normal marrow, in contrast, generally is of high signal intensity on T1-weighted scans and of less signal intensity on T2-weighted scans (Fig. 21.5). Fast spin-echo (FSE)-type sequences must be used with caution because the persistent high signal of surrounding fat on T2-weighted images may decrease visualization of a tumor (Fig. 21.5). Fatsuppressed T2-weighted imaging, on the other hand, is often useful in depicting marrow lesions. In occasional cases, uninvolved marrow appears to be low in signal, especially in young patients, in whom the vertebral body marrow does not contain much fat or in patients with anemia of chronic disease, who are hypothesized to have altered metabolism of iron. In these cases, the low-intensity lesions are not highlighted by the surrounding high-intensity marrow, and it may be difficult to detect tumor on unenhanced T1-weighted images. In these instances, T2-weighted sequences, short–inversiontime inversion recovery (STIR) sequences, or gradient-echo (GRE) sequences may help for further evaluation. Impingement on the thecal sac can occur by extension of a vertebral body tumor or by neoplastic growth in the epidural space itself. Good-quality MR scans of the spine are generally very precise in showing impingement on the thecal sac. T1- and T2-weighted sequences are both excellent for depiction of epidural disease, particularly when lesions are visualized in two orthogonal planes (Fig. 21.6). However, in some cases, particularly when disease is extensive, T2 GRE or balanced steady-state free precession acquisitions can also help. By producing a myelographic effect with the CSF of high signal, they can better delineate regions of impingement. MR can also be useful in patients with compression fractures of the vertebral bodies to differentiate between benign osteoporotic collapse and pathologic collapse due to neoplastic replacement. In the chronic situation, nonneoplastic involvement is typified by preservation of normal bone marrow signal, absence of edema, and no associated paravertebral soft tissue. Tumor causing compression fractures are 1612

usually lower signal intensity on T1-weighted images (Figs. 21.5 and 21.7). Unfortunately, in more acute cases, the distinction between the two causes is more difficult, in that both may display altered signal because of marrow edema in nonneoplastic causes (Fig. 21.8) and because of tumor with edema in neoplasms. Benign acute vertebral compression fractures can also show paravertebral edema and hemorrhage, which further complicates the imaging distinction from metastatic tumor. In some cases of acute benign osteoporotic collapse, incomplete signal loss is seen. An even band of normal high-signal marrow with smooth margins may remain adjacent to a band of lower signal in the same vertebral body. This appearance is suggestive of a nonneoplastic deformity (Fig. 21.7). Linear fluid signal adjacent to the fractured endplate is suggestive of a benign fracture, although it does not exclude a neoplastic process. In a series of 87 patients, this finding was present in 21 of 52 benign fractures (40%) but only in 2 of 35 neoplastic fractures (6%) (4).

FIGURE 21.5 Eosinophilic granuloma. T1-weighted imaging (A) shows complete replacement of the normal vertebral marrow signal and mild vertebral body compression deformity. Notice that the signal alteration is much less conspicuous on T2-weighted imaging (B). Diffuse signal abnormality and solid enhancement (C) distinguish this appearance from that of a benign compression fracture. T1-weighted imaging (D) and lateral plain film (E) obtained 6 months later show progression to vertebra plana after treatment. Microscopy (F,G) demonstrates multinucleated histiocytes, eosinophils, and lymphocytes.

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FIGURE 21.6 Vascular metastasis from renal carcinoma. T1-weighted imaging (A) demonstrates replacement of the normal marrow fat with epidural extension of tumor. The marrow signal is heterogeneous on T2-weighted imaging (B). Axial T1-weighted (C) and axial T2-weighted (D) images show numerous flow voids in the center of the mass, suggesting hypervascularity. Axial images define the extent of epidural extension. Note the lobulated appearance in the anterior epidural space, resulting from the limiting posterior longitudinal ligament in the midline. The mass demonstrates avid solid enhancement (E). Angiography (F) confirms the hypervascularity of the tumor, which was

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then embolized. Microscopy (G) demonstrates nests of cells with clear cytoplasm with intervening vascular septa, consistent with metastatic renal cell carcinoma (clear cell type).

FIGURE 21.7 Benign osteoporotic compression fractures. A: T1-weighted (500/12) sagittal MR image reveals multiple compression deformities. Those that are of similar signal intensities to normal marrow are chronic. However, the two vertebral bodies superiorly are of low signal intensity because of the acuteness of the compression fractures. Note the straight line separating hypointense from normal intensity marrow, strongly suggestive of benign compression fracture rather than metastases. B: Gadolinium-enhanced, T1-weighted (500/12) sagittal magnetic resonance image displays enhancement of the acute compression fractures. This finding demonstrates that compression fractures, by themselves, can enhance. The enhancement should not be thought of as indicative of neoplastic involvement.

FIGURE 21.8 Acute benign compression fracture. A: Sagittal T1 shows compression deformity of T12 in patient with multiple levels of degenerative disk disease. B: Sagittal T2 with fat suppression shows heterogeneous high-signal edema, consistent with recent timing of compression fracture, even though this was not neoplastic.

There has been considerable debate about the use of diffusion-weighted imaging (DWI) to differentiate between benign and pathologic compression fractures. A number of studies have been published using a variety of techniques, including steady-state free procession, line scan imaging, and quantification of apparent diffusion coefficient values (5,6). Because the results have been mixed and some false positives have been demonstrated, the utility of DWI in making this important distinction has been controversial (7). A few studies have, however, shown that the use of apparent diffusion coefficient (ADC) values can aid in making this differentiation, reducing the incidence of false positives (6,8). When gadolinium compounds are given for spinal lesions, enhancement is extremely variable (3). Some tumors enhance mildly and remain hypointense to normal marrow; others enhance markedly and 1615

become hyperintense; still others enhance moderately and become isointense to normal marrow. This variability of enhancement often occurs even in different metastatic lesions within the same patient. Because low-intensity lesions tend to enhance after the administration of gadolinium, they often become isointense with surrounding marrow and are less easily detectable (3,9). In fact, gadolinium can even obscure some lesions. If the detection of vertebral body lesions is a consideration, a noncontrast scan is often sufficient. If postcontrast imaging is performed for vertebral column lesions, it should be combined with fat suppression. One study has shown fat-saturated T1-weighted fluid-attenuated inversion recovery (FLAIR) imaging to increase conspicuity of extradural enhancing lesions when compared with fat-saturated T1-weighted FSE imaging (10). Although not usually essential in the detection of vertebral lesions, gadolinium contrast agents can be particularly useful as an adjunct when epidural tumors are considered (3,9). Contrast may be helpful in (a) more specifically characterizing possible epidural tumor, (b) indicating regions of more active tumor for biopsy, and (c) outlining areas of cord compression, when necessary. In specific cases, it also may be helpful in (a) differentiating diffuse marrow involvement with tumor from marrow that is abnormal in signal for nonneoplastic reasons, and (b) in evaluating response to therapy. Contrast can further help to characterize suspected epidural tumors (3,9). For example, although disc herniation usually is easily differentiated from epidural tumors on noncontrast MR scans, occasionally an epidural mass is seen adjacent to a narrowed disc. In these cases, the etiology of the mass may be in question. Gadolinium enhancement may prove helpful in this specific clinical situation. Although discs and disc fragments generally do not enhance on immediate postcontrast acquisitions, tumor does. Therefore, these cases may benefit from the administration of gadolinium because enhancing tumor can be differentiated from nonenhancing disc material. Gadolinium-enhanced imaging can help to highlight areas of cord compression (3). Occasionally, especially in patients who have diffuse metastatic disease and congenitally narrow spinal canals, exact localization of areas of cord compression may be difficult on unenhanced T1-weighted MR scans. This is particularly true in the cervical and thoracic regions, where a paucity of fat in the spinal canal prevents outlining of epidural lesions. Because of the extent of the vertebral body involvement, placement of the axial scans also is difficult. After the administration of gadolinium, enhancing tumor surrounding nonenhancing cord is better delineated. Alternatively, high-quality, T2-weighted scans or GRE acquisitions can provide similar information. Finally, for patients in whom spinal cord compression is suspected, it should be remembered that intradural or even intramedullary lesions can mimic extradural compressive lesions; therefore, it is also of use to perform postcontrast imaging in those cases in which no compressive lesion is found. Primary Extradural Tumors Vertebral Hemangioma Vertebral hemangiomas are benign vascular tumors in the spinal column, present in approximately 11% of all patients. In autopsies of 3,829 spines, Schmorl and Junghanns found hemangiomas in 409. Vertebral hemangiomas tend to increase in incidence with age. These lesions are solitary in 66% and multiple in 34% of cases. Sixty percent occur in the thoracic region, 29% in the lumbar region, 6% in the cervical region, and 5% in the sacrum. They are slightly more common in women. The vast majority of vertebral hemangiomas are discovered incidentally. Rarely, they may be symptomatic. Symptomatic lesions tend to occur in the thoracic region. In one study, 13 of 14 cases (93%) of symptomatic vertebral hemangiomas were located in the thoracic region, specifically between T3 and T9 (11). Initially, symptoms include localized pain and tenderness, often associated with muscle spasm. Radiculopathy may result from impingement on a nerve root. Myelopathic symptoms, such as motor and/or sensory abnormalities, can be seen with cord compression. Cord compression may occur secondary to (a) mechanical compression of the spinal cord by the expansion of the tumor within the vertebral body and/or posterior elements, (b) extension of tumor into the epidural space, (c) epidural hematoma secondary to the hemangioma, and (d) rarely, compression fracture of the involved vertebral body. Compression fractures in hemangiomas are unusual because the involved vertebrae usually have thickened vertical trabeculae, which tend to protect against axial collapse. PATHOLOGY. Grossly, these lesions are characterized by their dark red color (11). Histologically, they consist of vascular structures within bony sinuses lined by endothelium and filled with blood. This 1616

angiomatoid tumor can destroy some bony trabeculae, resulting in compensatory thickening of the remaining vertical trabeculae. IMAGING. The thickened vertical trabeculae of hemangiomas cause parallel linear densities producing a “jail bar” or “corduroy cloth” appearance in the vertebral body on plain films. This appearance can also be seen on sagitally or coronally reformatted computed tomography (CT), and even sometimes on sagittal MR images. Extension into the posterior elements can occur. On axial CT, the remaining thickened trabeculae give a typical spotted appearance to the vertebral bodies. This appearance can also sometimes be appreciated on axial MR images, particularly on T2-weighted sequence (Fig. 21.9). MR is extremely sensitive in the detection of hemangiomas. On both T1-weighted and T2-weighted images, these lesions tend to have increased signal intensity (Fig. 21.9). This high signal largely reflects the adipose tissue in these lesions rather than a hemorrhagic component. Occasionally, hemangiomas within the bony confines can have a paucity of adipose tissue and even appear diffusely hypointense making their identification more difficult. These lesions may be more aggressive and can enhance markedly with contrast. MR is able to show paravertebral and epidural extension of tumor. Extraosseous components tend to lack adipose tissue and to appear isointense on T1-weighted images. MR readily defines spinal cord and/or thecal sac compression or displacement. In those occasional cases in which multiple vertebral hemangiomas are present and lack the typical T1 hyperintense signal, it may be impossible to distinguish these benign lesions from metastases without the benefit of other clinical information or other imaging studies.

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FIGURE 21.9 Aggressive vertebral hemangioma with multiple additional typical hemangiomata. Sagittal T1-weighted image (A) shows thickened vertical trabeculae as well as increased T1 signal throughout the T5 and T8 vertebral bodies. Note the dorsal epidural involvement at the T8 level, which is lower in signal. Sagittal T2-weighted images (B,C) similarly show hyperintensity within the aforementioned levels; the dorsal epidural component at T8 compresses the cord. Additional more ovoid hemangiomata are also apparent at L1 and L2. Sagittal STIR image (D) demonstrates heterogeneously increased signal within the hemangiomata, including another smaller lesion at T3. Involvement of the T8 spinous process is evident. Sagittal T1-weighted, postcontrast, fat-suppressed image (E) shows corresponding enhancement within the lesions and more marked enhancement within the extraosseous dorsal epidural component. Axial T2-weighted image (F) depicts the aggressive hemangioma at T8 involving the posterior elements with marked narrowing of the canal by the epidural component. Note the characteristic “spotted” appearance of the thickened vertical trabeculae in cross section. Axial T2-weighted image at a different level (G) shows two adjacent, more typical hemangiomata confined to the L1 vertebral body. Axial and sagittal CT images (H,I) also depict the classic spotted and “jail bar” appearance of the hemangiomata.

TREATMENT. Asymptomatic lesions are left untreated. Symptomatic lesions can be treated with surgical decompressive laminectomy. Preoperative angiography can be useful to identify and occlude feeding arteries. Radiation therapy may also be used, either preoperatively or by itself. Percutaneous therapeutic techniques have also been described, including direct injection of ethanol into the lesion. Osteochondroma Although osteochondromas are the most common benign bone tumors (35.8%), only 3% of solitary and 7% of multiple osteochondromas occur within the spine (12). Nevertheless, because osteochondromas are much more common than many other bone tumors, they actually are encountered in the spine with regularity. Osteochondromas of the vertebral column are nearly always confined to the posterior elements, with a predilection for the spinous processes. Involvement of the vertebral body is unusual but has been reported (12). Most cases occur in the thoracic or lumbar region; the cervical spine is only rarely the primary site (12,13). Three-fourths of osteochondromas occur in patients younger than 20 years. There is a slight male predilection. Any bone preformed in cartilage can give rise to this lesion. These lesions occur in two different patterns—solitary and multiple. Solitary lesions have no known genetic component, whereas multiple lesions are seen in multiple hereditary exostosis. Signs and symptoms of osteochondromas are nonspecific. Frequently, pain is present; there may or may not be associated swelling or a palpable soft tissue mass. The lesions are usually large by the time they are symptomatic and come to medical attention (14). 1618

Neurologic symptoms are rare, occurring in less than 0.1% of patients. There is, however, a greater incidence of spinal cord symptoms in the teenage years, implying that growth spurts of the osteochondroma could compromise a marginally narrowed canal. Thoracolumbar lesions can present with bowel or bladder dysfunction and lower-extremity weakness, but cervical lesions have a varied presentation (12,13). In addition to myelopathy, the presence of a mass may be noted. Dysphagia and even sudden death from partial transection of the cervical cord from an osteochondroma of the dens have been reported. If lesions bridge multiple vertebrae, fusion and restricted motion can result, most evident in the cervical region. PATHOLOGY. Osteochondromas are composed of cancellous bone surrounded by cortical bone (12,13). They have a pedicle that attaches to the adjacent bone, usually at the site of ligamentous insertions (14). Marrow is present within them and a thin layer of hyaline cartilage covers the tumor. IMAGING. Plain films show a pedunculated or sessile lesion with its cortex in direct contiguity with the cortex of the adjacent bone. These lesions generally originate from the posterior elements. CT accurately delineates the exact site of attachment of the lesion to the adjacent bone, the presence of the cartilaginous cap, and any compromise of the spinal canal (14). In addition, CT can be helpful in distinguishing between benign osteochondromas and malignant degeneration into an osteosarcoma or chondrosarcoma. The incidence of malignant degeneration is 1% in cases of solitary osteochondroma and 5% to 25% in cases of multiple hereditary exostoses; rapid growth of the tumor should prompt suspicion of malignancy. Osteochondromas have a heterogeneous appearance on MR. The cartilaginous portions of this lesion are of increased signal intensity on the T2-weighted images, whereas the osteoid or calcified portions demonstrate low signal intensity. Both MRI and CT can effectively depict the “corticomedullary continuity” with the parent bone, that is characteristic of this tumor (Fig. 21.10). Because a large portion of the tumor is bony, the extent of thecal sac impingement may be easier to delineate on T2weighted or GRE sequences rather than T1-weighted sequences, in which the low-intensity regions may blend into CSF. As with other imaging modalities, the rapid growth of the lesion is an ominous sign. Factors favoring benignity include cortical margins that are contiguous with the adjacent bone, welldefined lobular surfaces, lack of adjacent bone involvement, and a thin cartilaginous cap (usually less than 1 cm).

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FIGURE 21.10 Osteochondroma. A pedunculated mass protrudes posterolaterally from the spinous process. Corticomedullary continuity between the lesion and the parent bone is well demonstrated on both axial T2-weighted (A) and T1-weighted (B) images. The cartilaginous cap demonstrates a peripheral ring of T2 hyperintense signal and diffuse enhancement on the postcontrast, fat-suppressed, T1-weighted (C) image.

TREATMENT. Because these lesions are benign, no treatment is required unless they are large and compress adjacent structures. In this instance, surgery can be performed and is usually curative, with only a 5% recurrence rate. Obviously, tumors with malignant degeneration require additional therapy. Osteoid Osteoma Osteoid osteoma comprises 11% to 12% of all benign bone tumors (15). It has been reported in virtually every bone, with a 0% to 25% incidence in the spine (average, approximately 10%) (16). The most common locations in the spine are the lumbar region (59%), followed by the cervical (27%), thoracic (12%), and sacral (2%) regions (16). The posterior elements are involved in 75% of cases. Thirty-three percent of cases involve the laminae, 19% affect the articular facets, and 15% affect the pedicles (16). The vertebral body is affected in only 7% (16). Osteoid osteomas are more common in males than females by a 2:1 to 4:1 ratio. This tumor is rare after age 30 years; 87% of the cases occur before this age. In MacLellan and Wilson’s review of the literature in 1967, of 36 documented cases of spinal osteoid osteoma, the average age was 16.7 years, and 72% of the patients were between 10 and 25 years old. Localized pain at the site of the lesion is highly characteristic; only rarely are they asymptomatic (1.6%) (13). Classically, the pain is worse at night and relieved by aspirin. Although it may be intermittent at first, it soon becomes constant and severe. Radicular pain can occur if the lesion encroaches on the neural foramina, which is seen in 50% of patients. There can be a significant delay in evaluation and diagnosis until the symptoms increase in severity. The average delay from initial symptoms to diagnosis in the series of Jackson et al. (17) was 11.3 months. In the absence of trauma, back pain is very unusual in a child and should prompt evaluation. Focal tenderness is the most common sign of osteoid osteoma and is seen in 69% of patients (16). Scoliosis is also frequently seen resulting from muscle spasm and consequent pelvic tilt. Scoliosis was seen in 29 of 36 cases in one literature review. PATHOLOGY. Grossly, this tumor has a central, vascular nidus that is reddish gray. Histologically, the tumor contains multinucleated giant cells. The nidus consists of very vascular fibrous connective tissue with surrounding osteoid matrix, and may contain irregular calcification (Fig. 21.11). The size of the nidus is by definition less than 1.5 cm (if greater than 1.5 cm, the lesion would be classified as an osteoblastoma), with an average size of 0.9 cm. The nidus is surrounded by sclerotic bony reaction. The extent of sclerosis is extremely variable but tends to be less in spinal lesions.

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FIGURE 21.11 Osteoblastoma. The left lateral mass of C1 is expanded with heterogeneous hypointensity on parasagittal T1-weighted imaging (A) and hyperintensity on proton density–weighted imaging (B). Axial T2-weighted imaging (C) shows a multiseptated mass with varying signal. Axial computed tomography (CT) (D) reveals a “blowout” lesion of the lateral mass. Note that the cortex is thinned but not destroyed. An axial image from a CT angiogram (CTA) (E) shows areas of arterial phase enhancement (arrowheads) within the mass, confirming the hypervascularity of the lesion. A three-dimensional reconstruction of the CTA (F) again shows an expansile process without frank bone destruction. Light microscopy (G) shows osteoblasts scattered throughout irregularly shaped trabeculae of woven bone and osteoid in loose fibrovascular stroma.

IMAGING. The appearance of osteoid osteoma in the spine resembles its appearance elsewhere in the 1621

skeleton. Plain films, which demonstrate the classic findings in 66% to 75% of cases, show a lucent nidus (Fig. 21.12). Frequently, a small amount of calcification can be seen within the nidus. Surrounding bony sclerosis can be seen but its extent is variable. If there is extensive bony sclerosis, the exact location of the nidus can be difficult to discern on plain films, and further imaging is required to localize the nidus. If the initial plain films are negative and clinical suspicion is still high for an osteoid osteoma, nuclear medicine bone scans are generally recommended. Osteoid osteomas are focally “hot” on bone scan (Fig. 21.12). Once the level of the lesion is localized with the bone scan, then further cross-sectional imaging with either CT or MR can be performed to confirm the precise location of the nidus preoperatively. Frequently, the nidus can be seen only on cross-sectional imaging. CT shows a small, rounded area of low attenuation with or without calcification (Figs. 21.12 and 21.13). Surrounding sclerosis is evident and can be extensive. On MR, osteoid osteomas have a heterogeneous appearance. The calcification within the nidus and the surrounding bony sclerosis are of low signal intensity on T1-weighted and T2-weighted images. The noncalcified portions of the nidus itself demonstrate increased signal intensity on the T2-weighted images. The administration of gadolinium, like that of iodinated contrast material, causes intense enhancement within the highly vascular nidus. This enhancement may help not only to localize the nidus, but also to differentiate it from a nonenhancing lytic lesion such as Brodie’s abscess, which can also demonstrate similar surrounding edema and sclerosis. MR also may show an associated reactive soft-tissue mass. This soft-tissue swelling usually demonstrates inhomogeneous signal on T1-weighted images and increased signal on T2-weighted images (Fig. 21.12). Adjacent bone marrow may also demonstrate these signal changes. Both the soft tissue and the reactive marrow often enhance with contrast. Although CT has traditionally been the primary modality for evaluation of suspected osteoid osteomas due to its sensitivity to bone detail, MR is being used with increasing frequency. In one case report, MR was able to localize the nidus of a lesion that could not be defined on any other modality. Dynamic postcontrast MRI of osteoid osteomas was described with good results in a series of 11 patients. The nidus demonstrated arterial phase peak enhancement in 9 of 11 (82%) patients and was equally or more conspicuous compared with thin-section CT in all cases (18).

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FIGURE 21.12 Osteoid osteoma. A 14-year-old girl presented with pain. Plain films (A) showed a lucent lesion in the right posterior elements with a central ringlike calcification (arrowhead). Bone scintigraphy demonstrated intense focal uptake (B). Axial (C) and parasagittal (D) computed tomography images better demonstrate the same findings and place the lesion in the right superior facet. Note the sclerotic change in the adjacent bone. On T1-weighted imaging (E), the lesion is hyperintense (arrowhead) and there is infiltration of the surrounding soft tissues. Extensive soft tissue edema is well demonstrated on short–inversion-time inversion recovery imaging (F,G) surrounding the nidus (arrowheads). The mass enhances after contrast (arrowhead), as does the adjacent soft tissue reaction (H).

TREATMENT. Osteoid osteomas can be conservatively treated with medication (nonsteroidal antiinflammatory drugs) because some may regress spontaneously after several years. Definitive treatment requires complete removal of the nidus. Traditionally, this meant surgical excision; however, percutaneous ablation (radiofrequency, laser, and other techniques) has emerged as a primary modality of treatment in both appendicular and axial skeletal locations. This treatment option has demonstrated good outcomes, with the benefit of decreased hospitalization and recovery time. Osteoblastoma Osteoblastomas are uncommon, benign bone tumors accounting for 1% of all primary bone neoplasms (19). Although they have been described in almost every bone, there is a particular predilection for the spine, which accounts for 25% to 50% of cases (19). In the Mayo Clinic series, 39 of the 123 tumors were located in the spine. The lumbar spine is most often involved, followed by the thoracic and cervical spine (19). Osteoblastomas most often occur in the posterior elements. In 1988, Myles and MacRae reported 10 cases of spinal osteoblastoma in children and found that 9 were located in the posterior elements (19). In 14% of cases, the lesions were located in the vertebral body (19). In 24% of cases, both the vertebral body and posterior elements were involved. Epidural extension of tumor could be seen (19).

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FIGURE 21.13 Osteoid osteoma. Axial (A) and parasagittal (B) computed tomography images demonstrate a small lucent nidus (arrowhead) in the left lamina with surrounding bony sclerosis.

Osteoblastomas are more common in men (19,20). In the Mayo Clinic series, 87 of 123 cases were found in men. Ninety percent of the cases occur before age 30 years. The lesion usually presents in patients within the second or third decade of life (19,20). Osteoblastomas most often present with pain and local tenderness (19). Scoliosis or torticollis may result. The symptoms may occur before the lesion becomes evident on plain films. Frequently there is a delay in diagnosis (average 9.3 to 12.3 months) (19,20). PATHOLOGY. Grossly, these masses are soft, hemorrhagic, and very vascular and friable. Because of mineralized osteoid, they often have a granular texture. They also contain fibrovascular stroma (19,20). Histologically, osteoblastomas appear similar to both osteoid osteoma and osteosarcoma. Osteoid osteoma and osteoblastoma are differentiated by their size. Osteoblastomas are larger than 1.5 cm, whereas osteoid osteomas are smaller than 1.5 cm. The average size of the nidus in one study was 2.4 cm. In another study, the size ranged up to 10 cm. In addition, osteoblastomas may lack the identifiable central nidus and have less surrounding sclerosis than osteoid osteoma. IMAGING. On plain films and CT, these lesions tend to be expansile, with surrounding thinned cortex. In the spine, the lesions usually involve the posterior elements (Fig. 21.14) (19,20). The tumor may have a lucent or an ossified center (20). The margins are often but not always well defined. There can be dense sclerotic reaction associated with these lesions (20,21). CT also shows associated soft tissue masses and epidural extension (19).

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FIGURE 21.14 Osteoblastoma. A: Plain films show an enlarged left L4 pedicle (arrow). B: The pedicle is expanded and hypointense on T1-weighted imaging (arrows). C: Heterogeneous areas of low and high signals are seen on T2weighted imaging. D: The lesion enhances avidly after contrast administration.

MR readily shows the lesion and any associated soft tissue mass. Impingement on the thecal sac can be detected. These lesions are inhomogeneous if areas of hemorrhage or calcification are present (Fig. 21.14). A thin rim of signal void as a result of the bony shell may be visible. On T2-weighted images, osteoblastomas demonstrate high signal intensity, possibly corresponding to regions of vascularized stroma. Irregular linear areas of signal void may be seen, corresponding to osseous trabeculae (Fig. 21.11). Osteoblastomas demonstrate enhancement after administration of contrast on T1-weighted images (Fig. 21.14). TREATMENT. The goal of treatment is total excision of the lesion (19). If the lesion is removed completely, there is usually complete disappearance of symptoms with relatively little chance for recurrence, although recurrence is more common in lesions involving the spine (19,20). Preoperative embolization is often used to decrease intraoperative bleeding in hypervascular tumors. Long-term follow-up is essential because recurrences may occur as long as 9 years after surgery. Radiation therapy may be given for incompletely removed recurrent lesions (19). Rarely, malignant degeneration has been reported. Aneurysmal Bone Cyst Aneurysmal bone cysts (ABCs) are benign disorders of bone with an unknown etiology. These tumors represent 1.4% to 2.3% of primary bone neoplasms (15). Generally, these lesions arise de novo; however, they can be associated with other lesions (32%), such as giant cell tumor, chondroblastoma, chondromyxoid fibroma, fibrous dysplasia, and nonossifying fibroma. There is either a slight female 1625

predilection or no sex predilection. The patients are usually in their first two decades, with 66% to 78% of the cases occurring in patients less than 20 years of age (15). In a study reviewing 81 cases of ABC in the spine, the average age was 16.6 years, and most occurred between 10 and 25 years of age (22). Giant cell tumors, which may appear similar, are usually seen in patients older than 30 years of age (23). Although these lesions have been found in almost every bone, the spine is involved frequently. In the Mayo Clinic series of 134 cases of ABCs, 27 were located in the spine, including 5 in the sacrum. In other studies, between 3% and 20% of cases involve the spine. The neural arch is the most frequently affected site. Sixty percent of ABCs involve the posterior elements; 40% arise in the vertebral bodies (21). Forty-four percent occur in the lumbosacral region, 34% in the thoracic spine, and 22% in the cervical spine. They can cross the intervertebral disc space and involve an adjacent vertebral body. About 22% of lesions extend into the paraspinal soft tissues. There may or may not be an associated soft tissue mass. Symptomatology varies tremendously based on the size and degree of differentiation of the lesion. A small lesion can be entirely asymptomatic. When symptoms are present, they usually consist of localized pain and/or swelling. Large lesions can impinge on the spinal cord with resultant long-tract symptoms and signs. In one study of 15 patients, compression fractures contributed to symptoms in four cases. In addition, neural foraminal narrowing can result in radiculopathy. Often the symptoms may be longstanding before diagnosis. The average duration of symptoms in one series was 8 months. PATHOLOGY. Grossly, ABCs are clearly delineated by the eggshell-thin cyst of subperiosteal new bone. The interior of the lesion can be solid and vascular or cystic and hemorrhagic. ABCs are composed of large, anastomosing cavernous spaces filled with unclotted blood (23). The linings of these spaces lack normal features of blood vessels and do not contain endothelium, muscle fibers, or elastic laminae (22,24). This benign lesion also has solid portions, which are frequently composed of osteoid material, sometimes intermixed with fibrous tissue (22). Histologically, these lesions can be mistaken for other entities, such as telangiectatic osteosarcoma. Giant cells are present within the trabeculae of this lesion and can lead to confusion with giant cell tumor (22). IMAGING. Plain films of ABCs of the spine show an expansile lytic lesion usually involving the posterior elements (24). An eggshell-thin cortical margin is often seen. Severe lesions can destroy the vertebral body and result in collapse and vertebra plana (22). CT confirms the expansile appearance of the lesion and better defines any soft tissue extension (23,24). The absence of permeative bone destruction decreases the possibility of more aggressive processes. In addition, multiple small fluid levels sometimes can be seen on CT. Frequently, to visualize these fluid levels best, the patient must remain motionless for 10 minutes before scanning to allow the different components of blood to settle out within the cavernous spaces of the tumor (24). MR exhibits similar findings to those seen on CT. Expansile lesions are noted, often with internal septations and lobulations (Fig. 21.15). A thin, well-defined rim of low signal intensity is often visualized on both short and T2-weighted images. Multiple small fluid–fluid levels and internal septations may be present (24). The fluid can have varying signal intensity based on the presence of intracystic hemorrhage of different ages (24). These vary from high to low signal on short and T2weighted images. In other cases, the lesions may exhibit uniformly high intensity on T2-weighted images. Paravertebral extension of the mass is well demonstrated on MR. Epidural extension or spinal cord compression is better depicted on MR than on CT. After the administration of contrast, the septations within the lesion generally enhance (25). Altogether, the MR appearance of an ABC is characterized by involvement of the posterior elements of the spine, a rim of low signal intensity, and multiple fluid levels. TREATMENT. Curettage is the initial treatment employed. Recurrence develops in 10% to 20% of patients (15). If the lesion recurs several times, radiation therapy may be used. Giant Cell Tumor Giant cell tumors constitute approximately 4% to 5% of all primary bone tumors and 21% of the benign tumors (15). These lesions are most common in adults. There is no sex predilection. Although these tumors occur most often at the knee, giant cell tumors are not infrequently seen in the spine. In the Mayo Clinic series of 2276 bone tumors, they were the most common benign spinal column tumors, excluding hemangiomas (15). This lesion is the most frequent benign tumor to involve the 1626

sacrum (11 of 209 cases) (26). Giant cell tumors less often involve the rest of the spine (2 of 135 cases, 2 of 25 cases, and 3 of 209 cases) (26). Malignancy can rarely develop in giant cell tumors, either primarily or more commonly secondarily, after radiation or surgery. When malignancies do develop, they are usually high-grade sarcomas with a poor prognosis (27). Pain is the most common symptom and is seen in up to 97% of patients (26). In giant cell tumors of the spine, radiculopathy may result from irritation of adjacent nerve roots. Initially, the pain is intermittent and relieved by rest; however, it eventually becomes persistent (26). An associated soft tissue mass often is present (35 of 135 patients) (28). PATHOLOGY. Although giant cell tumors are characterized by multinucleated giant cells, the presence of giant cells is not specific and may be seen in numerous other lesions, including chondroblastoma, chondromyxoid fibroma, ABC, and osteosarcoma (26). Most of the tumor is composed of mononuclear round or spindle-shaped fibroblastic mesenchymal cells (26). Jaffe et al. (29) stated that the aggressiveness of this lesion is determined by the stromal cells. Many histologists divide giant cell tumors into three grades according to the degree of malignant features, but the presence of metastatic disease does not always correlate with the grade.

FIGURE 21.15 Aneurysmal bone cyst. There is an expansile mass (arrowheads) involving the lateral mass of C1,

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which is isointense on T1-weighted imaging (A). Note the small internal foci of T1 hyperintensity representing methemoglobin (arrow). After contrast (B), the mass enhances heterogeneously, with a few internal cystic or hemorrhagic nonenhancing foci. Coronal T2-weighted images (C,D) reveal fluid–fluid levels (arrow) and loculations, characteristic of an aneurysmal bone cyst. Correlative enhanced computed tomography images (E,F) show a “blowout” lytic lesion with arterial phase heterogeneous enhancement.

FIGURE 21.16 Giant cell tumor. Sagittal T1-weighted (A) and T2-weighted (B) images demonstrate low signal completely replacing the normal marrow signal within a midthoracic vertebral body, with loss of vertebral body height. Note the particularly low signal on the T2-weighted image, reflecting intratumoral blood products. The T2-weighted image also well demonstrates the retropulsed epidural component narrowing the ventral subarachnoid space.

IMAGING. Plain films show a lytic lesion with an expansile appearance. Rarely, the border of this lesion is sclerotic. In the spine, no definite characteristic radiographic appearance is seen. CT can show an associated soft tissue mass (28). MR is readily able to demonstrate the bony and soft tissue components of the lesion. Unenhanced T1weighted images can show the extent of the tumor within the bone because the lesion displaces the normal higher signal of fat-containing marrow. The extent of the lesion is also well assessed. On T2weighted images, giant cell tumors may be inhomogeneous, with areas of decreased and increased signal intensity. Areas of decreased T2 signal are typically related to intralesional blood products (Fig. 21.16). After the administration of contrast, T1-weighted images may help to differentiate enhancing tumor from adjacent normal structures. TREATMENT. The usual treatment for this tumor is curettage. If surgery is not optimal because of location or numerous recurrences, then radiation therapy can be used. One long-term study of 18 patients found embolization to be a useful treatment option. Sacrococcygeal Teratoma Sacrococcygeal teratomas are rare tumors of childhood. They arise from multipotential cells of Hensen’s node that migrate to lie within the coccyx. As a result, the soft tissue mass may be accompanied by bony abnormalities of the coccyx. The American Academy of Pediatrics grades these tumors into four types. Type 1 tumors are almost always completely external and distort the buttocks. Type 2 tumors have an intrapelvic portion, but most of the tumor is external. Type 3 tumors are predominantly intrapelvic with significant displacement of invasion of surrounding structures. Type 4 tumors have no external portion, and almost all of the tumors are intrapelvic. Sacrococcygeal teratomas occur in 1 in 35,000 to 40,000 births (28). Most sacrococcygeal teratomas are benign and identified at birth. They are associated with a high frequency of other congenital anomalies, especially anorectal malformations. Females predominate over males in a ratio of 4:1. Malignant lesions tend to be more common in males. Malignancy is also more frequent in lesions with a greater internal component (types 3 and 4), with a long delay in diagnosis and treatment and with more solid and fewer cystic components. PATHOLOGY. Grossly, these tumors can be cystic, solid, or a combination of the two. Histologically, tissues arising from all three germ layers can be found. These tumors often contain squamous or intestinal epithelium, appendages, cartilage, bone, or neuroglial fibers. They tend to be very vascular. 1628

IMAGING. Plain films may show a pelvic soft tissue mass. Coccygeal erosion may or may not be present. The mass can lie in a presacral location and displace pelvic structures such as the urinary bladder or bowel loops. The solid portions of this tumor are calcified in 60% of all cases (30). CT is more sensitive than plain film or MRI for demonstration of calcification. Both CT and MRI may demonstrate focal areas of fat, which are highly suggestive of the diagnosis. MR shows a mass adjacent to the coccyx (Fig. 21.17). Any intrapelvic or external components can be assessed. The lesion may be entirely solid, or it may have cystic components. Although cysts generally appear to be of decreased intensity on T1-weighted images or increased intensity on T2-weighted images, some cysts may have different intensities if they contain hemorrhage. Focal fatty components are hyperintense on both T1- and T2-weighted images. After the administration of gadolinium, solid portions of the tumor enhance. The diagnosis can also be made prenatally, with either sonography or fetal MRI. A series of 22 patients demonstrated prenatal MRI to be more accurate than ultrasound in characterizing extent of the tumor and compression of adjacent organs (31). TREATMENT. The treatment for both benign and malignant sacrococcygeal teratomas involves immediate surgical excision. These tumors have increased malignant potential with age; therefore, early surgery is advocated. The prognosis for benign lesions is excellent, although there may be morbidity secondary to surgical damage of the sacral plexus or to severe blood loss at the time of surgery because of the vascular nature of these tumors (30). If metastases occur, these tumors have an extremely poor prognosis because there is limited response to chemotherapy or radiation therapy. Eosinophilic Granuloma Eosinophilic granuloma is a nonneoplastic condition with an unknown etiology. The disease is most common in children. In one series of 28 patients, the disorder was most frequently seen in the 6- to 10year-old age group. In another series of 46 patients, 38% were less than 10 years of age, and an additional 26% were between 10 and 19 years old (30). Overall, there is a male predilection, with 36 cases found in males and 7 cases in females in one review. Symptoms are extremely variable, ranging from nonexistent to severe. The most common symptom is localized pain with or without an associated soft tissue mass. Systemic symptoms and signs, such as fever and weight loss, may also be present. The duration of the symptoms can range from days to months. These lesions can be single or multiple. In a study of 46 patients, 36 had solitary lesions and 10 had multiple lesions. Overall, the skull, pelvis, vertebrae, ribs, and long bones can be involved. When the lesions are multiple, the ribs and vertebrae are involved more commonly, frequently at numerous levels. With spinal lesions, collapse of the vertebral body can result in spinal cord compression, nerve root impingement, and deformity of the spine (32). Complete or near-complete vertebral body collapse, termed “vertebra plana,” may be seen with eosinophilic granuloma.

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FIGURE 21.17 Sacrococcygeal teratoma. Mass surrounding the lower sacrum and coccyx (arrow) demonstrates hyperintensity on short–inversion-time inversion recovery (A) and T2-weighted (B) images. The rectum is displaced anteriorly by this mass. Note the ringlike area of hyperintensity (arrow) on both T2-weighted (C) and T1-weighted (D) imaging, consistent with a focus of bulk fat, as confirmed on computed tomography (E).

PATHOLOGY. Initially, these lesions are cystic and hemorrhagic. The cysts vary from 1 to 4 cm in size and have a yellow to reddish brown appearance. As these lesions evolve, they develop increased amounts of lipid and appear friable and yellow. They heal into gray fibrous lesions, with bone formation in the later stages. Histologically, these lesions are initially infiltrated by many eosinophils, accompanied by variable numbers of lymphocytes. Finally, in the healing stages, connective tissue is present, which in turn is transformed into bone. IMAGING. Plain films show round or oval, sharply marginated lytic lesions with well-defined borders. There may or may not be an associated soft tissue mass. CT demonstrates findings similar to the plain films and better delineates any associated soft tissue mass. On MR, lesions usually have decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images, unless hemorrhage is present. Spinal cord compression is well delineated. When the vertebral body is involved, it is usually affected in its entirety. The weakened vertebral body can collapse, resulting in vertebra plana (Fig. 21.5). A secondary kyphosis may develop. 1630

Associated epidural hematoma also can cause spinal cord compression. The lesions may be difficult to differentiate from metastatic disease. Chordoma Chordomas constitute 3% to 4% of all primary bony tumors (33). They arise from remnants of the notochord. Because the notochord, which forms the early fetal skeleton, extends from the clivus to the sacrum, chordomas can occur anywhere along the skull base and spine: 50% arise in the sacrum, 35% in the clivus, and 15% in the vertebrae (33). In the spine, the areas most commonly involved are the cervical, lumbar, and, finally, the thoracic spine, in descending order of frequency. There is a definite male predominance, with roughly a 2:1 male-to-female ratio. Of 155 cases from the Mayo Clinic, 103 were male and 52 were female. In this same study, the age range was from 8 to 83 years, with an average age at diagnosis of 48 years. Pain is the most common symptom in spinal chordomas, and is usually localized to the site of origin. As they grow, vertebral chordomas can show signs and symptoms of cord compression. In one series of 46 cases, the average duration of symptoms to the time of diagnosis was almost 1 year. Although chordomas often invade adjacent structures, they metastasize less frequently. However, chordomas arising in the vertebral bodies are more malignant than their counterparts in the sacrum or the clivus. Although metastases have been reported in 10% to 15% of all cases, metastases occur in 80% of the vertebral body cases. PATHOLOGY. Grossly, chordomas may be soft or firm. They often appear lobulated. Histologically, these lesions are composed of large, vacuolated physaliferous cells. The cells are usually arranged in cords and contain abundant glycogen. Fibrous septae subdivide the tumors into lobules. IMAGING. Plain films show bony destruction with areas of amorphous calcification in 50% to 70% of the cases. In one study of 16 cases, 7 patients exhibited involvement of two or more adjacent vertebral bodies and the intervening disc, a finding generally associated with infectious etiologies and unusual in neoplasms. In addition, paravertebral masses can be seen. CT can better demonstrate the calcification and paravertebral soft tissue masses. CT after intravenous contrast or after myelography can show an associated epidural component. Chordomas may show areas of hypodensity on CT, likely reflecting mucinous content or cystic degeneration (34). MR is inferior to CT in showing bony destruction or calcification (35). MR, however, is superior in outlining epidural disease and the true extent of disease involving the bone (Figs. 21.18 and 21.19). These lesions may involve neural foramina, mimicking nerve sheath tumors (34). Seventy-five percent of chordomas are isointense to cord on T1-weighted images and 25% are hypointense. The lesions are high signal on T2-weighted images (35). Seventy percent of cases show internal septations and a surrounding capsule of low signal intensity. Areas of hemorrhage and cystic change are readily demonstrated if present. After the administration of contrast, prominent enhancement is typically seen. TREATMENT. Treatment consists of surgical resection with radiation therapy. The prognosis is poor, with a 5-year survival rate of 10%. In one study, an average survival of 3 years after the time of diagnosis was seen. Although metastases are not common, local recurrence is the major problem, usually within 2 to 4 years after initial surgery and radiation therapy. Neuroblastoma, Ganglioneuroma, and Ganglioneuroblastoma Neuroblastoma, ganglioneuroma and ganglioneuroblastoma are considered together because they all arise from the same primitive cells—neuroblasts, which are of neural crest origin (36). These tumors, however, vary significantly in degree of cell maturity and behavior. The neural crest cells embryologically form the adrenal medulla and the paravertebral sympathetic chain. Therefore, neuroblastomas (the most common of the three) can originate in the adrenal medulla (36% to 40%) or in the paravertebral sympathetic chain. The adrenal medulla and upper abdominal parasympathetic chain are the primary sites of 65% of neuroblastomas (36) Ganglioneuroma is the most well differentiated lesion and is composed almost entirely of mature ganglia cells. Neuroblastoma is a disease of infancy and childhood that occurs in 1 in every 10,000 births. Children less than 5 years of age are affected most often (36). Excluding central nervous system (CNS) tumors, neuroblastoma is the most common solid tumor of children (36). There is a slight male predilection in some studies (36). Both ganglioneuroma and ganglioneuroblastoma tend to present later than 1631

neuroblastomas and are most often seen in the 5- to 8-year-old age group. Because the tumors often originate in a paraspinal location, they can extend through the neural foramina to impinge on the thecal sac. Epidural extension occurred in 17 of 129 cases of neuroblastoma in a study from the Hospital for Sick Children. One percent to 4% of patients present with spinal cord compression. Punt et al. (37) reviewed the records of 21 children with neuroblastoma who presented with spinal cord compression. Four children had spinal cord compression at birth (37). Involvement of the spine occurs most frequently in the thoracic and lumbar regions and is rare in the cervical area. In Punt et al.’s (37) series of 21 cases with cord compression, 9 occurred in the thoracic region, 5 in the thoracolumbar, 6 in the lumbosacral, and only 1 in the cervical region. Symptomatology can vary tremendously according to the location and extent of disease. With intraspinal involvement, the most common presenting symptoms include local pain and spinal cord dysfunction (36). The patient may notice a paraspinal mass or may have signs of spinal cord compression. In one series of 11 cases, impaired motor and sphincter function were seen in 8, weakness of the lower extremities in 6, and weakness of the arms in 2. Cord compression is also common in terminal stages of the disease because of the frequent occurrence of osseous metastases. Actual brain and spinal cord parenchymal metastases from neuroblastoma are rare, although leptomeningeal tumor spread is not unusual. PATHOLOGY. Histologically, neuroblastomas are composed of small, round cells with hyperchromatic dense nuclei, which can be confused with Ewing sarcoma, rhabdomyosarcoma, lymphoma, and Wilms tumor (36). Neuroblastoma is composed of primarily primitive cells and lacks elements characteristic of further maturation, such as increased size of nuclei, increased amount of cytoplasm, and production of fibrillar elements (36). The tumor is frequently hemorrhagic, and calcifications are seen in 10% of cases. Ganglioneuroblastoma is a mixture of immature neuroblastoma and more mature elements, whereas ganglioneuroma is composed of primarily mature cells. The nuclei are large, and there is more cytoplasm present within the cells than in neuroblastoma. As the axonal processes develop, more mature fibrillary structures are seen. Calcifications are seen in 20% of cases (36). Neuroblastomas can differentiate into ganglioneuroma. In fact, neuroblastoma metastases can have ganglioneuroma elements within them.

FIGURE 21.18 Sacral chordoma. A,B: Coronal and sagittal T2-weighted images demonstrate a large lobulated and exophytic mass destroying and protruding from the lower sacrum and coccyx into the presacral space. The marked T2 hyperintensity and septated, lobulated appearance is typical of a chordoma. C: Coronal T1-weighted image shows the mass to be diffusely iso- to hypointense in signal. D,E: Postcontrast axial and sagittal fat-suppressed T1-

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weighted images demonstrate marked diffuse enhancement.

FIGURE 21.19 Cervical chordoma. Sagittal T2-weighted (A) and sagittal T1-weighted, fat-suppressed, postcontrast (B) images show a T2 hyperintense and enhancing mass spanning the C5 to C7 vertebral bodies. Chordoma is one of the tumors that are more likely to cross the disc spaces. Note the prominent epidural component narrowing the subarachnoid space and compressing the spinal cord.

IMAGING. As tumor extends through the neural foramina, plain films disclose erosion of the pedicle, widening of the foramina, scalloping of the vertebral body, thinning of the ribs, or widening of the spinal canal (37). The intraspinal component of the tumor can spread through the epidural space over several levels, resulting in cord block remote from the site of the paravertebral mass. Rarely, these lesions can directly invade the intradural space. MR generally demonstrates relatively low intensity on T2-weighted images, owing to the marked hypercellularity and paucity of free water content, although patchy hyperintensity also can be seen (Fig. 21.20). Other small, round cell tumors with hypercellularity can look identical on T2-weighted images (Fig. 21.21). More importantly, MR accurately demonstrates intraspinal extension of tumor through the intervertebral foramina and the resultant mass effect on the spinal cord. Areas of nonhemorrhagic necrosis have low signal intensity on T1-weighted images and increased signal intensity on T2-weighted images. Focal areas of hemorrhage can have a varied appearance. Acute hemorrhage is characterized by decreased signal intensity on both T1-weighted and T2-weighted images. Subacute hemorrhage initially tends to show increased signal on T1-weighted images and decreased signal on T2-weighted images, but it slowly progresses to display increased signal on all pulse sequences. Large areas of calcification may be visualized as areas of signal void. Finally, with contrast administration, these tumors tend to enhance. Contrast frequently helps to separate the epidural component from the normal thecal sac and spinal cord on T1-weighted images (Fig. 21.20). TREATMENT. In the initial diagnosis, accurate assessment of intraspinal extension is crucial because symptoms referable to spinal cord compression can be permanent if not treated (37). In addition, when debulking the tumor, it is helpful to remove any epidural component because significant blood loss can occur if an unsuspected portion of the tumor remains within the spinal canal (37). Prognostic factors in neuroblastoma depend on the age at diagnosis, the extent of the disease, the site of the primary tumor, and the degree of maturation of the cells. Factors associated with a favorable outcome include younger age at diagnosis, extra-adrenal location, more differentiated histology, and more localized disease (36). There also appears to be a better prognosis for children presenting with spinal cord compression (37). Of 21 children with this presentation, 13 survived, 11 with long-term survival at the time of the report (37).

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FIGURE 21.20 Ganglioneuroma. Sagittal T1-weighted image (A) demonstrates a large, smoothly contoured, dorsal hypointense mass spanning from T12 to L5. Sagittal T2-weighted image (B) shows the mildly low signal throughout the mass and compression of the thecal sac. Sagittal T1-weighted postcontrast, fat-suppressed image (C) shows avid homogenous enhancement. Sagittal DWI image (D) and sagittal ADC map (E) demonstrate moderately reduced diffusion throughout the mass due to tumor cellularity. Fat-suppressed axial T2-weighted (F) and axial T1-weighted postcontrast (G) images demonstrate the “dumbbell” appearance of the lobulated mass extending through bilateral neural foramen, with prominent bilateral paravertebral components. Note the ventral displacement and compression of the thecal sac and cord. (Courtesy of Dr. Nilesh K. Desai.)

Osteosarcoma Of all primary malignant bone tumors, osteosarcomas are one of the two most common. In a Mayo Clinic series of 2,276 primary bone tumors, there were 490 osteosarcomas (15). Osteosarcomas, however, are unusual when they occur as primary tumors in the spine. Only 2 of 552 cases in the study from Memorial Sloan-Kettering Cancer Center arose in the spine. In a more recent study of 4,887 osteosarcomas from the Mayo Clinic, 198 (4%) were of primary vertebral origin (38). Metastatic disease to the spine from osteogenic sarcoma arising elsewhere, however, is very common. 1634

Osteosarcoma is the most common primary malignant bone tumor in the pediatric population. Although appendicular osteosarcomas are known to have a male predilection (39), the 2004 Mayo clinic series failed to demonstrate a significant gender bias in primary vertebral osteosarcoma (38). This series also demonstrated a mean age of incidence in the fourth decade of life, whereas appendicular osteosarcoma peaks in the second decade of life (38,39). Osteosarcomas generally occur de novo. However, they may arise within bone that has previously been irradiated (16 of 600 cases in the 1967 Mayo Clinic series). There usually is a 5- to 25-year latent period after the radiation before the development of the osteosarcoma. Osteosarcomas can arise in osteochondromas, as in 2 of the 600 cases reported in the Mayo Clinic series. Osteochondromas that become painful and show swelling should be regarded with suspicion. Finally, osteosarcomas can arise within pagetic bone in patients older than 60 years of age (38).

FIGURE 21.21 Paraspinal germinoma with extensive epidural component in a child. A large paraspinal thoracolumbar mass extends into the spinal canal and compresses the lower thoracic spinal cord on both T1-weighted (A) and T2weighted (B) images. The homogeneous low signal on T2-weighted magnetic resonance is consistent with a hypercellular neoplasm, and hypercellular germinoma was confirmed at surgery.

PATHOLOGY. Grossly, these lesions are calcified and firm. They are composed of primarily sarcomatous connective tissue that forms osteoid or bone. The amount of osteoid or bone may be extremely variable. These tumors can be subcategorized further based on their dominant histologic differentiation. In the Mayo Clinic series (1967), 55% were osteoblastic, 23% fibroblastic, and 22% chondroblastic. A series from the St. Jude’s Children’s Hospital reported a telangiectatic subtype in 22 of 323 patients (6.8%) (40). Other subtypes reported to occur in the spine include small cell and epithelioid (38). IMAGING. Plain films of osteosarcoma arising in the vertebral bodies are nonspecific. CT can show osteoblastic or osteolytic bony changes. An associated soft tissue mass, either within the epidural space or paraspinal region, may be present. The osteoblastic subtype most commonly demonstrates matrix mineralization, which can be marked. A purely osteolytic pattern is less common (20%) but may be more commonly seen with telangiectatic, fibroblastic, and chondroblastic subtypes (38). The Mayo clinic series found 27 cases in the cervical spine (14%), 66 in the thoracic spine (33%), 64 in the lumbar spine (32%), and 41 in the sacrum (21%). Seventy-nine percent of nonsacral tumors arose in the posterior elements (38). On MR, the degree of osteoid, bone, cartilage, or fibrotic tissue affects the appearance of osteosarcomas. On T1-weighted sequences, tumor demonstrates low signal compared with the high signal in the marrow cavity (39). As with other invasive bone tumors, MR is superior to CT in demonstrating the extent of osteosarcoma within the marrow space (41). On T2-weighted sequences, intraosseous tumor can display low intensity, high intensity, or a combination of signal intensities. When the normal signal void of cortical bone is infiltrated by tumor, a mottled appearance results (32). 1635

T1-weighted images after gadolinium are not as useful as unenhanced T1-weighted images for showing bony extent of the tumor because the signal intensity of enhancing lesions can approach the signal intensity of fatty marrow unless fat suppression sequences are employed (42). Areas of periosteal reaction or areas of cortical thinning or cortical expansion can be shown with MR as areas of low signal (39,41). Telangiectatic osteosarcoma has a characteristic imaging appearance of a multiloculated lytic lesion with fluid–fluid levels and hemorrhage, which may be mistaken for an ABC. Thick nodular peripheral or septal tissue, associated soft tissue mass, or CT evidence of matrix mineralization can help to differentiate this entity from an ABC (43). MRI is extremely sensitive for evaluating the extent of spinal canal invasion, which has been reported in up to 84% of cases (38), and of course any consequent effect on the spinal cord. MR can also accurately delineate tumor extension into the paraspinal soft tissues. Although the tumor can be hypointense or isointense with muscle on T1-weighted images, obliteration of normal fat planes can indicate extension of the neoplasm out of the vertebral bodies (39). On T2-weighted images, extraosseous tumor is usually high in signal, permitting demarcation from uninvolved muscle. In addition, after the administration of gadolinium, these tumors often show immediate enhancement, again allowing separation from muscle, which only minimally enhances (42). Enhancing areas may reflect the more vascular and probably the more “aggressive” viable areas of the tumor (42). Biopsy is usually directed at these areas to characterize the mass best. Associated necrotic or sclerotic areas will either slowly enhance or fail to enhance (42). MR is not as good as CT in showing associated calcification within the tumor or in defining the bony margins of the tumor (41). TREATMENT. Although therapy for osteosarcoma in an extremity initially involves surgery, when the spine is involved, generally only chemotherapy and/or radiation therapy are given. Because curative amputation is not possible, the prognosis is poor. None of the nine cases in which follow-up was possible in the Mayo Clinic series (1967) survived 7 years. Chondrosarcoma Chondrosarcomas are malignant tumors arising from cartilage. They account for 7% to 20% of all primary malignant bone tumors (15). Approximately two-thirds of the patients are males. The peak incidence in Henderson and Dahlin’s series of 288 cases was between 30 and 60 years of age. Chondrosarcomas can arise de novo as primary tumors or as secondary tumors from a preexisting cartilaginous lesion, especially osteochondromas or enchondromas (44). Chondrosarcomas rarely arise in the spine. Huvos and Marcove found that only 3.8% of cases of children and 2.6% of cases in adults involved the spine. Torma studied 250 malignant tumors of the spine and extradural space and reported only 11 chondrosarcomas. All areas of the spinal column may be involved. Camins et al. (45) found a fairly equal distribution of cases throughout the spine. Of 19 cases, 6 were located in the cervical region, 2 in the cervicothoracic junction, 3 in the thoracic region, 3 in the lumbar region, and 5 in the sacrum. The signs and symptoms of chondrosarcomas are nonspecific, though pain is the most frequent symptom. The pain is often mild, leading to a delay in evaluation. In addition, a palpable mass can be present. When the lesion involves the spine, there can be signs of spinal cord compression. PATHOLOGY. The differentiation of chondrosarcoma from osteosarcoma has been controversial. However, chondrosarcomas are considered to arise from cartilage. Calcification or ossification of the cartilage may occur, but chondrosarcomas, unlike osteosarcomas, do not show neoplastic osteoid tissue or bone evolving from a sarcomatous matrix. Histologically, chondroblasts with varying nuclear pleomorphism and mitotic activity are surrounded by a myxoid matrix. In addition to conventional chondrosarcomas, variants include myxoid, mesenchymal, and dedifferentiated subtypes. Survival in chondrosarcoma is correlated closely with the grade of malignancy. Low-grade tumors are indolent and predisposed toward long-term survival. However, high-grade tumors are aggressive, and only 25% of patients with chondrosarcomas of this grade in any location survive 15 years. IMAGING. On plain films, chondrosarcomas cause lytic destruction. They often have a calcified matrix; the amount of calcification varies according to the differentiation of the tumor (44). Frequently, there is an associated soft tissue mass. On MR, the signal intensity of chondrosarcomas is heterogeneous because of the mixture of soft 1636

tissue, cartilage, calcification, and other components. Focal areas of decreased signal intensity on T2weighted images can be seen when the calcifications are very prominent. Areas of hemorrhage also contribute to the overall heterogeneity of this lesion. Again, MR is excellent at defining associated soft tissue masses. Chondrosarcomas have also been reported in the extradural space, without bone involvement (Figs. 21.22 and 21.23). MR may help in differentiating a malignant chondrosarcoma from a benign osteochondroma. This distinction is critical, especially in multiple hereditary exostosis. Malignant lesions tend to have large soft tissue masses, irregular disorganized calcifications, destruction of bone, and growth into adjacent soft tissues. The cortical margins may appear irregular and discontinuous with the parent bone. The thin cartilaginous cap typical of benign osteochondromas usually is not seen.

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FIGURE 21.22 Chondrosarcoma. A mass replaces the right sacral ala and a portion of the right iliac bone. Coronal (A) and axial (B) T1-weighted images demonstrate the mass to be of hypointense signal. Corticated margins (arrow) are seen at the interface of the mass and normal appearing marrow, which suggest slow growth of the lesion. Heterogeneous hyperintensity is seen on axial T2 fat-suppressed images (C,D). There is a large lobulated extraosseous soft tissue component, seen on the axial images. On coronal (E) and axial (F) postcontrast, T1-weighted, fat-suppressed images, there is peripheral and internal septal enhancement. Axial CT (G) demonstrates characteristic chondroid matrix calcifications within the extraosseous portion of the mass.

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FIGURE 21.23 Recurrent epidural chondrosarcoma. This patient had a recurrent epidural mass (arrowheads) compressing the cauda equina after prior resection. The mass is hypointense on T1-weighted imaging (A) and hyperintense on T2-weighted imaging (B). Axial T2-weighted images (C,D) demonstrate a lobulated bubbly appearance. The epidural mass extends the neural foramen, compresses the thecal sac, and invades the vertebral body. After contrast administration, peripheral enhancement is seen (E).

TREATMENT. Because of the location of chondrosarcomas of the spine, cure is difficult. However, radical surgery to remove the tumor is advocated if possible. Because total extirpation is difficult, recurrence, and ultimately metastasis, is common. In the series of Camins et al., the 5-year survival rate for chondrosarcomas of the spine was 21%. Ewing Sarcoma Ewing sarcoma is a primary malignancy of bone affecting children and young adults, most commonly in patients 15 to 25 years of age (21). Ewing sarcoma is rarely seen in patients less than 5 years of age (21). Although Ewing sarcoma is the second most common primary malignant bone tumor after osteosarcoma in younger individuals and represents 7% to 15% of all primary bone malignancies, it does not typically originate in the spine (4%) or in the sacrum (1% to 2%). Metastases, however, often involve the skeleton (92 of 229 cases), and when they occur, they frequently affect the spine. Clinically, these lesions usually present with pain. Focal tenderness with swelling and a palpable mass also can be seen. PATHOLOGY. Grossly, these tumors are soft, gray–white masses. There can be areas of hemorrhage, necrosis, and cyst formation within them. Histologically, they are composed of small, round cells, which may arise from mesenchymal connective tissue of bone. IMAGING. Plain films show mottled lytic changes (88 of 107 cases) and an associated soft tissue mass (52 of 107 cases) (46). The “onion peel” periosteal reaction is classic. CT shows the soft tissue mass associated with the bony lesion (Fig. 21.24). Occasionally, bony spiculation is seen in the vertebral body, suggesting a hemangioma (Fig. 21.25). CT is limited in its evaluation of the disease within the marrow cavity (47). MR successfully demonstrates marrow invasion, which has decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images. Both the osseous and extraosseous components typically enhance. The tumor can 1639

be inhomogeneous secondary to hemorrhage, calcification, or necrosis. Its MR appearance, therefore, is nonspecific (Fig. 21.24). Soft tissue paravertebral masses are readily assessed with MR. TREATMENT. Because amputation is not possible, the primary treatment for Ewing sarcoma of the spine is radiation therapy. The tumor is extremely radiosensitive. Radiation therapy also can decrease symptoms such as pain and any associated soft tissue mass. Leukemia Leukemia is the most common malignancy in children, with an incidence of 42 cases per 1 million in the United States (48). It is also the ninth most common malignancy in adults. One-third of childhood neoplastic deaths are caused by leukemia. Acute lymphoblastic leukemia (ALL) represents 80% of all childhood leukemia; acute myelogenous leukemia accounts for another 10% (48,49,50). The remaining 10% is composed of less common histologic forms. ALL is most common in the 2- to 5-year-old age group, with a peak incidence at 3 years of age (50). There is a slight male predilection in ALL (49,50).

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FIGURE 21.24 Ewing sarcoma. T1-weighted images (A,B) show poorly marginated hypointensity within the left sacral body and ala. T2-weighted images (C,D) demonstrate heterogeneous areas of high and low signals, which are also poorly marginated. There is an extraosseous soft tissue component extending into the left epidural space (arrowhead) and left sacral foramen (asterisk). Both the osseous and extraosseous components demonstrate marked enhancement (E,F). Computed tomography demonstrates loss of trabeculae and frank bony destruction (G). The illdefined margin suggests an aggressive process.

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FIGURE 21.25 Ewing sarcoma. T1-weighted image shows a homogeneous extradural mass compressing the spinal cord. The mass is low signal, approximately isointense to gray matter. The C7 vertebra is compressed and is decreased in signal with preservation of the disk spaces. A,B: Proton density–weighted and T2-weighted images confirm the preservation of disk spaces. The mass is fairly homogeneous and of intermediate signal intensity. Compression of the C7 vertebra with an increase in the anterior–posterior diameter also is present. C: After contrast, heterogeneous enhancement is seen in the vertebral body lesion. D: Axial computed tomography shows a coarse trabecular pattern with disruption of the vertebral body. (From Bemporad JA, Sze G, Chaloupka JC, et al. Pseudohemangioma of the vertebra: an unusual radiographic manifestation of primary Ewing’s sarcoma. AJNR Am J Neuroradiol 1999;20:1808–1813, with permission.)

Children with leukemia are systemically ill (48). Because of the abnormally low production of all cellular components, as leukemic cells replace normal marrow cells patients display an increased susceptibility to infection, thrombocytopenia, and anemia (48,49). Spinal involvement can cause local pain and swelling (48). The pain can be migratory in nature, thus mimicking juvenile rheumatoid arthritis. IMAGING. Plain films disclose osteoporosis in 60% of cases because of infiltration of the marrow by leukemic cells (48). Secondary compression fractures can result. Other findings in the spine include lucent bands and multiple focal defects (48). Osteosclerotic areas rarely are noted. On MR, patients with leukemia demonstrate homogeneously decreased signal on T1-weighted images secondary to the replacement of the high-signal fatty marrow by leukemic cells (Fig. 21.26) (51). Compression deformities of the vertebral bodies are not uncommon. Foci of leukemic infiltration display increased signal intensity on T2-weighted images. Although sclerotic foci are rare, they can be seen as low–signal-intensity regions on both T1- and T2-weighted images. More likely, regions of low intensity on T2-weighted images indicate hypercellular tumor. Young children, especially those younger than 7 years of age, may have a paucity of fat in their marrow. In these cases, leukemic infiltration may be more difficult to detect. Enhancement with gadolinium in conjunction with fat suppression may be useful because diffuse tumor infiltration enhances, whereas normal marrow does not. 1642

FIGURE 21.26 Leukemia. T1-weighted (600/20) sagittal magnetic resonance image discloses marked hypointensity in the marrow of this patient in relapse. Incidentally noted is high signal in the thecal sac due to bleeding after a lumbar puncture as a result of the patient’s coagulopathy.

Moore et al. (52) examined T1 relaxation times in 17 children with ALL in different stages: newly diagnosed, in relapse, or in remission. A significant increase in T1 relaxation time occurred in the marrow of patients with newly diagnosed ALL or ALL in relapse when compared with those of healthy children or patients with ALL in remission. The authors suggested that MR relaxation times may be helpful in following progression of disease and in differentiating inactive disease from active disease, thus eliminating the necessity of serial bone biopsies. T2-weighted sequences were not helpful in distinguishing the different stages of the disease. In patients with myelogenous leukemia, chloromas can occur. These collections of leukemia cells, often with a grossly green color, are unusual, but when they occur, they are often located in the spine. They appear as expanding masses, isointense on T1-weighted images. Non-Hodgkin Lymphoma Non-Hodgkin lymphoma can involve the spine as an isolated primary lesion or as part of a systemic disease (48). It occurs with an incidence of approximately 7 per 1 million population. Primary non-Hodgkin lymphoma, previously referred to as reticulum cell sarcoma of bone, is seen most frequently in adults. Ninety-five percent of cases occur after 20 years of age (48,53). Men are affected twice as often as women. Although primary non-Hodgkin lymphoma usually occurs in long bones, review of several series demonstrated that 13 of 94 cases arose in the spine. Non-Hodgkin lymphoma affects the spine much more often as metastatic disease. Patients frequently present with localized pain but characteristically lack constitutional symptoms (48). PATHOLOGY. The tumor is grossly gray–pink in color and has frequent areas of necrosis. It is highly cellular and has a very vascular stroma. IMAGING. Plain films show a wide spectrum of radiographic manifestations. Findings range from a permeative moth-eaten appearance to a more lytic geographic area of bony destruction to rare osteosclerotic lesions (48). On MR, infiltration of the normal high–signal-intensity fatty marrow of the vertebral bodies results in focal or diffuse areas of decreased signal intensity on T1-weighted images. As the fatty marrow is replaced by cellular elements, the signal intensity decreases (54). On T2-weighted images, focal areas of tumor infiltrate typically have only slightly increased signal intensity or even hypointensity. The appearance is suggestive but nonspecific and is identical to that of metastatic disease, particularly of those tumors with hypercellularity, as well as plasmacytoma or multiple myeloma (Fig. 21.27). In cases of diffuse marrow abnormality, it can be difficult to differentiate neoplastic involvement from nonneoplastic marrow variations. Dynamic postcontrast imaging may help in this differentiation by showing increased enhancement in cases of neoplastic involvement (55). Secondary Extradural Tumors Metastatic Disease to the Spine and Extradural Space 1643

The spine is the second most common location for metastatic disease to the CNS in patients with malignancies, after the brain. Thecal sac impingement as a result of tumor occurs in 5% of patients with systemic cancer (56). Nearly every malignancy can involve the spine or the soft tissues in the epidural space. However, myeloma, breast carcinoma, prostate carcinoma, lung carcinoma, and lymphoma particularly are seen often, both because of the frequency of these tumors and because of their propensity to metastasize to vertebral bodies. In autopsy series, the tumors that frequently affect the vertebrae, regardless of their overall frequency, are myeloma (77%), breast (61%), prostate (50%), stomach (44%), lymphoma (40%), melanoma (38%), uterus/cervix (36%), bladder (33%), pancreas (33%), and oropharynx (33%). Although myeloma is a primary bone malignancy, its usual multifocal involvement is often indistinguishable from metastatic disease in the spine, and is therefore also considered in this section. The average age of patients with metastatic epidural disease ranges from 53 to 58 years. Metastatic involvement of the spine, however, can, of course, occur at any age. The site of epidural tumor is thoracic in approximately 68% of cases, lumbar or sacral in 16%, and cervical in 15%. Different primary tumors appear to have a propensity to metastasize to different sites. For example, breast and lung tumors metastasize more frequently to the thoracic spine, whereas gastrointestinal, prostate, and renal carcinomas metastasize more often to the lower thoracic and lumbosacral (57). The most frequent symptoms of spinal cord compression are pain, weakness, autonomic dysfunction, and sensory loss. Back pain is the initial symptom in 80% to 96% of patients and may be the only symptom present in patients with documented cord compression. The pain may be local or radicular. Weakness is a very common symptom at the time of diagnosis and is seen in 76% of patients. Bladder and bowel dysfunction occurs in 57% of patients and is an unfavorable prognostic sign. Sensory loss is noted in 35% to 51% of patients. Multiple sites of epidural metastasis are associated with a poorer survival rate (57). IMAGING. Plain films can show a diversity of appearances. Although metastatic lesions most often are destructive and lytic, they can be sclerotic, especially in prostate carcinoma (Figs. 21.28–21.32). On CT, destructive lesions of varying size, often with cortical breakthrough and extension into the paravertebral space, are seen. Bone scintigraphy is sensitive for detection of metastatic disease involving cortical bone, but can miss lesions that are completely intramedullary or small (58). MR is extremely sensitive to the detection of metastasis in the vertebral bodies or extradural space (Fig. 21.28) (3). The multiplicity of lesions is strong evidence for a metastatic origin. However, in the case of single lesions, differentiation of a metastatic lesion from a primary tumor or from a lesion of another etiology is difficult. This evaluation is particularly important in patients who have had known malignancies but have not had documented metastatic involvement. In these cases, biopsy is typically necessary.

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FIGURE 21.27 Multiple myeloma. This patient with multiple myeloma presented with diffuse bone pain and was found to have innumerable lesions. The lesions are isointense on T1-weighted imaging (A), heterogeneously hyperintense on short–inversion-time inversion recovery imaging (B), and enhance after contrast administration (C,D). The axial postcontrast image (D) demonstrates mild right epidural extension of one of the lesions (arrowhead) and involvement of both iliac bones. An axial T2-weighted image of the cervical spine shows a hypointense lesion arising from the right lamina causing cord compression (E).

FIGURE 21.28 Multiple myeloma. Sagittal STIR image (A) shows a heterogeneous appearance of the vertebral marrow with multiple foci of mild hyperintensity. T1-weighted image (B) demonstrates a more apparent hypointense lesion of the L1 vertebral body, as well as multiple other smaller foci. The lesions are markedly hyperintense on the corresponding diffusion weighted sequence (C). In this case the lesions are more conspicuous on the diffusionweighted image, with multiple additional smaller lesions appreciable within vertebral bodies and the posterior elements.

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FIGURE 21.29 Multiple myeloma before and after treatment. Sagittal noncontrast T1-weighted and STIR (A,B) images prior to treatment demonstrate a mass infiltrating the C2 vertebral body with prevertebral and ventral epidural extensions of tumor. Sagittal and axial diffusion images and apparent diffusion coefficient maps (C–F) before treatment demonstrate restricted diffusion given the high DWI signal and low ADC signal throughout the mass. Following treatment, there is no significant change in signal characteristics on T1-weighted (G), STIR (H), or even DWI (I) sequences, although the prevertebral and epidural components have significantly decreased in size.

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However, the apparent diffusion coefficient map after treatment (J) demonstrates significant interval increase in signal throughout the C2 lesion, indicating facilitated diffusion due to decreased cellularity.

FIGURE 21.30 Plasmacytoma. A–C: Axial T2-weighted images demonstrate hyperintense marrow signal throughout the vertebral body. There are thickened cortical struts radiating inward from the periphery, giving the vertebral body a “mini brain” appearance on axial imaging. D: Sagittal T2-weighted image shows the curvilinear appearance of the internal cortical struts. These findings are also well demonstrated on correlative axial (E) and sagittal (F) CT images.

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FIGURE 21.31 Osteoblastic metastasis from ovarian carcinoma simulating an enostosis. A nodular nonenhancing focus in the L4 vertebral body demonstrates signal hypointensity equivalent to cortical bone on T2-weighted (A) and postcontrast (B) imaging. Computed tomography demonstrates a spiculated border, typical of a bone island or enostosis (C). A deceptively similar well-circumscribed nodule in a different patient also demonstrates marked signal hypointensity, similar to cortical bone, on T2-weighted (D) and postcontrast, fat-saturated (E) imaging. There is no contrast enhancement. On subsequent follow-up imaging (F), this nodule developed a prominent ring of surrounding enhancement (arrow), proving to be a sclerotic metastasis in this patient with ovarian carcinoma.

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FIGURE 21.32 Lytic vertebral metastases from lung carcinoma. There is replacement of the normal marrow signal involving most of the L2 vertebral body and a smaller area in the L5 vertebral body on T1-weighted imaging (A) in this patient with lung cancer. These lesions are heterogeneously dark on T2-weighted imaging (B) and demonstrate avid contrast enhancement (C). Contrast-enhanced images better define the degree of epidural extension of tumor at the L2 level. Sagittally reformatted computed tomography (D) shows a corresponding area of osteolysis. Welldifferentiated irregular cuboidal gland-forming cells with variable hyperchromatic nuclei are seen on light microscopy (E).

FIGURE 21.33 Leptomeningeal metastatic disease. T1-weighted, postcontrast, fat-suppressed sagittal (A) and axial (B) images show a thickened, nodular coating of abnormal enhancement along the conus and cauda equina.

On the basis of signal intensity alone, metastatic lesions appear identical to most primary bone tumors. They generally have low signal on unenhanced T1-weighted images. Rarely, metastatic lesions are hemorrhagic and have high signal intensity on T1-weighted images. On T2-weighted images, they may have a varied appearance and may be hypointense, isointense, or hyperintense. The presence of marked sclerosis predisposes to lesions that are hypointense on both T1-weighted and T2-weighted sequences, as does histologic hypercellularity (Fig. 21.31). If intravenous contrast is administered for 1649

the workup of these lesions, it is helpful to use fat suppression techniques as well (Fig. 21.32). A recent study by Khadem et al. (59) suggested that utilizing dynamic contrast-enhanced MRI can help differentiate hypervascular metastases, such as renal or thyroid carcinomas, from hypovascular lesions, such as lung, breast, prostate, or myeloma. Dynamic contrast-enhanced imaging was also shown to be useful when monitoring tumor response to chemotherapy or to detect viable tumor prior to resection. Metastatic lesions may involve any portion of the vertebra. Because they usually spread hematologically, the large marrow space of the vertebral body is affected most often. However, metastases may also arise in the posterior elements. As with primary tumors, impingement on the thecal sac is well delineated on MR. On axial images, impingement from tumor extending posteriorly from involved vertebrae often appears bilobulated because of the posterior longitudinal ligament and attached midline septum (Fig. 21.6). The imaging characteristics of multiple myeloma are worth some specific attention. On plain films and CT, myeloma can range from its common appearance of diffuse permeative osteopenia to the classic discrete punched-out, lytic lesions. The MR signal characteristics of multiple myeloma mimic that of metastatic disease from systemic malignancy; therefore, distinguishing the two often proves difficult with imaging alone. Recent studies have utilized whole-body DWI and apparent diffusion coefficients to evaluate treatment response in myeloma (Figs. 21.28 and 21.29) (6,8). A solitary plasma cell tumor is called a plasmacytoma, and can demonstrate some highly characteristic features aiding in diagnosis. Specifically, plasmacytomas can have thickened vertically oriented cortical struts that radiate inward from the periphery of the vertebral body. The bony struts are of low signal on T1- and T2-weighted sequences. On axial imaging, these appear as curvilinear structures that extend partially through a vertebral body and can resemble the sulci of a brain. This cerebriform appearance has been termed a “mini brain” (Fig. 21.30) (60). TREATMENT. Patients with spinal metastases confined to the vertebral bodies without extradural or paravertebral extension are usually not treated or are treated with chemotherapy. Once thecal sac impingement occurs, however, patients are generally handled aggressively. Radiation therapy accompanied by the administration of steroids is the treatment of choice for most patients with extradural spinal cord compression. Decompressive laminectomy may be useful in patients who do not respond to radiation and in patients who relapse and cannot be treated with further radiation.

INTRADURAL EXTRAMEDULLARY TUMORS Technique Neoplastic disease in the intradural extramedullary space is best divided into primary and secondary diseases. Primary tumors, such as meningiomas and neurofibromas, are generally well seen on noncontrast MR images. These tumors tend to be compact and to stand out against the lower intensity surrounding CSF on T1-weighted sequences. On T2-weighted sequences, contrast is reversed and the tumors often appear of lower signal intensity against the high intensity of CSF. Occasionally, small neuromas and meningiomas may be difficult to visualize without contrast. In addition, better delineation of tumor from cord may be possible with gadolinium. As opposed to primary tumors, noncontrast MR frequently fails to evaluate adequately and, in some cases, even to detect secondary tumors or leptomeningeal disease in the intradural extramedullary space (61). Myelography has been shown to be much more sensitive than noncontrast MR. Of 15 positive myelograms for subarachnoid tumor, only 4 had positive findings on noncontrast MR (61). A large number of the noncontrast MR images were equivocal or falsely negative (31% and 44%, respectively) because leptomeningeal tumor tends to blend with the adjacent CSF (61). The reasons that leptomeningeal tumor is difficult to visualize on noncontrast MR images are multiple. First, intradural extramedullary disease is characterized by marked elevations of protein levels in the CSF. In addition, leptomeningeal tumor spread is often delicate and friable, with high water content. Both these factors combine to decrease the difference in the relaxation characteristics of the lesions from those of the surrounding CSF. Because of the marked protein elevation, the T1 and T2 relaxation times of the CSF decrease relative to those of pure CSF. Similarly, the high water content of the tumor acts to increase the relaxation times of the leptomeningeal tumor relative to those of more compact tumors. Therefore, even extensive tumor spread can often be poorly delineated on noncontrast MR. Second, visualization of edema does not increase sensitivity to detection. Although lesions in both the brain and the spinal cord often are highlighted by the presence of edema, no such mechanism can 1650

operate in the detection of intradural extramedullary disease. Third, technical difficulties often mar interpretation of MR spine images. Movement artifact particularly is a problem. CSF pulsation tends to blur lesion conspicuity (62). Additionally, small nodules hanging off nerve roots can also move when the patient is positioned differently or with CSF pulsation. This movement degrades the delineation of lesions. Although noncontrast MR can be equivocal in the detection and delineation of leptomeningeal tumor, contrast-enhanced MR is usually superb in this evaluation. The enhancement of intradural extramedullary lesions with gadolinium is often dramatic. Even small nodules generally enhance brightly and are easily seen on T1-weighted sequences. Mild enhancement stands out against the background of dark CSF and is detected readily (Fig. 21.33). Leptomeningeal spread of tumor along nerve roots also can be demonstrated. The ease and efficacy of administration of contrast are equally as important as its sensitivity. Most likely, if evidence of intradural extramedullary disease is sought, T1-weighted sagittal sequences before and after the administration of gadolinium will be sufficient. T2-weighted scans may not be necessary. The enhancement of intradural extramedullary disease is generally most prominent on the immediate postcontrast scans, helping to shorten examination times. Primary Intradural Extramedullary Tumors Nerve Sheath Tumor Neurofibroma, neurinoma, neurilemoma, and schwannoma are various names for tumors that arise from Schwann cells of nerve sheaths. Schwannoma, neurinoma, and neurilemoma are synonyms. Schwannomas and neurofibromas are different entities, however (63). Schwannomas do not envelop the adjacent nerve root, which usually is the dorsal sensory root, generally are solitary, and clinically are not typical of neurofibromatosis (64). In contrast, neurofibromas envelop the dorsal sensory root, frequently are multiple, and usually are associated with neurofibromatosis, even when single (63,64). All of these tumors may be referred to together as nerve sheath tumors. In the general population, nerve sheath tumors are the most common intraspinal lesion, representing 16% to 30% of all intraspinal masses. These lesions most commonly present in the fourth decade of life. In the pediatric population, they probably constitute less than 10% of all intraspinal lesions, although some authors report an incidence as high as 29%. The youngest case was reported in a 13-month-old girl. Nerve sheath tumors are most commonly intradural extramedullary in location (58%). The remainder are purely extradural (27%), dumbbell shaped with both an extradural and an intradural component (15%), and, rarely, intramedullary (less than 1%). Harwood-Nash and Fitz reported 13 cases in children and found the most common location to be the cervical region, followed by the lumbar and thoracic regions. The most common symptoms of nerve sheath tumors are pain and radiculopathy. These symptoms are present for an average of 26 months before diagnosis. Neurofibromatosis type 1 (NF1) is a phacomatosis that occurs spontaneously in 50% of cases and occurs as an autosomal dominant condition in 50% of cases. Numerous spinal neurofibromas are characteristics of this disease and are not uncommonly present bilaterally and at multiple levels throughout the spine. A series of 54 patients with NF1 found that 65% had spinal tumors (65). Skin manifestations consist of café-au-lait spots that are greater than 15 mm in size. The presence of six or more spots is considered diagnostic. Patients with NF1 have a predisposition to other neoplasms in addition to neurofibromas, including intramedullary lesions, such as astrocytomas, ependymomas, and hamartomas. Neurofibromatosis type 2 (NF2) is a rare phacomatosis with an autosomal dominant inheritance pattern. Although bilateral acoustic schwannomas are the best known findings in this disorder, spinal tumors are also a characteristic feature. The diagnosis of NF2 is made by the presence of bilateral vestibular schwannomas or a first-degree relative with NF2 in combination with either a unilateral vestibular schwannoma or a meningioma, schwannoma, neurofibroma, glioma, or cataract at a young age. Recent studies of patients with NF2 found spinal tumors in 63% to 89% and extramedullary spinal tumors in 55% to 82% (66,67). A series of 73 patients demonstrated multiplicity of spinal tumors in 56%. Of 19 extramedullary tumors removed in this study, 10 were schwannomas, 7 were meningiomas, and 2 were neurofibromas (66). Malignant degeneration is uncommon in nerve sheath tumors and is seen in 1% to 12% of cases. 1651

Malignant neoplasms arise either from preexisting nerve sheath tumors or de novo from nerve sheaths. When they arise from preexisting neoplasms, they probably have a latency period of 10 to 20 years (68). These tumors have a variety of names, including malignant schwannoma, malignant neuroma, nerve sheath fibrocarcinomas, and neurofibrosarcoma. The existence of numerous terms reflects controversy about their origin; however, they all can be grouped as malignant nerve sheath tumors. These malignant neural tumors are seen most often in the 15- to 39-year-old age group. The 5-year survival rate is poor and is between 15% and 30% (68). Those cases associated with neurofibromatosis tend to occur at a young age and to have a worse prognosis. PATHOLOGY. Schwannomas appear as masses that project from one side of the nerve (Fig. 21.34) (63). Because they arise from a single focus, they displace normal nerve fibers to appear as lobulated, rather than fusiform, tumors. Histologically, schwannomas are composed of Schwann cells that develop into neoplastic compact interlacing groups associated with fibrous strands. Antoni A and Antoni B tissue patterns are recognized as important histologic features of nerve sheath schwannomas. Antoni A refers to highly cellular regions of fibrillary, intensely polar and elongated tissue; whereas Antoni B refers to seemingly distinct loose microcystic tissue that can be lipid-laden (69). Accordingly, cyst formation is common. Fatty degeneration may less commonly occur. Neurofibromas consist of mixtures of fibroblasts and proliferated Schwann cells between dispersed nerve fibers. The matrix of a neurofibroma contains acid mucopolysaccharides and large amounts of tissue fluids with numerous fibrous strands. The matrix spreads apart the axons to produce the fusiform shape of the neurofibroma.

FIGURE 21.34 Nerve sheath tumors. A: An intradural schwannoma involving a left upper thoracic posterior spinal root compresses the spinal cord. B: Extensive plexiform neurofibromas involving the right lumbar and sacral plexuses in a child. (From Okazaki H, Scheithauer B, eds. Atlas of Neuropathology. New York: Gower Medical Publishing, 1988, with permission.)

IMAGING. Plain-film findings of nerve sheath tumors include posterior scalloping of the vertebral bodies and widening of the neural foramina (63). On CT, they are of decreased attenuation and present as paraspinal or intraspinal masses. Differentiation of the intraspinal portion of the neurofibromas from the adjacent spinal cord and thecal sac can be difficult without instillation of intrathecal contrast material. Nerve sheath tumors on MR tend to have increased signal intensity compared with muscle on noncontrast T1-weighted images (11 of 12 patients). The increased signal intensity on T1-weighted images may be secondary to shortening of the T1 relaxation time by mucopolysaccharide molecules interacting with tissue water. On T2-weighted images, these lesions can have markedly increased signal intensity secondary to the high water content of these lesions (70). Neurofibromas frequently demonstrate central areas of decreased T2 signal intensity (“target sign”) (Figs. 21.35 and 21.36) (7 of 12 patients), which may represent denser areas of collagen and Schwann cells, as shown pathologically. Decreased signal may result from the fact that fewer mobile protons are available within the fibrous 1652

matrix in the central portions of these lesions. In schwannomas, areas of T2 hypointensity may also be encountered; however, they often reflect old blood products. These lesions usually enhance intensely and fairly homogeneously, although occasional schwannomas may initially enhance peripherally, sparing the central portion. MR is able to demonstrate with superb detail the intraspinal portions of these tumors, especially on T1-weighted images after gadolinium, and to show any displacement or compression of the spinal cord (Figs. 21.35–21.37) (70).

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FIGURE 21.35 Schwannoma. Sagittal images show a well-circumscribed elongated ovoid intradural extramedullary mass extending from C2 to C4. The mass is isointense to the spinal cord on T1-weighted imaging (A) and approaches cerebrospinal signal intensity on short tau inversion recovery (STIR) imaging (B). Only patchy central enhancement is seen in this case (C), although this is not typical. The mass is heterogeneously hyperintense on T2weighted imaging (D–F) with a region of internal low signal (arrow), which in a schwannoma most likely reflects old blood products. The mass extends through and widens a right-sided neural sided neural foramen, seen on axial T2weighted images (F,G), and a parasagittal STIR image (H). Panel G demonstrates compression of the spinal cord (c) by this intradural extramedullary mass (m).

Imaging modalities can help to differentiate plexiform neurofibromas (Fig. 21.38) from malignant nerve sheath tumors. On CT and MR, both benign and malignant lesions show inhomogeneity. However, malignant schwannomas more often have irregular, infiltrative margins, whereas benign lesions tend to have smooth margins (68). In addition, malignant nerve sheath tumors tend to lack the decreased central area of low signal intensity on T2-weighted images that is frequently noted in benign schwannomas (68). Finally, malignant nerve sheath tumors tend to be larger than benign lesions (Fig. 21.39). Meningioma Meningiomas of the spinal canal generally are lesions of adults (71). The average age of presentation is in the fifth and sixth decades, with 60% to 80% seen in females. Roughly 3% to 6% of all spinal meningiomas occur in children, most commonly in the setting of neurofibromatosis type 2. Meningiomas in the spine tend to be encapsulated and are attached to the dura. They do not invade the spinal cord but rather displace it. The location of spinal meningiomas within the canal varies depending on which study is cited. In general, these lesions usually are posterolateral in location except in the cervical region, where they are more likely to be anterior. They primarily are intradural extramedullary (76 of 84 cases) but can be both intradural and extradural (5 of 84 cases) or, less likely, 1654

purely extradural (3 of 84 cases). When meningiomas are purely extradural, they tend to be malignant. Multiple spinal meningiomas are rare and may be associated with neurofibromatosis type 2.

FIGURE 21.36 Schwannoma. Fat-suppressed, postcontrast T1-weighted sagittal (A) and axial (B) images demonstrate a well-demarcated enhancing mass. There is central hypoenhancement and corresponding T2 hyperintensity on axial T2-weighted image (C), reflecting mild cystic degeneration, which is not uncommon in schwannomas. The mass is intradural extramedullary in location, with slight widening of the subarachnoid space and mild mass effect on the spinal cord.

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FIGURE 21.37 Neurofibromatosis type 1. Sagittal T1-weighted (A), T2-weighted (B), and postcontrast (C) images show an enhancing well-circumscribed intradural extramedullary mass compressing the spinal cord. Axial T1weighted (D), T2-weighted (E), and postcontrast (F) images at a lower level demonstrate confluent enhancing extramedullary masses compressing the spinal cord and widening the neural foramina bilaterally. Additional neurofibromas are seen throughout the soft tissues of the neck. Parasagittal postcontrast (G) and short–inversiontime inversion recovery (H) images of the cervical spine demonstrate enhancing masses widening the neural foramen at every level. There is also involvement of the lumbosacral spine (I,J) and the pelvis (K). Some of these neurofibromas are plexiform in appearance.

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FIGURE 21.38 Plexiform neurofibroma. A large right paraspinal conglomerate mass in a patient with neurofibromatosis type 1 causes scoliosis. The mass is plexiform and hyperintense on T2-weighted images (A–C). Numerous central hypointense foci are seen on a parasagittal short–inversion-time inversion recovery image (D), characteristic of neurofibromata. The mass extends into multiple neural foramina (B), which are shown on computed tomography to be markedly widened (E).

FIGURE 21.39 Malignant nerve sheath tumor. There are masses seen extending through the neural foramina and

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into the paravertebral regions bilaterally on axial T2-weighted image (A). The benign right sided mass is homogeneously T2 hyperintense, whereas the much larger malignant lesion on the left demonstrates heterogeneous signal characteristics. Axial (B) and coronal (C) fat-suppressed, postcontrast, T1-weighted images demonstrate the left-sided mass to have solid enhancing (*) and cystic (c) components, as well as enhancement extending into the adjacent vertebral body (arrow). There is bowing and enlargement of the overlying left psoas muscle. Note the multiple other neurofibromata on the coronal image, seen bilaterally at most levels.

In females, 83% of spinal meningiomas are in a thoracic location, with a 7:1 ratio of thoracic to cervical meningiomas. In males, approximately 47% of meningiomas are found in a thoracic location and 41% at the cervical level. Considering the population as a whole, approximately 80% of meningiomas are found in the thoracic region, 16% are cervical, and 3% are lumbar. Within the cervical spine, excluding the foramen magnum, the segments most often affected are C3 and C4. The most common symptom is pain, either local or radicular. Other findings include paresthesias, numbness, weakness, and bowel or bladder abnormalities. Symptoms of cord compression are more frequent than those of root compression. In one study, only 21% of patients had distinctly radicular pain. When symptoms are unilateral, the tumor has been found to be on the ipsilateral side of the symptoms in 95% of cases. More rarely, symptoms can include headaches, dizziness, nausea, and vomiting. The intracranial symptoms are felt to result from elevated intracranial pressure as a result of an absorption block from high protein, recurrent hemorrhage, or venous obstruction. The average duration of symptoms before correct diagnosis is 28 months. The acute onset of symptoms may be indicative of a bleed into an angioblastic-type meningioma. On physical examination, the nature of the neurologic deficit is reported as approximately 50% sensory and 50% motor (72). In one study, only 17% of patients had intact motor function. Seventy-nine percent had abnormal reflexes, the most common being lower-extremity hyperflexia. The high incidence of laterally positioned tumors is the explanation for the frequency of a Brown–Séquard syndrome with ipsilateral paralysis, decreased tactile, and deep sensation, and a contralateral deficit in pain and temperature sensation. PATHOLOGY. The tissue of origin of meningiomas other than the angiomatous type appears to be the covering cell of the arachnoid layer, known as the “cap cell” layer. Meningiomas arise from persistent arachnoid-cell remnants in the spinal coverings, usually from arachnoid. Meningiomas usually adhere to, but do not arise from, dura. Because they arise from arachnoid, dural attachment is fortuitous and is a result of infiltration. Meningiomas may also become attached to dentate ligaments, nerve roots, or even the cord itself (73). Histologically, meningothelial, fibroblastic, psammomatous, and angiomatous types are more commonly seen, which are classified as World Health Organization (WHO) grade I (73,74). Calcifications are present in up to 72% of the cases. The angiomatous (angioblastic) form differs from the other types of meningiomas in lacking arachnoid cap cells. The angioblastic form is subdivided into hemangioblastic and hemangiopericytic categories. The hemangioblastic form arises from capillary walls and is similar histologically to the cerebellar hemangioblastoma. The hemangiopericytic form arises from pericytes, tends toward recurrence at a younger age, has a higher rate of recurrence, and lacks psammoma bodies. Some researchers state that it is more prone to metastasize than other forms, whereas others claim that no valid correlation can be drawn between the histologic type and the tendency toward recurrence or metastasis. There are also grade II and III meningiomas included in the WHO classification system (atypical, clear cell, rhabdoid, papillary, and anaplastic subtypes), which may exhibit more aggressive growth and carry greater risk of recurrence (74). IMAGING. Plain films can show bony abnormalities associated with spinal meningiomas such as pedicle erosion and widening of the neural foramina, although these changes are seen more commonly with neurofibromas (73). On CT, an isodense or slightly hyperdense mass can be visualized. Prominent enhancement occurs after the administration of contrast. Adjacent hyperostosis can be seen, though it is not as common as in the intracranial forms. CT can also readily demonstrate tumor calcification, a common finding in meningiomas. On MR, T1-weighted images disclose lesions that are hypointense to isointense to the spinal cord (75). Meningiomas in the spine tend to be well circumscribed, frequently located anterolateral or posterolateral to the spinal cord, and tend to displace it. T2-weighted images show meningiomas to be slightly hyperintense to the spinal cord. In the intradural extramedullary location, they are silhouetted against the high signal intensity of the CSF on the T2-weighted images. These vascular tumors usually enhance immediately, intensely, and homogeneously after gadolinium administration (75,76). Rarely, 1658

tumoral flow voids may be appreciated, reflecting prominent vessels. Finally, there may be areas of signal void, representing calcifications, especially in the psammomatous type. These may be particularly well demonstrated on susceptibility-weighted or other GRE sequences (Fig. 21.40). The most common lesion in the differential diagnosis with a spinal meningioma is a nerve sheath tumor. Several criteria help to differentiate these two lesions. Neural tumors tend to be more anteriorly located within the spinal canal, whereas spinal meningiomas have a posterolateral location except when they are located in the cervical region, where they are more likely to be anterior. Frequently, neurofibromas are multiple, whereas meningiomas tend to be solitary. Nerve sheath tumors are not attached to the dura, unlike meningiomas, and therefore have more mobility. Neurofibromas, in particular, can have a central region of decreased signal on T2-weighted images which is not seen with meningiomas. And finally, nerve sheath tumors tend to be more generally T2 hyperintense than meningiomas, which are usually only mildly hyperintense compared with the spinal cord. TREATMENT AND PROGNOSIS. Early diagnosis and surgical intervention for spinal meningiomas can bring about a dramatic improvement in symptomatology. A complete cure is possible if patients receive an operation before irreversible cord ischemia occurs. At 6 months after surgery, 85% of patients are found to be either neurologically intact or improved. Even paraplegic patients have a chance of returning to ambulation after surgery, given an appropriate interval of time. The recurrence rate after surgery for meningiomas is approximately 4% on long-term follow-up, with recurrences reported up to 38 years postoperatively. Calcified meningiomas tend to have a poor neurologic outcome because of difficulty in mobilizing the tumor from surrounding tissues at surgery.

FIGURE 21.40 Meningioma. Sagittal T2-weighted (A) and postcontrast T1-weighted (B) images of the thoracic spine show an intradural, extramedullary mass with a broad dural attachment. The ventral portion of the mass, which compresses the cord, is isointense to the cord on T2-weighted images and avidly enhances after contrast. Note the hypointense and nonenhancing dorsal portion of the mass contiguous with the dura representing calcification. Axial T2-weighted gradient echo (C) demonstrates susceptibility in the region of calcification, causing marked signal loss in the posterior aspect of the spinal canal. Axial postcontrast T1-weighted (D) images demonstrate the posteriorly located mass ventrally displacing the cord. The dorsal thoracic location is typical for meningioma.

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Secondary Intradural Extramedullary Tumors Spinal Leptomeningeal Tumor Both primary intracranial neoplasms and systemic tumors may spread to the CSF. Primary intracranial neoplasms are the most common, especially in the pediatric population (61). In 42 cases of leptomeningeal tumor resulting from primary intracranial neoplasms, medulloblastoma was the most frequent, representing 48% of the cases (77). Glioblastoma and high-grade astrocytomas (grades III and IV) were next, occurring in 14%. Ependymoma was seen in 12% of the cases, oligodendroglioma in 12%, other astrocytomas in 7%, retinoblastoma in 5%, and pinealoma in 3% (77). In the pediatric population, choroid plexus papilloma can also show subarachnoid spread. In fact, virtually all brain tumors can seed the subarachnoid space, even the relatively benign juvenile pilocytic astrocytoma (Fig. 21.41). The importance of establishing the presence of leptomeningeal disease with an intracranial lesion is paramount because this information significantly alters therapy. If tumor is present within the spinal canal, spinal axis radiation is employed. Two age peaks for leptomeningeal carcinomatosis in the pediatric population are seen, the first roughly at 6 years and the second at 14 to 15 years (37). The second peak occurs in patients who have had spinal axis radiation and either have delayed spread of a primary tumor into the radiated spine or have secondary recurrence intracranially with later spread through the subarachnoid space into the spinal column (37). Thirty-three percent of patients with intracranial recurrence of medulloblastoma have leptomeningeal spread into the spine at the time of diagnosis of the recurrence. Although the tumors that spread to the subarachnoid space are often primary intracranial neoplasms, tumors outside the CNS can also spread to the meninges. Systemic tumors may spread to the leptomeninges by many mechanisms, including direct extension into the subarachnoid space, peripheral lymphatic invasion, hematogenous dissemination, and seeding via the choroid.

FIGURE 21.41 Dropped metastases from intracerebral juvenile pilocytic astrocytoma. T1-weighted, postcontrast, fatsuppressed sagittal (A,B) and axial (C,D) images show extensive thin as well as nodular coating of abnormal enhancement indicating tumor spread along the cervicothoracic spinal cord and conus.

In the spine, leptomeningeal tumor most often spreads to the lumbosacral region (73%), probably because of the effects of gravity, with most of the tumor cells settling in this area. However, some 1660

lesions are seen in the cervical and thoracic regions. In one series, 3 of 26 patients with subarachnoid spread had lesions within the cervical region. Lesions in the cervical and thoracic regions tend to be dorsal in location. Again, this distribution may reflect the natural flow of CSF because CSF travels from the brain dorsal to the cord and then returns to the brain ventral to the cord. Frequently, subarachnoid spread of tumor can be asymptomatic. However, leptomeningeal tumor often produces a characteristic constellation of symptoms. Because the patients have neoplastic cells in the CSF, symptoms may be referable to any location in which the tumor cells localize. Thus, patients will often have symptoms referable to many locations in the neuraxis at the same time. For example, a patient may have headache, cranial nerve symptoms, and focal back pain at the same time. In the study of Wasserstrom et al., (78) 50% of 90 patients initially complained of cerebral symptoms. Headache was seen in 33%. Change in mental status was noted in approximately 17%. Other symptoms referable to the brain included seizures, nausea and vomiting, and polyuria, resulting from diabetes insipidus. Cranial nerve symptoms were seen in 38% of patients. Seventy percent of patients had evidence of spinal root involvement. Of the systemic tumors, carcinoma of the breast is the most common cause, followed by carcinoma of the lung, malignant melanoma, carcinoma of the genitourinary tract, and carcinoma of the head and neck or colon. IMAGING. Contrast-enhanced MR scans, as mentioned previously, are very sensitive to the detection of subarachnoid tumor in the spine. Tumor spread can have a variety of appearances. In some cases, tumor may coat the cord or the nerve roots, resulting in a fine layer of enhancement overlying all the structures, which has been referred to as a “sugar-coated” appearance (Fig. 21.33). In other cases, tumor growth may be very local rather than diffuse, resulting in the appearance of multiple nodules in the subarachnoid space (Fig. 21.41). Metastatic nodules on the surface of the spinal cord may indent the contour of the cord or, if large enough, can cause cord compression. Finally, in severe cases, enhancement of the entire thecal sac may be seen as a result of tumor permeating all of the CSF space. Although the advent of gadolinium-enhanced MR has permitted a less invasive method of evaluating suspected leptomeningeal tumor, it has replaced the traditional modalities (myelography and postmyelography CT). Although myelography and gadolinium-enhanced MR may be roughly comparable in most cases, examination of the CSF still is the most sensitive modality for determining leptomeningeal tumor spread. In the study of Wasserstrom et al., positive CSF cytology was identified in 54% of patients on initial lumbar puncture. Subsequent examinations of the CSF increase the yield of malignant cells, although CSF cytology may remain persistently negative in some patients. Findings on gadoliniumenhanced MR scan in the spine have been estimated to occur in no more than 15% to 20% in cases with proved leptomeningeal carcinomatosis. Nevertheless, the finding of the focal tumor is clinically important because these patients are best treated with radiation directed at the tumor in addition to whatever other therapy they may receive. TREATMENT. Patients with primary intracranial tumors and subarachnoid spread are treated with radiation to the spinal axis. Patients with metastatic tumor from systemic sources generally are treated with intrathecal chemotherapy and radiation therapy directed at any tumor nodules that may be seen in the spine. The chemotherapy used in this case is nearly always methotrexate. The prognosis for patients with leptomeningeal carcinomatosis is poor. However, with aggressive therapy, a small percentage of patients actually may have tumor cells cleared from their CSF. Although they will eventually succumb to metastatic disease elsewhere, they may have their CNS cleansed of tumor.

INTRAMEDULLARY TUMORS Technique In the intramedullary space, MR is essential to the diagnosis (1,79). The advent of MR has tremendously increased the ability to detect and characterize lesions of the spinal cord. Despite the more detailed characterization of signal changes with the improvement of imaging in recent years, the accurate distinction between histologic subtypes remains problematic by MR because a significant overlap in appearances exists. Generally, T1-weighted sagittal sequences usually demonstrate excellent morphologic detail and disclose cord widening (79). The presence and extent of any cystic cavities generally is assessed easily, although proteinaceous cysts may appear isointense (80). T2-weighted 1661

sagittal scans demonstrate high signal within the substance of the cord consistent with either tumor or surrounding edema (79). STIR sequences are more sensitive than FSE T2-weighted sequences for the detection of intramedullary pathology; however, cord tumors generally are sizable at the time of diagnosis, and STIR sequences are not essential. Because of the sensitivity of MR to hemorrhage, areas of bleeding are detected easily. A number of different appearances may be seen. If hemorrhage into a cystic cavity occurs, fluid levels may result. Because of the evolution of hemoglobin breakdown products and other factors, the relative signal intensities of the inferior and superior components may vary. T2-weighted GRE sequences have excellent sensitivity for detection of hemorrhage. In addition, hemorrhagic cord tumors often are associated with superficial hemosiderin deposition along the surface of the cord, known as superficial siderosis. On T2-weighted sequences, this is seen as marked hypointensity along the periphery of the cord. Although noncontrast MR scans generally detect lesions in the cord accurately, gadolinium can help in further characterization and delineation (81,82). Enhancement with gadolinium is most useful in cases of focal masses, especially hemangioblastomas and metastases (81). Both of these lesions tend to be fairly well circumscribed and produce extensive associated changes: Metastases typically are associated with extensive edema, whereas hemangioblastomas are commonly associated with syrinx cavities. Because of this, cord swelling far beyond the region of the actual tumor often is seen. The use of gadolinium can be effective in pinpointing the exact location of the lesion (75,81,82) and is essential to treatment. Although the area of cord enlargement can be extensive, the actual lesion may be small, often much less than one vertebral body in height. Results with primary spinal cord gliomas are less dramatic. First, as in the brain, it is certain that areas of enhancement do not coincide with the actual boundaries of these infiltrative tumors because their boundaries are infiltrative even on microscopic histopathology. Second, unlike that seen with hemangioblastomas and metastases, enhancement is variable and incomplete. Having said that, however, we also note that at least partial enhancement is nearly always present in spinal cord gliomas. In gliomas of the cord, enhancement again tends to be fairly focal (81,82). Areas of enhancement may be representative of more active tumor and pinpoint sites for biopsy, as is the case in the brain. Often, these tumors are associated with cysts. Although low-grade gliomas of the brain tend not to enhance, the large majority of gliomas of the cord tend to enhance, regardless of grade (81,82). In fact, nonenhancing gliomas of the cord are distinctly unusual, although they have been documented. Even very low-grade tumors tend to show some enhancement. Of the 55 reported cases of cord glioma in which contrast MR was employed, enhancement was seen in 54 (75,81,82). Because of this, the use of contrast can be helpful in differentiating suspected neoplasms from other etiology, for example, infection or benign syrinx. If no enhancement is seen, the likelihood of a glioma of the cord is reduced significantly. MR spectroscopy can help further characterize intramedullary lesions, although several technical challenges limit its use. Similar to its use in the brain, identifying a reduced NAA/Cr, an increased Cho/Cr, and an increased myo-inositol/Cr can help distinguish tumor from nonneoplastic etiologies. However, the challenges of utilizing spectroscopy are magnified by the inherent strong susceptibility changes found around the spinal cord. Additionally, the small diameter of the cord, pulsatile flow of CSF, patient motion artifacts, and limited SNR reduce the spectral quality of the exam (83). Primary Intramedullary Tumors Astrocytoma Gliomas are reported to constitute between 9.5% and 22.5% of all tumors of the spine, with an average of 18.7% (84,85). Astrocystomas comprise 36% to 54% of these lesions. Astrocytomas are especially more common in children. They represent up to approximately 60% of intramedullary mass lesions in children, whereas ependymomas constitute approximately 24% to 38% of cases. Overall, the peak incidence of spinal astrocytomas is in the third and fourth decades. In the Mayo Clinic series, the average age was 31 years. There is either no sex predilection or a slight male predilection (86). Astrocytomas are most often found in the thoracic cord. Sloof et al. (87) found that 17 of 86 astrocytomas were located in the cervical region, 41 were thoracic, 11 were in both the cervical and thoracic cords, 13 were in both the thoracic and lumbar cords, and 4 were lumbar. The prevalence of astrocytomas decreases in the lower thoracic and lumbar regions, unlike the prevalence of 1662

ependymomas, which increases in the caudal spinal canal. In fact, it is rare for astrocytomas to be located in the filum terminale, a common site for ependymomas. Most astrocytomas are intramedullary, although rarely they can be exophytic and intradural extramedullary in location (37). The presenting symptoms frequently are nonspecific and ill defined, resulting in a delay in diagnosis (86). Patients present with pain (local or remote), gait difficulties, and bladder disturbances (86). On physical examination, motor and sensory changes can be seen (86). In children, progressive scoliosis may occur. PATHOLOGY. These lesions usually result in fusiform expansion of the spinal cord. Grossly, astrocytomas are gray–yellow in color to reddish gray, depending on the degree of hemorrhage. Malignant tumors tend to be more vascular (88). Cystic change is present between 25% and 38% of the time in these potentially friable lesions (86). These low-grade tumors do not have a clear line of demarcation from the normal spinal cord. Frequently, they are eccentric in location, usually posteriorly located by the posterior columns (18,76). They often involve the spinal cord over multiple segments; holocord astrocytomas involve the entire cord and are most commonly seen in low-grade astrocytomas. Astrocytomas are generally less often hemorrhagic, less often necrotic, less often grossly hypervascular, and hence less often markedly heterogeneous on MR as compared to ependymoma. However, these entities quite commonly overlap in these pathologic features and MR features as a consequence. Astrocytomas are composed of neoplastically transformed astrocytes that vary from well differentiated to anaplastic. Between 75% and 92% of cord astrocytomas are benign in adults (grades I and II) (88,89). High-grade spinal cord tumors (glioblastoma multiforme and anaplastic astrocytomas) are rare neoplasms with a dismal prognosis. They have a high incidence of CNS metastases (15/36) and can even have extraneural metastases (2/36). IMAGING. Plain films can show widening of the spinal canal and bony erosion. Imaging with myelography and postmyelography CT reveals an intramedullary mass expanding the cord. Because of its superior ability to evaluate and characterize lesions of the spinal cord, MR is the modality of choice in the evaluation of suspected intramedullary tumors, including astrocytomas. On T1-weighted images, these lesions demonstrate low signal intensity. Cord enlargement, often marked, is virtually always present. On T2-weighted images, these lesions and the associated edema display high signal intensity. After contrast administration, these lesions typically enhance, but because of the infiltrative nature of the tumor, without a capsule or cleavage plane between the lesion and the spinal cord, the margins of the lesion often are poorly defined and irregular (75,81). The contrast enhancement can be inhomogeneous in nature (75), but it is usually present in at least part of the lesion (Figs. 21.42 and 21.43). However, nonenhancing astrocytomas are likely more common than previously appreciated. A series of 19 patients and a review of the literature by Seo et al. (90) suggests that up to 20% to 30% of cases may be nonenhancing. Although many astrocytomas are rather homogeneous in signal intensity (Fig. 21.43), it is not uncommon for these lesions to display marked heterogeneity more reminiscent of ependymoma. Enhancement is evident soon after the administration of contrast, although in necrotic tumors, delayed enhancement can be seen.

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FIGURE 21.42 Cervical astrocytoma. The upper cervical spinal cord is expanded and demonstrates heterogeneous signal abnormality. There is predominantly T1 (A) hypointensity and T2 hyperintensity (B), with central areas of T1 hyperintensity, which likely reflect hemorrhage. Sagittal (C) and axial (D) postcontrast images demonstrate poorly marginated enhancement, which is peripheral in location, characteristic for an astrocytoma. A cyst at the superior aspect of the mass demonstrates enhancement along its superior margin (arrowhead), indicating that it is a tumoral cyst rather than a peritumoral reactive cyst.

FIGURE 21.43 Conus astrocytoma in patient with radiculopathy. Sagittal T1-weighted (A) and T2-weighted (B) images show an expansile, predominantly T2 hyperintense mass with partial, irregular and eccentric enhancement (C). The enhancement pattern is more suggestive of astrocytoma, although the location would be more characteristic of an ependymoma.

Grade I pilocytic astrocytomas are well-marginated lesions and will displace white matter tracts. The higher grade tumors, grades II–IV astrocytomas, tend to infiltrate the white matter fiber tracts. 1664

Diffusion-tensor imaging (DTI) and fiber tractography can be useful tools in demonstrating the relationship between an intramedullary tumor and the local white matter tracts (Figs. 21.44–21.49). MR also is advantageous in its ability to differentiate the tumor from associated cyst formation (Fig. 21.44). Cysts can be either intratumoral or rostral and caudal (79). Rostral and caudal cysts tend to be benign. Even though the fluid within them might be proteinaceous or hemorrhagic, these cysts are not usually lined by tumor, nor do they contain tumor cells. Unlike tumor cysts, they do not require excision but are merely drained at surgery (91). Gadolinium enhancement has been useful in identifying the nature of cysts associated with tumors (75,81,82). Tumor cysts are generally surrounded by enhancement, whereas the walls of benign cysts lack associated contrast uptake.

FIGURE 21.44 Thoracic astrocytoma with extensive cyst formation. Precontrast (A) and postcontrast (B) T1weighted imaging show an enhancing mass with extensive cyst formation both superiorly and inferiorly. Complete lack of enhancement around the margins of the cysts suggests that these are peritumoral reactive cysts. The peritumoral cysts are difficult to distinguish from the hyperintense mass on T2-weighted imaging (C).

FIGURE 21.45 Ependymoma with cyst formation and hemorrhage. Septated cyst formation and heterogeneous T2 hyperintensity are seen in the cervical cord on T2-weighted imaging (A). On short–inversion-time inversion recovery imaging (B), an area of hypointensity (arrow) reflects hemorrhage. There is a solid enhancing component in the upper thoracic region, indicated by the arrows on T2-weighted (A) and postcontrast (C) imaging.

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FIGURE 21.46 Ependymoma with “hemosiderin cap sign”. Sagittal T1-weighted image (A) shows an isointense lesion within the substance of the mid-to-lower thoracic cord with consequent cord expansion. Sagittal T2-weighted image (B) demonstrates central hyperintensity of the mass, though with a thin rim of hypointense signal at the periphery of the lesion. This “cap sign” is due to hemosiderin from prior hemorrhage, typical of ependymomas. There is T2 hyperintensity within the cord extending cranially and caudally from the mass reflecting edema. Sagittal and axial T1-weighted postcontrast, fat-suppressed images (C,D) show avid well-circumscribed enhancement of the lesion within the central cord. Axial gradient-echo image (E) exhibits focal markedly low signal (susceptibility) within the left cord reflecting blood products from prior hemorrhage.

Both reactive and neoplastic cysts tend to have decreased signal intensity on T1-weighted images and increased signal intensity on T2-weighted images in relationship to the tumor. However, the signal intensity can be indistinguishable from the solid tumor on noncontrast MR, especially when the cavity is caused by necrosis within the tumor (80,91). Hemorrhage or increased protein within the cyst fluid can decrease T1 and T2 relaxation times in relation to pure CSF, making the cyst isointense with the spinal cord and tumor. Complex benign syrinxes can resemble cystic astrocytomas. They have gliosis within their walls secondary to chronic CSF pulsations. This tissue can display increased signal intensity on T2-weighted images and can be indistinguishable from tumor (91). On noncontrast MR, some characteristics may favor an underlying neoplasm. These characteristics include indistinct margins to the cyst, nonuniform signal intensity of the fluid that does not parallel CSF, and the absence of pulsations (92). It should be considered standard to administer intravenous contrast to detect enhancement at least once in the workup of any syrinx, with the exception of a Chiari malformation, in which case the etiology of the syrinx is obvious. TREATMENT. Surgery is advocated in all cases, followed by radiation therapy (88). Histologic grade is a major determinant in predicting prognosis. Low-grade tumors often have a protracted and indolent course, whereas high-grade tumors have a tendency to CSF dissemination (58%) and rapid deterioration. For all patients, the 5- and 10-year survival rates are 58% and 23%, respectively; patients with malignant tumors, however, rarely survive more than 2 years (88).

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FIGURE 21.47 Multiple ependymomas in a patient with neurofibromatosis type 2 (NF2). T1-weighted imaging (A) shows only mild signal abnormality. There is intramedullary T2 hyperintensity with small tumoral cysts (arrowheads) in the upper cervical cord on short–inversion-time inversion recovery imaging (B). Heterogeneous enhancement is seen on sagittal (C) postcontrast imaging. Axial postcontrast imaging (D) shows ring enhancement located centrally within the cord, a characteristic location for ependymomas. Sagittal (E) and axial (F) postcontrast imaging of the lower thoracic cord demonstrate two additional centrally located enhancing intramedullary lesions, which are presumed to be additional ependymomas in this patient with NF type 2. Note the small, broad-based, homogeneously enhancing extramedullary lesion at the same level (E, arrowhead), likely a small meningioma. Additional postcontrast images reveal a presumed nerve sheath tumor extending through a neural foramen (G) and multiple meningiomas in the brain (H).

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FIGURE 21.48 Cervical ependymoma in a patient with neurofibromatosis type 2. Sagittal T1 (A) image demonstrates a large heterogeneous mass enlarging the upper cervical cord and cervicomedullary junction. Cranial and caudal polar cysts demonstrate fluid signal on T2-weighted image (B). On postcontrast T1-weighted image (C), the solid tumor centered at the C2 level demonstrates diffuse, mildly heterogeneous enhancement. The polar peritumoral cysts (arrows) do not enhance; however, a small intratumoral cyst is appreciated at the inferior anterior portion of the enhancing lesion (arrowhead). Sagittal ADC map (D) demonstrates a large region of increased diffusivity involving both the tumor and polar cysts, compared with normal cord. Axial fractional anisotropy (FA) map (E) demonstrated a centrally located defect, with circumferential preservation of FA at the periphery of most of the cord, consistent with the typical central growth pattern of ependymoma. An axial postcontrast T1 image (F) through the posterior fossa reveals bilateral vestibular schwannomas in this patient with NF type 2.

Ependymoma Although ependymomas are certainly more often intracranial than intraspinal, they comprise a much higher percentage of spinal tumors than of brain tumors. They are the most common intramedullary cord tumor in adults. Of 74 ependymomas reported by Barone and Elridge (93), 36% were intraspinal. Of 62 patients with ependymoma, Rawlings et al (94). found that 31% were intraspinal. The lesion usually presents in patients in their fourth or fifth decade of life, far older than those with intracranial ependymomas. In Barone and Elridge’s series, the average age was 37 years. In Rawling et al.’s (95) series, the average age was 41 years. However, they may occur in other patients, from children to the elderly. Ependymomas represent 30% of pediatric intramedullary spinal neoplasms. Males predominate over females in a ratio of approximately 3:2. Ependymoma is the most common primary cord tumor of the lower spinal cord, conus medullaris, and filum terminale (86). It represents 58% of all conus tumors. One subtype of ependymoma—the myxopapillary form—is particularly common in the conus and filum. It constitutes from 27% to 30% of all ependymomas. Of the 77 cases of myxopapillary ependymomas in the Mayo Clinic series, 65% were limited to the filum, 30% involved the filum and the conus medullaris, and only 4% were located in the cervicothoracic spinal cord. Clinically, patients present most often with back or neck pain—seen in 63% of patients—or with radicular pain—seen in 89% of patients. Other symptoms include unsteady gait, numbness, and bowel or bladder dysfunction. 1669

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FIGURE 21.49 Ependymoma with diffusion tensor imaging and tractography. Sagittal T1- and T2-weighted (A,B) images demonstrate a localized mass within the cord at the C2 level. Axial T2 image (D) depicts the central location and well-demarcated margins of the lesion. The lesion demonstrates homogeneous contrast enhancement (C,E). No significant cord edema or cyst formation is present. The lesion is hyperintense on diffusion-weighted image (F), which may reflect both T2 effects and a degree of diffusion reduction. Sagittal, coronal and axial fractional anisotropy maps (G–I) demonstrate a focal defect in the region of the mass, with preservation of signal immediately outside the lesion including the cord periphery. The same can be seen on the sagittal and axial (J,K) colored orientation maps, also processed from DTI sequence. Fiber tractography (L,M) shows smooth outward displacement of white matter tracts by this centrally located lesion. Compare with a case of astrocytoma (N), where tractography demonstrates an infiltrated appearance of white matter tracts traversing the tumor. (From Ducreux D, Fillard P, Facon D, et al. Diffusion tensor magnetic resonance imaging and fiber tracking in spinal cord lesions: current and future indications. Neuroimaging Clin N Am 2007;17(1):137–47, with permission.)

PATHOLOGY. Ependymal cells line the central spinal canal as well as the remainder of the internal surfaces of the CNS. Thus, ependymomas often tend to be central in location and exhibit centrifugal growth (75). Grossly, ependymomas are cylindrical, elongated masses that cause localized fusiform expansion of the spinal cord (75). They are brownish red to blue in color, depending on their blood content. Ependymomas are soft, friable lesions that frequently have a delicate capsule forming a cleavage plane to separate tumor from spinal cord (75). They can grow into the conus and adhere to the lumbar nerve roots. Cyst formation is seen in 50% of the cases. Although ependymomas in the brain frequently calcify, calcification is extremely uncommon in spinal ependymomas. The most common histology is the cellular type. Well-defined cuboidal or low columnar cells are arranged in a papillary fashion. However, the most common lesion of the filum terminale is the myxopapillary type, in which mucinous change is also seen. This type is especially prone to hemorrhage and can present as an unexplained subarachnoid bleed. Rarely, ependymomas can also be pigmented, although the pigment in these lesions is not melanin. 1671

IMAGING. Plain films are positive in 63% of cases and show erosion of the pedicles or of the posterior surface of the vertebral bodies. CT and myelography disclose the typical intramedullary or conus/filum mass and can be performed to localize the lesion and show its extent and the degree of spinal cord block. These modalities, however, are frequently nonspecific. One small series demonstrated positron emission tomography (PET) avidity with both fluorodeoxyglucose (FDG) and methionine (MET) in four of six ependymomas (as well as in one case of anaplastic astrocytoma) (96). The MR in spinal cord ependymomas reflects their heterogeneous pathology. Noncontrast MR demonstrates spinal cord widening or a mass, frequently near the conus but not uncommonly elsewhere in the spinal cord (81,82). The lesion is hypointense or isointense with the cord on T1-weighted images and typically heterogeneous on T2-weighted images (Fig. 21.46). Areas of hemorrhage may have varying intensity on both sequences. Hemosiderin deposition is encountered frequently, particularly at the superior and inferior borders of the tumor, and appears mildly hypointense on T1-weighted images and markedly hypointense on T2-weighted images. Termed a “cap sign,” this rim of low T2 signal occurs in approximately 20% of cases and is highly suggestive of ependymoma. Areas of hypercellularity are seen commonly as regional hypointensity within the bulk of a relatively hyperintense lesion on T2-weighted images (Fig. 21.46).

FIGURE 21.50 Spinal cord astrocytoma versus ependymoma. A: Astrocytoma. Cross section of the upper cervical cord shows extensive replacement of the spinal cord with ill-defined tumor tissue with cystic necrosis as well as syringohydromyelia. B,C: Ependymomas. Typical, well-circumscribed, centrally located intramedullary tumor on axial section (B). Multiple well-circumscribed, centrally located ependymomas also are seen on longitudinal sections (C). (From Okazaki H, Scheithauer B, eds. Atlas of Neuropathology. New York: Gower Medical Publishing; 1988, with permission.)

After the administration of contrast, ependymomas tend to enhance intensely but irregularly (75). The lesions often have well-defined borders. Gadolinium helps to better identify intratumoral and peritumoral cysts, especially those that can be isointense with the lesion and cord on noncontrast MR (Figs. 21.47 and 21.48) (81,82,91). Although the tumors are characteristically quite heterogeneous and astrocytomas are characteristically more homogeneous, it is often very difficult to differentiate these tumors from astrocytomas by imaging criteria. There are a few suggestive criteria, however. First, ependymomas occur far more frequently in the lower cord and conus than astrocytomas. A significant proportion of ependymomas, however, does occur in the cervical or thoracic cord. Second, astrocytomas tend to arise eccentrically within the cord, especially posteriorly. Ependymomas arise from ependymal cells in the central canal and tend to be central (Figs. 21.47 and 21.50). Third, ependymomas are more frequently 1672

hemorrhagic than astrocytomas. Hemorrhage with cord astrocytomas, however, is also not uncommon. Fourth, regions of low T2 intensity reflecting hypercellularity are more common in ependymomas. Finally, because of the thin pseudocapsule that surrounds ependymomas, it may be possible on very thin sections to identify a plane separating the ependymoma from the cord (S. Hilal, personal communication, 1992), unlike astrocytomas, which tend to be infiltrative and have poorly defined borders (Fig. 21.49). This plane, however, may be difficult to identify. A variant of ependymoma found in the spinal canal is the myxopapillary ependymoma. These lesions are soft, expansile masses that nearly always are found in the region of the filum terminale (Fig. 21.51). Rarely, they can be found in the brain or elsewhere in the spinal cord. On histopathology, abundant mucin accumulation around vessels and between cells surrounding vessels is characteristic. The presence of these mucinous spaces, their classic location in the filum terminale, and their often large size give these lesions a typical appearance. The mucin may result in diffusely hyperintense signal on both T1and T2-weighted imaging in some cases, which is quite characteristic when present. TREATMENT. Treatment is aimed at surgical removal. With complete removal of an encapsulated tumor, there is little chance for recurrence (15%). However, sometimes the tumor is encapsulated poorly or cannot be removed entirely. These tumors can metastasize via CSF dissemination or by distant metastases. Hemangioblastoma Although hemangioblastomas are the most common primary posterior fossa tumor in the adult, they rarely involve the spinal cord. They constitute 3.3% of intramedullary tumors. There is no sex predilection. These lesions usually present in the fourth decade. In a review of 85 cases in the literature, Browne et al. (97) noted a median age of 30 years.

FIGURE 21.51 Myxopapillary ependymoma of the conus and filum terminale. A heterogeneously T2 hyperintense (A) mass expands the conus medullaris and extends into the filum terminale region, a characteristic location for this neoplasm. The mass is barely detectable on T1-weighted imaging (B) but demonstrates intense enhancement after contrast administration (C).

Approximately 30% of the patients with spinal cord hemangioblastomas have von Hippel–Lindau syndrome. von Hippel–Lindau syndrome, an autosomal-dominant disorder with almost 100% penetrance, is typified by cerebellar hemangioblastomas (35% to 60%), retinal angiomatosis (greater than 50%), renal cell carcinomas (25% to 38%), pheochromocytoma (greater than 10%), or spinal hemangioblastomas (less than 5%) (97–99). However, the incidence of spinal cord hemangioblastomas in von Hippel–Lindau syndrome may be underestimated because these lesions are frequently asymptomatic (99). An autopsy study of 10 patients with von Hippel–Lindau syndrome revealed hemangioblastomas of the cord in all of them. When patients with von Hippel–Lindau syndrome have retinal or cerebellar hemangioblastomas coexisting with spinal hemangioblastomas, they usually present with symptoms from the former lesions rather than from the spinal cord lesions (98,98). In patients with a positive family history for von Hippel–Lindau syndrome, even if asymptomatic, MR is now recommended to evaluate for cerebellar or spinal cord lesions. Tumor-to-tumor metastases to 1673

hemangioblastomas have been reported in von Hippel–Lindau syndrome, particularly from renal cell carcinoma. It has been suggested that hemangioblastomas may be a preferred early site for metastasis due in part to their hypervascular nature and slow-growing course (100). Hemangioblastomas involving the spinal cord tend to be single (79%), although multiple tumors in a single patient are not unusual. In spinal hemangioblastomas, the thoracic cord is most often involved (51%), followed by the cervical cord (41%) (91). Most hemangioblastomas are intramedullary (60%); however, they can also be intradural extramedullary or purely extradural. Of all spinal hemangioblastomas, 43% are associated with cysts; however, when purely intramedullary hemangioblastomas are considered, cyst formation is seen in up to 67% of the cases (97,101). The cyst fluid often is proteinaceous, either from previous hemorrhage or from transudation of fluid by the tumor. Cord hemangioblastomas are also associated with meningeal varicosities, which have been noted in 48% of cases and are usually located on the dorsal surface of the cord. PATHOLOGY. Histologically, hemangioblastomas are composed of endothelial cells intermixed with stromal cells containing fat and hemosiderin (97). The endothelial cells form masses, cords, and thinwalled blood vessels. It is this portion of the tumor that comprises the actual growing mass (97). Eventually, the tumor consists of a compact collection of capillaries with small feeding arteries and dilated draining veins. The cysts can be very large compared with the size of the tumor (98). They are lined with fibrillary neuroglia, similar to those seen with syrinxes. In three patients with cord hemangioblastomas, autopsy failed to show tumor cells in the wall of the cyst cavity (97). IMAGING. Plain films may demonstrate widening of the spinal canal. Myelography frequently shows expansion of the spinal cord and serpiginous filling defects posterior to the cord representing meningeal varicosities. CT can show widening of the cord with a hypodense tumor nidus that markedly enhances (97). Spinal angiography reveals prominent feeding arteries and draining veins and an intense blush of the tumor nidus. Unenhanced MR demonstrates widening of the spinal cord as in any mass lesion or edema-associated process (Figs. 21.52 and 21.53) (101). Associated cyst formation may be striking, despite the small size of the lesion itself (Fig. 21.52). The cysts may vary in signal intensity, depending on their contents (101). Signal characteristics can parallel those of CSF or may be of greater intensity as a result of increased protein content (80,101). As a result of this increased signal intensity, the cyst may occasionally be indistinguishable from the tumor nidus and cord on noncontrast sequences. Cord hemangioblastomas are typically associated with considerable edema, similar to cord metastases, as shown by low signal on T1-weighted images and increased signal on T2-weighted images. Adjacent serpiginous areas of signal void or enhancement may be seen and, when present, clinch the diagnosis because the main mimic of these lesions, metastases, do not have associated enlarged vessels (Fig. 21.53). These can represent large feeding arteries or, more commonly, draining meningeal varicosities associated with the very vascular tumor nidus (97).

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FIGURE 21.52 Hemangioblastoma. A nodule is seen at the C3/4 level (arrow), which is isointense to hyperintense on T1-weighted (A) and isointense on T2-weighted imaging (B). After contrast administration (C) the nodule intensely enhances, characteristic of this neoplasm. Extensive tumoral cyst formation is seen both rostral and caudal to the nodule. Angiography (D) confirms the vascular nature of the nodule (arrowhead). A feeding artery (black arrow) and draining vein (white arrow) are seen.

Enhanced MR shows a markedly enhancing tumor nidus, permitting differentiation of the often small nidus from the adjacent edematous spinal cord and the cyst (81). This is essential to direct surgery toward accurate removal of the tumor nidus and decompression of the adjacent cyst. TREATMENT. Complete surgical removal offers the only chance of cure (97). Total removal is possible in some cases because a cleavage plane often separates tumor from adjacent cord. Incomplete excision results in recurrence. The use of radiation therapy is uncertain. Possible benefits are counterbalanced by the acute risk of increased cord edema and the chronic risk of radiation myelopathy (97). Secondary Intramedullary Tumors Metastatic Disease to the Spinal Cord Metastatic intramedullary tumors are rare, especially when compared with extradural metastases (102). The incidence of metastasis to the spinal cord in patients with systemic carcinomas has been estimated to range from 0.9% to 8.5% (102). Edelson et al. (103) found six cord metastases in 175 patients with 1675

symptomatic metastatic disease to the spine, or 3.4%. However, Costigan and Winkelman (102), in a retrospective autopsy series, noted an incidence of 8.5% of cases of metastasis to the cord. This estimate is high both because of the inherent bias of retrospective autopsy series and because, in a significant number of their cases, the metastases were asymptomatic and found only as microscopic deposits.

FIGURE 21.53 Multiple spinal cord hemangioblastomas and von Hippel–Lindau syndrome. A,B: Sagittal T1- and T2weighted images of the cervical spine show marked widening and heterogeneity of the spinal cord. Multiple areas of cyst formation are present, especially superiorly in the cervicomedullary region and inferiorly in the cervicothoracic portion of the spinal cord. On the T2-weighted images, several hypointense punctate foci can be seen along the posterior aspect of the cord, suggesting prominent vascular structures. C–E: After contrast, multiple enhancing nodules are seen, some of which are associated with cysts. Also note the markedly dilated draining veins extending from some of the tumor nodules. F: Contrast-enhanced magnetic resonance of the posterior fossa in this patient shows several small enhancing lesions, as well as a larger cystic lesion with a mural nodule.

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Of all intramedullary cord metastases, carcinoma of the lung accounts for 40% to 85% of the total (102). Breast carcinoma, melanoma, lymphoma, colon, and kidney are other common primary sites (102). Several routes have been suggested by which metastatic deposits may reach the cord (102). Because a very high percentage of patients have a primary or metastatic pulmonary neoplasm, arterial seeding is a possible mechanism because tumor must reach the lungs before disseminating through the arterial system. Tumor may also reach the cord through the vertebral venous system, known as Batson’s plexus. Finally, tumor may extend to the cord by direct invasion from nerve roots or CSF. This route would explain the frequent but not inevitable association of intramedullary metastasis with leptomeningeal tumor. Of all areas of the cord, the thoracic cord is most frequently involved, followed by the cervical and the lumbar cord. In Edelson et al.’s review of the literature combined with a contribution of nine cases, 41% occurred in the thoracic region, 29% in the cervical region, and 8% in the lumbar region. The remainder were at the cervicothoracic and thoracolumbar junctions. The high incidence of intramedullary metastases in the lumbar region, despite the disproportionately small length of the lumbar cord, may be because of the prevalence of leptomeningeal deposits in this location. Intramedullary metastases may present with a confusing clinical picture. Pain is a common complaint (70%). Although radicular pain characterizes extradural tumors, it may also be seen often with cord metastases. Weakness (100%), paresthesias (50%), and bowel and bladder disturbances (60%) are commonly encountered. A striking feature is the rapid clinical progression, unlike that seen with primary cord tumors. In Edelson et al.’s series, 70% of patients exhibited complete paraplegia within 2 months. IMAGING. Because of the rapid progression of the syndrome, plain films are usually negative, although metastases in the vertebral bodies may be incidentally noted. Myelography is frequently normal, as noted in 13 of 30 cases by Edelson et al. PET imaging has been shown to be a reasonable alternative in the evaluation of intramedullary metastatic disease in those patients for whom MR imaging or gadolinium is contraindicated (104). MR shows a widened cord, from the associated edema, often extending for a considerable length. On T1-weighted scans, the cord appears of slightly low intensity; on T2-weighted scans, the cord appears hyperintense (81). The low intensity on T1-weighted images may appear to be predominantly central. This appearance can also be seen on the axial images and can lead to confusion with a syrinx. The differentiation of edematous cord from cyst is important because metastases of the cord are rarely associated with cysts, whereas the other intramedullary lesion to show dramatic focal enhancement amid a larger region of nonenhancing abnormality, the hemangioblastoma, is frequently associated with a large syrinx. On T2-weighted images, the tumor deposit can sometimes be visualized as a lowerintensity structure surrounded by the higher intensity of the edematous cord (Fig. 21.54). The critical part of the study in the search for intramedullary metastases is the administration of contrast. Metastases typically enhance homogeneously and markedly (81), although ring enhancement can sometimes be seen. An ill-defined flame-shaped region of enhancement at the superior and/or inferior margin of an otherwise well-defined lesion (termed “flame” sign) and a more intense thin rim of peripheral enhancement around an enhancing lesion (termed “rim” sign) have both been recently described as specific findings for intramedullary metastatic disease (105). On DTI fiber tractography, metastatic nodules will smoothly displace white matter tracts rather than infiltrate them, as. This behavior is similar to ependymoma, but in contradistinction to astrocytoma (Fig. 21.55). The main diagnostic differential diagnosis if considering the appearance on routine MR sequences, in isolation from clinical information and age of the patient, is hemangioblastoma. The size of the metastasis often is disproportionately small compared with the amount of edema. Rarely, intramedullary metastases may be hemorrhagic and have areas of varying signal intensity on both T1- and T2-weighted images.

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FIGURE 21.54 Spinal cord metastasis from ovarian carcinoma. Sagittal T1-weighted imaging (A) demonstrates expansion of the conus medullaris with only subtle signal abnormality. On sagittal (B) and axial (D) T2-weighted imaging, a relatively hypointense, well-circumscribed nodule (arrow) stands out against the surrounding hyperintense edema. This is a typical appearance for a cord metastasis. The entire nodule avidly enhances (C,E). Note the more intense thin rim of enhancement around the periphery of the enhancing lesion (“rim sign”). An axial T2-weighted image superior to the lesion is a montage of metastatic disease (F). A single image shows cord edema, a sclerotic vertebral metastasis (arrow), left-sided lung masses (white arrowhead), a small right pleural nodule (black arrowhead), and a malignant right pleural effusion (asterisk).

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FIGURE 21.55 Intramedullary cord metastasis from breast carcinoma. Sagittal T1-weighted precontrast and postcontrast images (A,B) demonstrate a nodular enhancing intramedullary mass centered at the C2–C3 level. Mild hyperintensity on the precontrast T1 image may reflect blood products. Sagittal and axial T2-weighted images (C,D) hyperintense signal extending caudally with associated mild cord expansion, and suggestion of a small cystic focus. Colored orientation image (E) processed from diffusion tensor images shows a focal defect at the site of the metastatic tumor. Fiber tractography images (F–H) demonstrate smooth displacement of white matter tracts by the lesion.

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THERAPY. Radiation is the therapy of choice; surgery offers little hope. However, most patients with cord metastases die soon after they present. Two-thirds succumb within 6 months, usually because of widespread metastatic disease.

DEVELOPMENTAL INTRADURAL MASS LESIONS (LIPOMAS, DERMOID CYSTS, AND EPIDERMOID CYSTS) Mesenchymal tumors and tumorlike lesions can occur in the spine and are noted in brief in this chapter. The most common intradural mass of this type is the lipoma. Unlike the other lesions in this category, lipomas are in fact most commonly intraspinal rather than intracranial. Spinal lipomas are most often located in the lumbosacral region and are commonly associated with spinal malformations. In approximately 5% of adults, fatty infiltration or true lipomas of the filum are found. These lesions can present in patients with back pain, although they are more often incidental on MR. These lesions have specific characteristics on MR, in that they parallel fat in signal intensity because they are composed of mature adipose tissue on pathology. The distinction between filar lipomas and fatty infiltration lies in the diameter of the fatty lesion, where 2 mm is the upper limit of normal for the filum terminale (Fig. 21.56). The significance of these lesions in the absence of tethered cord is uncertain. Dermoid and epidermoids are found throughout the CNS but only rarely in the spinal canal. Dermoids are differentiated from epidermoids by their histologic contents; however, MR can readily make this discrimination because dermoids contain fat, whereas epidermoids do not (Figs. 21.57 and 21.58). Both of these lesions can rupture and evoke a chemical meningitis. Dermoids are found more commonly in the midline and most are diagnosed in children. MR distinguishes dermoid from lipoma by virtue of the nonfatty component of the lesion (Fig. 21.59). In fact, the main diagnostic differential diagnosis is the teratoma, which is extremely rare.

FIGURE 21.56 Lipoma of the filum terminale in a patient with a tethered cord. Sagittal T1-weighted imaging (A) shows a tethered cord with thickening and hyperintensity of the filum terminale (arrowhead). On T2-weighted imaging, the fat is indistinguishable from the surrounding hyperintense cerebrospinal fluid (B). The filum suppresses on short–inversion-time inversion recovery (STIR) imaging (C,E), becoming hypointense and confirming that the mass is fatty. Axial T1-weighted imaging (D) and axial STIR (E) show that the lesion is nodular (arrowhead), differentiating it from a fatty infiltration.

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FIGURE 21.57 Intradural dermoid, incidental finding. Sagittal T1-weighted (A), T2-weighted (B), and fat-suppressed, T1-weighted (C) images show an intradural fatty mass along the dorsal aspect of the cervicomedullary junction near the midline. Note the characteristic chemical shift artifact. Axial postcontrast, fat-suppressed (D) and axial T2weighted (E) images show the nonfatty component and a tiny region of enhancement, proving that the lesion is more complex than a simple lipoma.

FIGURE 21.58 Intradural dermoid, conus region, presenting as radiculopathy. A complex exophytic intradural mass involving the conus demonstrates fatty and nonfatty components on T2-weighted (A), T1-weighted (B), and postcontrast, fat-suppressed, T1-weighted (C) images.

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FIGURE 21.59 Intradural dermoid in child, lumbar region. Note expansion of lumbar canal with erosion of L1 and L2 due to longstanding, complex mass associated with conus on T1 (A) and T2 (B). The lesion fills the lumbar spinal canal. Focus of fat is clear on T1 (A). Minimal if any enhancement on fat-suppressed T1 postcontrast (C), partial suppression of fatty component, and obliteration of normal nerve roots of cauda equina are well visualized.

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Malignant nerve-sheath neoplasms in fibromatosis neuro: distinction from benign tumors by using imaging techniques. AJR Am J Roentgenol 1987;149:1059–1064. 69. Wippold FJ 2nd, Lubner M, Perrin RJ, et al. Neuropathology for the neuroradiologist: Antoni A and Antoni B tissue patterns. AJNR Am J Neuroradiol 2007;28(9):1633–1638. 70. Scotti G, Scialfa G, Colombo N, et al. MR imaging of intradural extramedullary tumors of the cervical spine. J Comput Assist Tomogr 1985;9:1037–1041. 71. Ng TH, Chan KH, Mann KS, et al. Spinal meningioma arising from a lumbar nerve root. J Neurosurg 1989;70:646– 648. 72. Davis RA, Washburn PL. Spinal cord meningiomas. Surg Gynecol Obstet 1970;131:15–21. 73. Kaya U, Ozden B, Turantan MI, et al. Spinal epidural meningioma in childhood: a case report. Neurosurgery 1982;10:746–747. 74. Kleihues P, Louis DN, Scheithauer BW, et al. The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 2002;61:215–225. 75. Parizel PM, Baleriaux D, Rodesch G, et al. GD-DTPA enhanced MR imaging of spinal tumors. AJNR Am J Neuroradiol 1989;10:249–258. 76. Bydder GM, Kingsley PE, Brown J, et al. MR imaging of meningiomas including studies with and without gadolinium-DTPA. J Comput Assist Tomogr 1985;9:690–697. 77. Bryan P. CSF seeding of intracranial tumors: a study of 96 cases. Clin Radiol 1974;25:355–360. 78. Wasserstrom WR, Glass JP, Posner JB. Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients. Cancer 1982;49:759–772. 79. Goy AM, Pinto RS, Raghavendra BN, et al. Intramedullary spinal cord tumors: MR imaging with emphasis on associated cysts. Radiology 1986;161:381–386. 80. Rubin JM, Aisen AM, DiPietro MA. Ambiguities in MR imaging of tumoral cysts in the spinal cord. J Comput Assist Tomogr 1986;10:395–398. 81. Sze G, Krol G, Zimmerman RD, et al. Intramedullary disease of the spine: diagnosis using gadolinium-DTPA– enhanced MR imaging. AJNR Am J Neuroradiol 1988;9:847–858. 82. Valk J. Gadolinium-DTPA in MR of spinal lesions. AJNR Am J Neuroradiol 1988;9:345–350. 83. Hock A, Henning A, Boesiger P, et al. 1 H-MR Spectroscopy in the human spinal cord. AJNR Am J Neuroradiol 2013;34(9):1682–1689. 84. Mortara R, Parker JC, Brooks WH. Glioblastoma multiforme of the spinal cord. Surg Neurol 1974;2:115–119. 85. Bernasconi V, Cassinari V. Tumori e malformazioni vasali/spinali. Acta Neurochir (Vienna) 1961;10:1–50. 86. Reimer R, Onofrio BM. Astrocytomas of the spinal cord in children and adolescents. J Neurosurg 1985;63:669–675. 87. Sloof JL, Kernohan JW, MacCarty CS. Primary intramedullary tumors of the spinal cord and filum terminale. Philadelphia: WB Saunders, 1969. 88. Cohen AR, Wisoff JH, Allen JC, et al. Malignant astrocytomas of the spinal cord. J Neurosurg 1989;70:50–54. 89. Johnson DL, Schwarz S. Intracranial metastases from malignant spinal cord astrocytoma. J Neurosurg 1987;66:621– 625. 90. Seo HS, Kim JH, Lee DH, et al. Nonenhancing intramedullary astrocytomas and other MR imaging features: a retrospective study and systematic review. AJNR Am J Neuroradiol 2010;31(3):498–503. 91. Slasky BS, Bydder GM, Niendorf HP, et al. MR imaging with gadolinium-DTPA in the differentiation of tumor, syrinx and cysts of the spinal cord. J Comput Assist Tomogr 1987;11:845–850. 92. Williams AL, Haughton VM, Pojunas KW, et al. Differentiation by intramedullary neoplasms and cysts by MR. AJNR Am J Neuroradiol 1987;8:527–532. 93. Barone BM, Elridge AR. Ependymomas, a clinical survey. J Neurosurg 1970;33:428–438. 94. Rawlings CE, Giangaspero F, Burger PC, et al. Ependymomas: a clinicopathologic study. Surg Neurol 1988;29:271– 281. 95. Huisman TA. Pediatric tumors of the spine. Cancer Imaging 2009;9(Spec No A):S45–S48. 96. Tomura N, Ito Y, Matsuoka H, et al. PET findings of intramedullary tumors of the spinal cord using [18 F] FDG and [11 C] methionine. AJNR Am J Neuroradiol 2013;34(6):1278–1283. 97. Browne TR, Adams RD, Roberson GH. Hemangioblastoma of the spinal cord. Review and report of five cases. Arch Neurol 1976;33:435–441. 98. Kendall B, Russell J. Hemangioblastomas of the spinal cord. Br J Radiol 1966;39:817–823. 99. Sato Y, Wazirim M, Smith W, et al. Hippel-Lindau disease: MR imaging. Radiology 1988;166:241–246. 100. Jarrell ST, Vortmeyer AO, Linehan WM, et al. Metastases to hemangioblastomas in von Hippel–Lindau disease. J Neurosurg 2006;105:256–63.

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101. Kaffenberger DA, Sah CP, Mortagh FR, et al. MR imaging of spinal cord hemangioblastoma. Associated with syringomyelia. J Comput Assist Tomogr 1988;12:495–498. 102. Costigan DA, Winkelman MD. Intramedullary spinal cord metastasis. A clinicopathological study of 13 cases. J Neurosurg 1985;62:227–233. 103. Edelson RN, Deck MDF, Posner JB. Intramedullary spinal cord metastases. Neurology 1972;22:1222–1231. 104. Mostardi PM, Diehn FE, Rykken JB, et al. Intramedullary spinal cord metastases: visibility on PET and correlation with MRI features. AJNR Am J Neuroradiol 2014;35(1):196–201. 105. Rykken JB, Diehn FE, Hunt CH, et al. Rim and flame signs: postgadolinium MRI findings specific for non-CNS intramedullary spinal cord metastases. AJNR Am J Neuroradiol 2013;34(4):908–915.

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22 MRI of Spinal Trauma Adam E. Flanders, Eric D. Schwartz, and Sidney E. Croul

INTRODUCTION Prior to the development of magnetic resonance imaging (MRI), the extent of associated soft tissue injury to the intervertebral discs, ligaments, and spinal cord was determined primarily by inference from known biomechanical principles rather than by direct imaging of the affected tissues (1,2). Consequently, many of the established therapies for spinal cord injuries (SCIs) are based on radiologic classifications of osseous injury to the spinal column. These traditional therapeutic interventions for SCI are directed primarily by radiographic findings such as re-establishment of normal anatomic alignment of the spinal canal and removal of bone fragments. Current management of SCI, however, has become more directed toward correction of the associated soft tissue and spinal cord damage (3–6), and MRI has become increasingly important in the diagnostic evaluation of spinal injuries. The greatest impact that MRI has made in the evaluation of SCI has been in assessment of the intracanalicular and paraspinal soft tissues (3,4,6–14). The integrity of the intervertebral discs and ligamentous complexes can be routinely evaluated with MRI. In addition, MRI permits direct visualization of the morphology of the injured cord parenchyma and the relationship of the surrounding structures to the spinal cord (2,15). No other imaging modality has been able to faithfully reproduce the internal architecture of the spinal cord and it is this particular utility of MRI that promises to have the greatest impact on the management of the SCI patient in the future. Although MRI is a powerful diagnostic tool, it is not a replacement for modalities that assess bony integrity (15). Radiography is utilized far less often in the initial assessment of spine trauma. Multidetector CT (MDCT) with sagittal and coronal reformatted images is the mainstay for assessment of osseous injury in adults. Radiography is still reserved for the pediatric population because of radiation dose considerations (8,9,15–17). MRI is the primary imaging option available to assess for residual soft tissue compression of the spinal cord (7,12,18–20) due to factors such as acute disc herniations and epidural hematomas. Identification of residual compression of the spinal cord has significant implications in regard to timing of subsequent surgery and the type of surgical approach that is required (7,9,19). MRI is also an essential diagnostic modality in cases of SCI without radiographic abnormality (SCIWORA) (14,16,19,21–25). An MRI examination in the acute period is warranted in any patient who has a persistent neurologic deficit after spinal trauma (12,14,16). The focus of this chapter is the application of MRI in the evaluation of injuries of the spinal axis and spinal cord. Demographics of Spinal Cord Injury SCI is a significant cause of disability in the United States. Although the number of individuals who sustain paralysis yearly is substantially less than the number of people who sustain moderate to severe traumatic brain injury (TBI) (11,000 SCI per year versus 70,000 to 90,000 TBI per year), the financial costs to society for SCI are significant. Since most patients survive the acute SCI, there are approximately 225,000 to 288,000 SCI patients with partial or complete paralysis currently being cared for in the United States. The total lifetime costs for medical treatment and rehabilitation range from $200,000 to $800,000 per individual. The lifetime direct costs may exceed $2.8 million, for a high tetraplegic patient inured at age 25 (26,27). Nearly 55% of all SCI occur in young adults between the ages of 16 and 30 years, although the most recent statistics suggest that the average SCI patient is much 1686

older than previously reported likely due to the larger proportions of SCIs from falls in the elderly population. The overall incidence of cervical spine injury from a multi-institutional survey of 615 US trauma centers was estimated to be 4.3%. The incidence of cervical spine injury without SCI was 3.0% and the incidence of cervical SCI without fracture was 0.7% (28). Most SCI victims are white males (81.7%). The etiologies of SCI are vehicular (37.4%), acts of violence (25.9%), falls (21.5%), and sports injuries (7.1%) (26). Since SCI primarily affects employed (60.5%) young adults, there is a tremendous financial loss to society in terms of overall lifetime productivity. Injuries to the spinal axis can be subdivided into spinal injuries (damage to the spinal axis without neurologic injury) and SCI (damage to the spinal cord with or without spinal axis abnormality). An accurate estimate of the total number of SCI is difficult to define because patients who expire in the field from a fatal SCI (i.e., high cervical cord) or from related injuries (e.g., cerebral trauma) are not included in the national statistics. Tetraplegia (quadriplegia) is defined as an injury to one of the eight cervical segments of the spinal cord with paralysis of all four limbs. Paraplegia usually results from injury to the thoracic, lumbar, or sacral segments of the spinal cord with dysfunction of both legs. A neurologically complete lesion is one in which there is no motor or sensory function three segments below the neurologic level of injury (NLI) and no sparing of sacral sensation. Of those spinal cord– injured persons who survive to reach a medical facility, the most frequent neurologic deficit is incomplete tetraplegia (29.5%), followed by complete paraplegia (27.9%), incomplete paraplegia (21.3%) and complete tetraplegia (18.5%) (26). Less than 1% of SCI patients recover completely during the initial hospitalization.

MRI TECHNIQUES Imaging Considerations The spinal cord–injured patient requires special consideration before MRI with regard to patient transfer, life support, monitoring of vital signs, fixation devices, choices of surface coils, and pulse sequences. The potential risks from transporting a medically and neurologically unstable patient must be carefully weighed against the potential benefits derived from the diagnostic information provided by MRI. There are known inherent risks associated with removing a patient from an intensive care environment, transporting them to the MRI suite and allowing them to remain recumbent in the MRI unit for a prolonged period of time (29,30). There is an increased risk of secondary brain injury from hypoxia, aspiration, and vascular events by removing an unstable patient from the ICU environment. Patients with cervical spine injuries are usually stabilized with a fiberglass or foam cervical collar or, in more severe injuries, a halo and halo vest are used (31). For thoracic and lumbar injuries, the patient may be transported on a rigid spine board, a body cast, or occasionally in traction. MRI-compatible halo vests are often composed of a graphite composite, titanium, aluminum, and plastic, and are devoid of stainless steel components (32,33). If the fixation pins used for femoral traction are ferrous, they usually do not interfere to any noticeable degree with the images of the spine, although tissue heating can occur at the contact points with skin. Patient motion (voluntary or involuntary) can also be detrimental to the quality of any MRI study. Even a patient with acute tetraplegia can seriously degrade a cervical MRI examination either by movement of the head and neck or from irregular ventilation. Sedation may be necessary to complete an examination. Choice of surface coil is determined by the location(s) of injury, access to the area of interest, and the types of coils available. The proximity of the surface coil to the area of interest is a key factor in determining image quality. Temporary removal of a cervical collar, for example, will permit the use of specially designed quadrature or anterior/posterior neck coils. Wherever possible, a dedicated spine phased-array coil system should be used to maximize coverage and optimize MRI signal. Integrated head and neck phased-array systems work well and will produce quality vascular imaging. When the neck is fixed in a halo vest (Fig. 22.1), the use of a phased-array coil system can be problematic as the distance between the coil surface is increased, which can diminish the returned signal strength. Instead, a pair of surface coils closely applied to the back of the neck can be used effectively. A multi-coil phased-array system can be accommodated in most thoracic and lumbar evaluations. MRI evaluation of the spine following penetrating trauma requires special consideration because there is a potential for local heating or motion of a retained fragment if it is ferromagnetic. While most firearm projectiles are nonferrous and will not move in the static magnetic field, a ferrous fragment in the spinal canal could theoretically migrate, dislodge, or produce thermal injury when exposed to the 1687

strong static magnetic field and radiofrequency energy, potentially exacerbating neurologic injury (34,35). Military grade munitions that are encased in steel, copper, or copper–nickel exhibit significant deflection force in a high-field MRI unit (35). Any MRI examination following penetrating trauma to the spine should be performed at the discretion of the radiologist and in consultation with the ordering physician and the patient. Review of CT of the area of interest is imperative in developing an understanding of the relationship of the fragments to the neural elements and assessing relative risk. Additional consideration should be given to the length of time that the fragment has been embedded in tissue as the potential risk of movement is diminished in mature scar tissue. If there are sufficient safety concerns, and assessment of the intracanalicular contents are warranted, then CT myelography should be considered as an alternate method.

FIGURE 22.1 Detailed view of a standard halo vest applied to a normal volunteer. The fiberglass vest is fixed a rigid frame made of a nonferrous graphite alloy composite. The frame connects to a ring which encircles the head. The head is transfixed to the ring through a series of four pins. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

Imaging Methods At a minimum, evaluation of the injured spine should be performed both in the axial and sagittal planes using a combination of pulse sequences. T1- and T2-weighted information are both necessary to completely assess the spinal axis and the spinal cord. Additional sequences are performed as needed, depending on the portion of the spine that is injured, the degree of injury, and patient tolerance. Conventional fast spin-echo (FSE) or turbo spin-echo (TSE) and gradient-echo (GE) pulse sequences are used most often. An inherent property of the FSE pulse sequences is that the images exhibit less magnetic susceptibility artifact as compared to conventional SE and GE images (36,37). Although this property may seem theoretically disadvantageous when searching for small areas of acute spinal cord hemorrhage, FSE images have been shown to have comparable sensitivity to conventional SE images in detection of intramedullary hemorrhage (38). The decrease in magnetic susceptibility with FSE may be advantageous when imaging postoperative spines with instrumentation that otherwise would be obscured by artifacts (Fig. 22.2) (37). Use of hybrid techniques such as GRASE (GRAdient Spin Echo), may provide improved visualization of intramedullary hemorrhage in SCI over FSE images; however, the increase in artifacts and noise may prohibit its routine use in this application (Fig. 22.3) (39). Manually increasing receiver bandwidth (RBW) decreases the read-out period, which has the added benefit of diminishing susceptibility effects. Modern MRI equipment has the capacity to rapidly image multiple regions of the spine simultaneously without repositioning the patient. With the availability of integrated head and spine phased-array surface coils and integrated MRI tables, the entire spine can be imaged without repositioning the patient. This “survey” method may be useful when multiple levels of the spinal axis need to be rapidly interrogated at one time (Fig. 22.4).

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FIGURE 22.2 Effect of fat suppression and bandwidth in reducing artifact from hardware. A: Sagittal FSE T2weighted, fat-suppressed image (2500/85Ef/4 NEX/ETL 8, RBW 32 kHz) shows significant distortion of the image and artifact over the spinal cord. B: Sagittal FSE T2-weighted image without fat suppression (2500/85Ef/4 NEX/ETL 8, RBW 64 kHz) shows a dramatic reduction of the artifact and improved visibility of the spinal cord parenchyma.

The prescribed spatial resolution depends on the inherent limitations of the MR scanner, the type of sequence used, and acquisition time limitations. T2-weighted information is obtained using a single FSE acquisition using a split-echo train, resulting in an intermediate and T2-weighted image. Alternatively, two separate FSE acquisitions can be used with different echo train lengths. Fat suppression must be employed on the long TR sequences to improve visualization of edema in the posterior ligamentous complexes (PLCs). Typically, a spectrally selective fat saturation pulse is applied that is tuned to the resonance frequency of lipid on a T2-weighted image. Alternatively, a short tau inversion recovery sequence (STIR) can be employed to produce effective suppression of lipid signal in the soft tissues, thereby improving the conspicuity of edema. Increased signal-to-noise and shorter acquisition times can be achieved by applying driven equilibrium (DE) pulses (40). Fat saturation techniques can have a deleterious effect on image quality when ferromagnetic hardware is present (Fig. 22.2). Parallel imaging or sensitivity-encoding (SENSE) methods can be advantageous in spinal imaging by reducing imaging time, reducing blurring in FSE/TSE sequences and can help reduce motion artifacts (41). The phase-encoding axis is oriented parallel to the spine so that phase ghosting is not propagated across the spinal canal. A form of gradient moment nulling (GMN) should also be employed in the cervical and thoracic regions to compensate for cerebrospinal fluid (CSF) flow artifacts. Cardiac gating is another option for correcting cerebrospinal flow artifacts on T2-weighted sequences. Anteriorly placed saturation pulses are helpful in reducing artifacts produced by swallowing, breathing, and cardiac motion. Respiratory compensation may be of benefit when imaging the thoracic and lumbar regions. Resolution can be maintained with reduced imaging times by implementing options that vary the number of phasing encoding steps and field of view.

FIGURE 22.3 GRASE (gradient spin echo) sagittal image of a cervical injury. Note the increased amount of background noise associated with this technique. (From Flanders AE. Magnetic resonance imaging of acute spinal

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trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

FIGURE 22.4 MRI survey image of the entire spine. Patient with metastatic disease who sustained a fall and presents with new lower extremity weakness. This technique combines separate image acquisitions from the cervical, thoracic, and lumbar regions in one display for easier review. The patient has pathologic fractures in both the thoracic and lumbar regions. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

Cross-sectional information on MRI is essential, especially when assessing the cervical and thoracic spinal cords. The choice of axial pulse sequence varies, depending on the part of the spine being evaluated, extent of injury, type of tissue contrast required, personal preferences, and time constraints. Usually, axial images that provide hyperintense CSF are preferred and are obtained using GE and/or FSE pulse sequences (42). To maximize detection of acute intramedullary hemorrhage, at least one GE sequence should be employed. High-resolution cross-sectional imaging of the spinal cord can be performed using FSE techniques in the study of the cervical and thoracic spines. As a supplement to the cervical examination, a survey of the extracranial vasculature is useful to detect posttraumatic occlusion or dissection of the carotid and vertebral arteries. This may be achieved with routine two-dimensional (2D) time-of-flight (TOF) magnetic resonance angiography (MRA), 3D TOF MRA, or a contrast-enhanced MRA (CEMRA) using ellipticocentric reordering of k-space. An axial cross-sectional evaluation of the neck using a T1-weighted “black-blood” technique (employing superior/inferior spatial and fat saturation) is helpful to identify subtle arterial dissections of the extracranial vasculature. Although there are reported cases in which gadolinium was useful in the evaluation of acute SCI, the justification for routine use is unsubstantiated (43–46). In humans, some degree of enhancement of the posttraumatic spinal cord lesion has been reported at 1 to 14 weeks after injury (45,46). The enhancement is postulated to represent breakdown of the blood–brain barrier in the acute phase and reparative granulation tissue late after injury (45,46). In our experience, contrast agents have no clinical utility in the routine MRI evaluation of acute spinal trauma.

CHARACTERIZATION OF SPINAL INJURY USING MRI Although the biomechanics and types of injuries to the spine vary by location, the observed soft tissue and osseous changes to the spinal axis and spinal cord on MRI are relatively similar. Any interpretation 1690

of an MRI examination performed for spinal injury should include a discussion of the integrity of the intervertebral discs, vertebral bodies, vertebral alignment, ligaments, and neural elements. Specifically, the types of changes that are observed with MRI in SCI can be grouped into osseous injuries, ligamentous and joint disruption, intervertebral disc injury, fluid collections, vascular injury, and SCI. The force of injury is often dissipated primarily at one level in the spine; therefore, injury to all of the tissues (e.g., bone, ligament, disc, and spinal cord) is usually anticipated at one to two isolated levels. Identification of injury to one tissue type should prompt the observer to scrutinize the same level for injuries to other tissues. Most of the diagnostic information in SCI is derived from the sagittal images. Axial images serve as a supplement (2). Sagittal T1-weighted images offer an excellent anatomic overview. Disc herniations, epidural fluid collections, subluxations, vertebral body fractures, cord swelling, and cord compression are also visualized (17). The fat-suppressed sagittal T2-weighted images are usually relied upon to depict most of the soft tissue abnormalities including spinal cord edema and hemorrhage, ligamentous injury, disc herniation, and epidural fluid collections (10). Axial and sagittal GE images aid in the identification of acute spinal cord hemorrhage, disc herniations, and fractures. Routine anatomic MRI has not been successful in reliably demonstrating traumatic nerve root avulsions; however, occasionally, posttraumatic root pouch cysts are identified. High-resolution T2-weighted cross-sectional images may reveal traumatized rootlets (Fig. 22.5). CT with intrathecal contrast remains the diagnostic method of choice for demonstrating the characteristic empty nerve root sheath and the periradicular cavities (47,48). High-resolution MRI using heavily T2-weighted DE techniques has been shown to be equivalent to CT myelography in detecting root avulsions of the brachial plexus in neonates (49).

FIGURE 22.5 Dilated nerve root sheath following root avulsion. (A,B): Sagittal T2-weighted images show prominent intraforaminal cerebrospinal fluid (CSF)-filled space without characteristic hypointensity of exiting nerve root. (C–E): Axial T2-weighted images confirm dilatation of exiting nerve root sheath filled by CSF.

Osseous Injury Currently, MRI does not offer any advantage over plain radiography and/or high-resolution MDCT in the evaluation of associated osseous injuries following spinal trauma (9,15,17,21). Moreover, even when MRI is available, it should only be performed after appropriate CT evaluation of the osseous injury. The traumatic osseous changes to the spinal axis on MRI are divided into subluxations, fracture deformities, and compressive injuries. Relative loss of alignment at a specific level of the spinal axis is readily depicted on a midsagittal MRI image. The sensitivity of MRI in detecting anterior subluxation is probably better than conventional radiography or CT because the morphology of the thecal sac is also demonstrated and because portions of the spine obscured on plain radiography (e.g., cervical–thoracic junction) are clearly identified on MRI (15). Nondisplaced fracture lines through the vertebral bodies and posterior elements are usually only poorly demonstrated on MRI. The fracture line is sometimes visible on GE images as a thin hyperintense band that traverses the vertebral body. Depending on the mode of injury, this band may be oriented vertically, horizontally, or obliquely (Figs. 22.6–22.15) (2,7,12,15). A fracture line that extends through the cortex may interrupt the continuity of the characteristic hypointense peripheral margin of cortical bone (2,12). It may be difficult to distinguish cortical bone fragments from ligament on MRI because both structures exhibit low signal intensity on all pulse sequences (50). Displaced fractures produce 1691

concomitant deformity of the involved vertebral body and, if directed posteriorly, compress on the thecal sac. The latter is readily apparent on sagittal images (2). Although identification of a vertebral body or posterior element fracture is not predictive of a neurologic deficit, burst fractures do have a high propensity for associated neurologic deficit (9,15).

FIGURE 22.6 Depiction of fractures with MRI and CT. A: Axial CT image shows a comminuted fracture of L3. An oblique fracture line (arrow) demarcates a fragment of retropulsed bone. Fractures extend out to the peripheral cortical margin (curved arrows). B: Axial FSE intermediate-weighted image at the same level as (A). The fracture line (arrow) appears similar to the CT image; however, the additional fracture lines and fragments are poorly delineated. C: Axial GE images 3DFT in another patient show a vertically oriented fracture line that extends through the midportion of a cervical vertebral body (white arrows). There is a tiny focus of residual hemorrhage within the right ventral aspect of the cord (black arrow). D: Axial CT image obtained through the same level as (C) also demonstrates the vertical fracture line (black arrow). Additional fractures of the lamina are present bilaterally (white arrows). This finding is difficult to appreciate on the MR images.

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FIGURE 22.7 Chance fracture of L2. Sagittal gradient-echo image shows depression of the superior endplate of the L2 vertebral body and a horizontal fracture line extending from the posterior cortex of L2 through the posterior elements (arrow).

FIGURE 22.8 Burst fracture of L1. A: Sagittal FSE T2-weighted image shows changes of a burst fracture involving the L1 vertebra body. There is loss of height anteriorly with displacement of a fracture fragment, which is contained by the intact ALL (curved arrow). There is retropulsion of the posterior-superior corner of the L1 body into the spinal canal (black arrow). The T12/L1 intervertebral disc (asterisk) is hyperintense relative to the other levels secondary to injury. Note that the height of the posterior aspect of the body is maintained suggesting column stability. Also note the absence of ligamentous injury. B: Axial FSE T2-weighted image at the level of the lower half of L1 shows the retropulsed bone (arrows) compressing the ventral theca and the roots of the cauda equina (curved arrow).

FIGURE 22.9 Burst fracture of L1. Sagittal FSE T2-weighted image shows a burst fracture of the L1 vertebral body with rotation of the posterior-superior corner of the vertebral body into the spinal canal. The PLL is stretched, but appears intact (short arrow). The marrow of the vertebral body is hyperintense relative to the other segments due to compressive injury. A focal region of cord edema is present in the conus medullaris (curved arrow). No other ligamentous injury is demonstrated.

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FIGURE 22.10 Cauda equina compression from L5 fracture. A: Sagittal FSE intermediate-weighted images. There is diminished height of the L5 vertebral body both anteriorly and posteriorly. Disc material from L4/L5 has herniated into the centrum of the L5 vertebral body with interruption of the superior endplate of L5 (curved arrow). A fracture fragment is rotated into the prevertebral space (white arrow). The posterior cortex is retropulsed into the anterior epidural space (black arrows). A small epidural hematoma is incidentally noted (asterisk). B: Axial FSE intermediateweighted at the L5 level shows the retropulsed bone fragments compressing the thecal sac. Disc material has herniated through the endplate (open arrow).

FIGURE 22.11 Burst fracture of T1 without spinal cord injury. A: Sagittal T1-weighted image shows collapse of the T1 vertebral body (arrow) and diminished signal intensity of the marrow elements. B: Sagittal T2-weighted FSE image shows the hyperintense vertebral marrow elements. Note that the posterior cortex encroaches upon the spinal canal; however, there is no damage to the spinal cord.

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FIGURE 22.12 Flexion teardrop fracture of C5. A: Sagittal T1-weighted image shows loss of height of the C5 vertebral body anteriorly (large arrow). The marrow signal of the compressed segment is hypointense. The posterior aspect of the vertebral body is retropulsed into the spinal canal (open arrow). There is associated elevation of the PLL (small arrows) and there is mild swelling of the spinal cord. B: Sagittal FSE T2-weighted image depicts the hyperintense vertically oriented fracture line that interrupts the inferior endplate (small arrows). A small amount of prevertebral edema is also present (curved arrow). There is edema in the spinal cord without a discrete focus of hemorrhage. (Hypointense focus in brainstem is artifactual.)

FIGURE 22.13 Type I Hangman’s fracture of C2. A: Midline sagittal reconstructed image shows avulsion of a cortical fragment dorsal to the C2 vertebral body. B: Axial CT image shows a bilateral fracture line extending through the isthmus of C2. C: Midline sagittal T2-weighted MR image shows some signal in the posterior ligamentous complex but the fracture fragment is not visible. D: Axial gradient-echo image at the same level as (B) shows the distracted fracture line through C2.

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FIGURE 22.14 Compressive injury of the L1 vertebral body marrow. A: Sagittal T1-weighted image shows loss of height of the L1 vertebral body secondary to a burst fracture. The signal intensity of the marrow in the upper half of the involved vertebral body is hypointense relative to the other vertebral bodies. B: Sagittal FSE T2-weighted image shows that the marrow elements in L1 revert to hyperintensity secondary to compressive injury. Note that there is minimal retropulsion of the posterior aspect of the vertebral body; however, there is no significant compression of the theca.

MRI is notoriously insensitive to all types of fractures involving the posterior elements (Fig. 22.6) (4,15,21,51–53). This decreased sensitivity is attributed to the smaller size, the complex geometry, and the lower proportion of medullary space of the posterior elements relative to the vertebral bodies. These characteristics are particularly true in the cervical spine (2). Comparison of axial CT and axial GE MRI images shows that MRI has low sensitivity and moderate specificity for posterior element fractures (9,52). Moreover, fractures of C1 and C2 are also extraordinarily difficult to demonstrate on MRI (Fig. 22.13). In an evaluation of 32 patients with cervical spine fractures, MRI was found to have a sensitivity of 36.7% in the detection of anterior column fractures and 11.5% sensitivity for posterior element fractures in comparison to CT (51). The improved sensitivity to anterior column injury was attributed partly to marrow edema, which served as an indicator of deformity. MRI is unique, however, in its ability to demonstrate compressive injury to the marrow elements even without evidence of fracture deformity or cortical failure. Compressive injury is manifested by hypointensity of the marrow space within the involved vertebral body on the short TR images and relative hyperintensity on the long TR images (Figs. 22.14 and 22.15) (2,7,9,11,54). These signal alterations presumably are the result of microfractures within the medullary bone and resultant hemorrhage. As these signal changes are transient, they can be used as a secondary indicator of an acute osseous injury. One special case of traumatic osseus injury of the posterior elements of the spine where MRI has value is in symptomatic spondylolysis, a stress fracture of the pars interarticularis. The lesion is due to repetitive overuse, rather than an acute injury. Almost all cases involve L5 with the majority of the remainder situated at L4. This entity represents an important cause of back pain in young patients, particularly in athletes engaged in repetitive activities like football, gymnastics, and weight lifting who have otherwise unexplained low back pain exacerbated by the weight-bearing activity. The diagnosis of symptomatic spondylolysis is often elusive to the clinician, and plain films and CT are typically normal. Since early spondylolysis is treated conservatively with rest and can progress to become associated with contralateral injury if not treated, it is important to diagnose this disorder as early as possible. Early stages of symptomatic spondylolysis are seen as high signal in the ipsilateral marrow in the region (55), with or without demonstration of actual microfractures (Fig. 22.16A,B). In one study of 200 consecutive young athletes with back pain and negative plain radiography, 97 (48%) showed findings of spondylolysis on MRI (56).

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FIGURE 22.15 Burst fracture of L1 with multilevel axial loading injuries. Sagittal FSE T2-weighted image with fat suppression shows loss of stature of the L1 vertebral body consistent with a burst-type fracture. There is rotation of a fracture fragment which compromises the spinal canal. Note the increased signal in the endplates of the adjacent vertebral bodies of T10–T12 and L2–L4 indicative of compressive marrow injury. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

Ligamentous and Joint Disruption MRI is the only imaging modality available that directly visualizes changes to the ligaments as a result of trauma. The ligamentous structures that are readily identified on routine sagittal MRI of the spine includes the anterior longitudinal ligament (ALL), posterior longitudinal ligament (PLL), ligamentum flavum (LF), and interspinous ligaments (ISP) (Fig. 22.17). They are relatively avascular structures composed primarily of strong fibroelastic tissue with very short T2 relaxation properties. Therefore, ligaments appear relatively hypointense to other structures on all MRI pulse sequences. When overstretched or ruptured, a gap in the ligament may be identified and the surrounding tissues may increase in signal intensity on T2-weighted or GE images because of an increase in free water content from extracellular fluid and/or adjacent hemorrhage (11,12,15). Because of the similarity in imaging characteristics, distinction between a ligament fragment and cortical bone fragment may prove difficult on MRI (15,50). The longitudinal ligaments are solitary, continuous strips of fibroelastic tissue that extend from the skull base to the sacrum (Fig. 22.17). They function to maintain vertebral body alignment and provide elasticity during flexion, extension, and rotation. Failure of either ligament at any spinal level is indicative of spinal instability (Figs. 22.18–22.31). On MRI, the ALL is a thin, continuous band of low signal intensity that lies ventral to the anterior cortical surface of the vertebral bodies (57–59). The ALL is a critical component which defines the anterior column in the thoracolumbar spine which includes the anterior one-half of the vertebral body and annulus fibrosis. Normally, the ALL may be indiscernible from the cortex or the outer annulus of the intervertebral disc; however, when elevated by fluid, disc, or bone, it may be more apparent (Figs. 22.19 and 22.21) (59). Portions of the ligament merge with Sharpey’s fibers at the vertebral endplate and with the outer annular fibers. The ALL may rupture as the result of hyperextension injury (Figs. 22.26–22.27) (16,57,60–62). This is seen on all pulse sequences as a focal discontinuity of the hypointense band that is adherent to the ventral aspect of the vertebral bodies (Figs. 22.23–22.25). This finding may be associated with an avulsion of the vertebral endplate (Figs. 22.21–22.23) or hemorrhage in the prevertebral musculature (16,57,60–62). The accumulation of hemorrhage and fluid in the prevertebral space is seen on T2-weighted or GE sequences as a crescentshaped mass of high signal intensity centered over the segment of injured ligament (Figs. 22.20, 22.22–22.24) (18,21,57).

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FIGURE 22.16 Symptomatic spondylolysis in young athlete. Fat-suppressed MRI in sagittal (A) and axial (B) planes shows high signal of marrow edema in right pars interarticularis. The irregular linear low signal microfractures can be difficult to distinguish from vascular markings (arrows). Also note minimal hyperintensity in contralateral pars, possibly due to bilateral stress fractures.

FIGURE 22.17 Diagrammatic representation of the ligamentous structures in the spine. (From Oatis CA. Kinesiology —The Mechanics and Pathomechanics of Human Movement. Baltimore, MD: Lippincott Williams & Wilkins; 2004, with permission.)

Unlike the ALL, the PLL is much more variable in width. The PLL is widest at the level of the intervertebral disc and thinner as it passes behind the vertebral bodies (58). Therefore, the PLL may normally appear discontinuous on sagittal MRI images (18). The PLL is represented on MRI as a thin, hypointense band that is interposed between the ventral dural sac and the posterior margin of the vertebral bodies and intervertebral discs (Fig. 22.17). The PLL is the principal ligament of the thoracolumbar middle column that includes the posterior one-half of the vertebral body and the annulus fibrosis. The PLL is best visualized on T2-weighted and intermediate-weighted sagittal images; however, the PLL is often impossible to resolve as a separate structure from the ventral dura or annulus on midsagittal images. The PLL is better delineated when elevated away from the posterior cortex by a herniated disc or posttraumatic fluid collection (Figs. 22.18–22.21, 22.23–22.25, and 22.28). As with the ALL, rupture of the PLL is identified as a focal region of discontinuity. Typically, rupture of the PLL occurs in hyperflexion- and hyperextension-type injuries.

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FIGURE 22.18 Fracture dislocation at T12–L1. Sagittal FSE T2-weighted images show the associated soft tissue components to this injury. The ALL is torn at the L1 level (white arrow). The free end of the ruptured LF is demonstrated (curved black arrow). The PLL is disrupted and a portion of the attached bone fragment that has rotated into the spinal canal (black arrow) is displacing the conus medullaris. A small region of edema is noted within the spinal cord (small black arrows). The interspinous and supraspinous ligaments are also disrupted (dotted white arrow). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188– 253, with permission.)

FIGURE 22.19 Fracture dislocation at T11–T12 with locked facets. A: Sagittal intermediate-weighted FSE image shows subluxation and angulation at T11–T12. There is a fracture deformity of the T12 vertebral body. The disc at T11/T12 is damaged with interruption of the annulus anteriorly (curved white arrow) and posteriorly (long black arrow). There is an anterior disc herniation that appears contained by the ALL (large white arrow). The LF is ruptured (black arrows). A hematoma is present in the ventral epidural space (asterisk) that extends cephalad from the disc injury. B: Parasagittal intermediate-weighted FSE image shows the right inferior facet of T11 dislocated anterior to the superior facet of T12 (curved arrow). The same finding was present on the left side. C: Axial intermediateweighted FSE image of T11 demonstrates the abnormal relationship of the facet joints. The inferior facet surfaces (curved arrows) are displaced anterior to the superior facet surfaces (arrows). Note the edema in the central gray matter of the spinal cord (long arrow). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

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FIGURE 22.20 Flexion–rotation injury at C4–C5. A: Sagittal FSE T2-weighted image. The body of C4 is subluxed relative to C5. A moderate-sized disc herniation (curved black arrow) has impacted on the swollen and edematous spinal cord. No blood products are identified in the spinal cord. Note the separation of the PLL from the midportion of the C4 body (long black arrow). The ventral dura margin is represented by a thin hypointense line (small black arrows). There is associated disruption of the ligamentum flavum (black arrow) and the interspinous ligaments (asterisk). Prevertebral edema is also present (white arrow). B: Right parasagittal image (same sequence as A). The right C4 inferior facet is jumped and locked in front of the C5 superior facet (arrow). C: Unilateral facet dislocation at C3–C4 in another patient. There is increased fluid within the joint capsule in the subluxed facet joint (white arrow). Note the incidental thrombosed right vertebral artery (dotted arrows).

FIGURE 22.21 Complete dislocation at T12–L1. (A): Sagittal intermediate-weighted FSE image. The body of T12 is dislocated relative to L1. The T12/L1 disc is avulsed and free edges of the annular fibers are demonstrated (white arrows). The PLL is discontinuous. The posterior ligamentous complex is disrupted (asterisk). The spinal cord is markedly distorted and compressed at the level of the dislocation (open arrow). Hematoma is present in the anterior epidural space. The ALL is stretched over the dislocated segments (curved black arrow). B: Axial T1-weighted image shows the avulsed disc (arrows) displaced anteriorly to the L1 vertebral body. The spinal cord (open arrow) is draped over the vertebral body. Note the absence of the posterior elements.

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FIGURE 22.22 Flexion tear-drop fracture of C5 with severe SCI. A: Lateral radiograph shows the typical tear-drop configuration of the C5 vertebral body (arrow) in which a large anterior bone fragment is disassociated from the vertebral body from combined axial loading and flexion. B: Sagittal FSE T2-weighted image shows a flexion tear-drop fracture of the C5 vertebral body with avulsion of a fragment ventrally (white arrow). There is prevertebral soft tissue swelling (dotted white arrow). The ligamentum flavum (LF) and posterior ligamentous complex is ruptured (small black arrow) and the posterior musculature is edematous (asterisk). An extensive intramedullary hemorrhage is present (dotted black arrows). C: Sagittal gradient-echo image shows the extensive hypointense intramedullary hemorrhage (dotted black arrows).

FIGURE 22.23 Fracture dislocation at C6 in a 29-year-old man. A: Sagittal T2-weighted image reveals a horizontal fracture line that extends through the C6 vertebral body (arrow). There is offset of the upper segment relative to the lower segment. Spinal cord edema is present, extending the length of three vertebral segments. There is a mound of prevertebral soft tissue swelling/hemorrhage (asterisk). B: Sagittal FSE T2-weighted image shows the details of the injury with better clarity than the SE image. There is disruption of the ALL (curved white arrow), the PLL (curved black arrow), and the LF (straight black arrow). Note that the borders defining the spinal cord edema are better defined than in A. C: Parasagittal FSE T2-weighted image shows distraction of the C6 and C7 facet joints on the right (curved arrow).

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FIGURE 22.24 Multi-column ligamentous disruptions and spinal instability. A: Sagittal reformatted image from multidetector CT study is limited by artifact. There are extensive degenerative changes noted but no gross evidence of malalignment. B: Sagittal T2-weighted image shows a previously unsuspected instability with anterior angulation deformity at C6–C7 and subluxation. The ALL (white arrow), LF (black arrow), and PLL (dotted arrow) are disrupted. There is widening of the interspinous distance. Note that none of these findings are evident on the CT image. C: Sagittal STIR (fat-suppressed inversion recovery sequence) shows the edema in the posterior paraspinal soft tissues (asterisk) which is not clearly depicted in the nonfat-suppressed sequence in (B). Note that the damaged intervertebral disc is hyperintense. A prevertebral hematomas is also noted (white arrow).

FIGURE 22.25 Multi-column ligamentous disruption secondary to a bilateral interfacetal dislocation (BID) with and without SCI. A: Sagittal T2-weighted MR image shows the marked anterior subluxation of C6 relative to C7. The C6– C7 intervertebral disc is macerated (asterisk) and a portion of it is herniated anteriorly likely intermixed with hemorrhage. A portion of the disc is herniated posteriorly (dashed white arrow). The anterior-superior corner of C7 is fragmented. The anterior longitudinal ligament (ALL) is distorted and stretched (white arrow) and is peeled off the anterior cortex. The posterior longitudinal ligament (PLL) is also stretched and pulled away from the posterior cortical margin (dotted white arrow). The ligamentum flavum (LF) is ruptured (black arrow). A sizable spinal cord injury is present spanning from C4 to C7 comprised primarily of swelling and edema (curved white arrow). B: Sagittal T2weighted MR image using fat suppression in another patient with a BID-type injury and complete ligamentous disruption and the anterior and posterior columns. Note that the spinal cord shows no intrinsic signal abnormality and this patient was neurologically intact. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

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FIGURE 22.26 Hyperextension strain injury at C3/C4. A: Sagittal FSE T2-weighted image shows anterior widening of the C3/C4 disc space and an associated prevertebral hematoma (curved arrow). There is buckling of the LF (arrow). A discrete area of spinal cord edema is also present. B: Axial GE axial images show deformity of the right posterolateral aspect of the thecal sac by the buckled LF. The spinal cord was compressed between the vertebral body anteriorly and the LF posteriorly.

FIGURE 22.27 Extension mechanism injury at C5/C6. A: Sagittal FSE T2-weighted image shows changes of multilevel degenerative cervical spondylosis and stenosis spanning C3–C6. There is acute widening of the anterior aspect of the C5–C6 disc space (curved arrow) and the disc material is hyperintense secondary to injury. Spinal cord edema is also present. B: Axial GE axial image obtained through the C5–C6 interspace shows the retropulsed spondylotic disc fragment (arrow) compressing the thecal sac. C: Sagittal T2-weighted image in a different patient shows extension type injury at two distinct levels (C4/C5 and C6/C7). Note the anterior widening of the interspaces with increased signal in the damaged discs (arrows). There is a large prevertebral hematoma (asterisk). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

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FIGURE 22.28 Hyperflexion mechanism injury at C3–C4 in a 15-year-old male following a wrestling injury. A: Sagittal T1-weighted image shows acute angulation of C3 on C4 with spinal cord compression. B: Sagittal T2-weighted FSE image shows a large herniated disc fragment (arrow) compressing the spinal cord with the free edge of the ruptured PLL adjacent to the disc fragment. The posterior elements are splayed apart and there is rupture of the interspinous ligaments and ligamentum flavum (asterisk). Spinal cord edema is present from C2 to C5. C: Parasagittal T2weighted FSE image shows a perched C3–C4 facet complex (arrow).

FIGURE 22.29 Hyperflexion injury associated with ligamentum flavum and posterior ligamentous complex rupture. A: Sagittal intermediate-weighted image shows discontinuity of the ligamentum flavum at the C6–C7 level (arrow). B: Sagittal T2-weighted image with fat suppression shows the discontinuity of the LF (arrow) and edema in the posterior paraspinal musculature (star). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

FIGURE 22.30 Isolated rupture of the posterior ligamentous complex (PLC) at the thoracolumbar junction. A: Sagittal MPR CT image of the thoracic spine shows a wedge deformity of the T12 vertebral body. There is widening of the interspinous distance at T11–T12. Note that the posterior cortex of T12 is intact indicating no failure of the middle column. B: Sagittal T2-weighted image of the thoracic spine with fat suppression shows marrow edema in the T12 segment as well as in the adjacent L1 body (white arrow). The ligamentum flavum (LF) is disrupted (curved black arrow) and there is extensive soft tissue injury in the posterior paraspinal soft tissues (gray arrows). C: Axial T2weighted image at the T12 level shows the high signal intensity in the posterior paraspinal soft tissue indicative of edema/hemorrhage (black asterisk) compared to the normal adjacent paraspinal muscles (white asterisk). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

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FIGURE 22.31 Dorsal epidural hematoma from ligamentum flavum rupture. Sagittal fast spin-echo (FSE) T2-weighted images. A large dorsal epidural hematoma is displacing the posterior margin of the dura (small black arrows). The hematoma is heterogeneous with both hypointense and hyperintense components. The hematoma likely originates at the site of rupture of the ligamentum flavum at the L2 level. The roots of the cauda equina are compressed against the vertebral body by the hematoma (white arrows). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

FIGURE 22.32 Unilateral interfacetal dislocation at C4–C5. A: Sagittal T2-weighted (2,000/90/ETL 8) FSE image with fat suppression shows anterior subluxation of C4 on C5 with disc disruption and anterior herniation of disc material (arrow). Note the edema in the posterior paraspinal musculature (asterisk) related to the rotational component of the injury. B: Right parasagittal intermediate-weighted image shows the abnormal orientation of the C4 inferior articular process located anterior and inferior to the C5 superior articular process (arrow). C: Gradient-echo axial image obtained through the C4–C5 disc space shows the abnormal morphology of the right facet joint (arrow) compared to the left.

The LF forms a continuous strip of fibroelastic tissue that bridges adjacent lamina (Fig. 22.17). Along with the ISP, they act as check ligaments to oppose hyperflexion and distraction of the posterior elements and maintain alignment. They are the principal ligaments of the posterior column which includes all of the posterior elements. Normally, the LFs are small structures (especially in the cervical and thoracic regions), which are oriented parallel to the adjacent lamina. Focal discontinuity of the LF can be identified on the parasagittal MR images (Figs. 22.29–22.31). The LF may enlarge either on a degenerative basis or physiologically by bulging into the spinal canal in hyperextension. LF rupture is often associated with fractures of the posterior elements. The injured LF can be easier to visualize when the damaged segment projects into the spinal canal and distorts the posterolateral aspect of the thecal sac. This finding is best visualized on parasagittal images (Figs. 22.18–22.20, 22.22–22.25, and 22.28– 22.31). Disruption of the ISP is best appreciated on the fat-suppressed midsagittal T2-weighted views. Fat suppression is essential for the detection of the typical high signal intensity in the tissues interposed between the widened spinous processes (Figs. 22.18, 22.20–22.30, and 22.32) (15). The supraspinous ligament (SSL) forms a long contiguous band connecting the tips of the adjacent spinous processes and also serves as a posterior tension band that resists hyperflexion (Fig. 22.17). The ruptured free edge of this structure may be visible within the edematous posterior paraspinal soft tissues (Fig. 22.18). 1705

The facet joint complexes are easily identified on sagittal and axial images, particularly in the cervical and lumbar regions where the structures are somewhat larger in size and the joint plane is oriented in the sagittal direction. In the thoracic spine, the facet joints are small in size and the joint is oriented in the coronal plane. The facet joint complex is a dynamic structure that permits limited compression and distraction of the posterior elements during extension and flexion while resisting rotation and translation. Although fractures that involve the facet surfaces are better detected with MDCT, subtle damage to the synovial capsule and cartilaginous surface of the joint is best appreciated with MRI. The facets are demonstrated on the far left and right parasagittal images of a well-centered sagittal sequence. The articular surface of the superior facet normally maintains close apposition to the inferior facet surface. Widening of this space is suggestive of a distraction injury (Fig. 22.23). The imaging criteria of altered facet alignment or subluxation is similar to the plain film appearance (Figs. 22.19, 22.20, 22.23, 22.29, 22.32, and 22.33). Increased fluid within the joint space is suggested by a well-demarcated hyperintense focus interposed between the articular surfaces on T2-weighted and GE images (Fig. 22.20). The increased fluid is contained within the joint space and joint capsule.

FIGURE 22.33 Interfacetal dislocation. Sagittal fast spin-echo (FSE) T2-weighted image. There is fracture deformity of the T7 vertebral body with loss of height anteriorly. The marrow signal of T7 is hyperintense secondary to compressive injury (asterisk). The right T6–T7 facet joint is disrupted (curved arrow).

Disc Injury The identification and classification of a traumatic disc injury are important factors in determining the timing of and type of surgical decompression and stabilization (63,64). Although posttraumatic disc herniation does not correlate with the degree of associated injuries or neurologic deficit, unrecognized disc herniation is a cause of neurologic deterioration after stabilization (9,63–65). Noncontrast CT is relatively insensitive to disc herniation as compared to MRI; however, the high-resolution and isotropic datasets produced with MDCT often routinely depicts disc herniations and the soft tissue contents of the spinal canal (9,12,52,63). Although degenerative disc herniations are probably more common in the lumbar spine, posttraumatic disc herniations are encountered more frequently in the cervical and thoracic regions (16,55,64). In the cervical region, disc herniations most commonly occur at the C4–C7 levels (9,66). The incidence of posttraumatic thoracic disc herniations are more common than previously estimated— they occur in up to 50% of thoracic injuries (64). Prior to the general use of MRI, cervical disc herniations were estimated to occur in only 3% to 9% of all cervical spine injuries. In addition, a large number of false-positive cervical disc herniations were reported using CT and myelography alone (64). With the routine use of MRI, the reported incidence of cervical disc herniation is reported as high as 54% (9,63,65,66). Cervical disc herniations are associated with 80% of bilateral facet dislocations, 60% of hyperextension injuries, 47% of central cord injuries, and all cases of anterior cord syndromes (63). Twenty-two percent of neurologically normal patients demonstrated disc herniations on MRI after trauma (66). Cervical disc herniation is reported to occur more frequently in flexion-distraction and flexion-compression type injuries (67). The existence of thecal sac compression by herniated disc material is a significant factor in determining whether a discectomy should be performed at the time of surgical stabilization (63,67). In addition, residual spinal cord compression from a posttraumatic disc 1706

herniation is associated with more severe neurologic injuries than disc herniation without cord compression (9,68,69). However, Dai et al. (63) refuted this by finding no significant relationship between neurologic deficit or neurologic recovery rate and severity of spinal cord compression by herniated disc material. Nevertheless, the authors concluded that surgical management is advised when residual spinal cord compression is demonstrated on MRI (63). Posttraumatic disc changes on MRI can be classified as either disc injury or disc herniation. Normally, the well-hydrated intervertebral disc is hypointense relative to bone marrow on T1-weighted images and intermediate in signal on T2-weighted FSE images. The nondegenerated disc is uniform and symmetric in height and the peripheral fibers of the annulus fibrosus merge imperceptibly with the longitudinal ligaments. Disc injury is implied whenever there is asymmetric narrowing or widening of an isolated disc space on sagittal images and focal hyperintensity of the disc material on T2-weighted images. The injured disc is often higher in signal intensity than the adjacent discs on T2-weighted images and the level of injury is usually contiguous with other damaged tissues (Figs. 22.20, 22.24, 22.27, and 22.32). The observed signal changes in the disc may be the result of tearing of the disc substance during hyperflexion, hyperextension, or subluxation (9,18,57). As the adult intervertebral disc is an avascular structure, the observed, potentially hemorrhagic MR signal changes of a damaged disc may, therefore, be, in part, due to damage to the adjacent endplates. The signal changes of the injured disc may be easier to identify in patients with hypointense discs from pre-existing degenerative disc disease (Fig. 22.27). An acute, posttraumatic disc herniation has a similar MRI appearance to nontraumatic disc herniation. The nucleus pulposus is forced under pressure to extrude into the peripheral annulus fibrosus and, in some instances, extend beyond the outer annulus into the anterior epidural space. The herniation may be broad-based or eccentric and may or may not be associated with a vertebral body fracture. On sagittal MRI images, the disc herniation is isointense and contiguous with the disc of origin (2,7,9,12,14,17,18). A small herniated disc fragment often appears as a focal area of expansion of the annulus beyond the border of the posterior cortical margin (Figs. 22.20, 22.28, 22.34, and 22.35). Occasionally, a small rent in the annulus may appear that allows passage of nuclear material into the epidural space. On axial images, the herniated disc produces focal distortion of the ventral theca (Fig. 22.34). Depending on the size and location of the disc herniation, the fragment may be demonstrated on multiple sagittal and axial images. The degree of compressive injury to the neural elements depends on the size of the herniated fragment, the width of the spinal canal at the level of injury, and the diameter of the spinal cord. For example, a small disc herniation in the thoracic region may cause more neural impingement than an identical fragment would cause in the lumbar or cervical regions (70). Identification of an acute disc herniation can be difficult in the setting of superimposed degenerative spondylotic changes (16). In such instances, multiple chronic spondylotic disc herniations associated with osteophytes may complicate the correct identification of an acute traumatic disc herniation (21). Imaging factors that may aid in the identification of an acute disc herniation with superimposed spondylosis include alteration in signal of the disc material at one level, asymmetric width of the intervertebral disc space, subluxation, and associated injuries at the same level (Fig. 22.27). In some circumstances, definitive identification may be impossible. Epidural Hematoma The incidence of asymptomatic posttraumatic spinal epidural hematomas is greater than was previously recognized (15). They have been reported to occur in up to 41% of spine injuries (15). Spinal epidural hematomas occur as the result of tearing of a portion of the epidural venous plexus with focal extravasation of blood into the anterior epidural space. Most epidural hematomas from closed trauma are found in association with other injuries, are relatively small in size, and are probably not clinically significant (18). Since the spinal dura is not firmly adherent to the vertebral canal, relatively large epidural hematomas may remain clinically silent because they extend over multiple levels and therefore they do not result in substantial compromise to the thecal sac and contents. The imaging characteristics of epidural hematomas are variable as they depend on the oxidative state of the hemorrhage and the effects of clot retraction (Figs. 22.10, 22.19, 22.31, 22.34, 22.36, 22.38, and 22.39) (55,71,72). In the acute phase, the epidural hematoma is isointense with spinal cord parenchyma on T1-weighted images and isointense with CSF on intermediate- and T2-weighted sequences (2). In some instances, an epidural hygroma forms which may be difficult to distinguish from the adjacent CSF in the subarachnoid space (Figs. 22.37 and 22.38). This distinction can often be made by the hypointense dura, which separates 1707

the two compartments (Figs. 22.34, 22.37, and 22.39). The reported incidence of posttraumatic epidural hematoma in patients with ankylosing spondylitis (AS) is greater than in the general population, ranging from 10% to 50% and occur more often in the posterior epidural space (Fig. 22.39) (73).

FIGURE 22.34 Traumatic disc herniation with epidural hematoma. A: Sagittal SE T1-weighted image shows interruption of the posterior annulus at the C6/7 level (white arrow). A mound of tissue projects behind and above the disc space (curved arrow) representing herniated material bounded by the elevated PLL. The associated epidural hematoma (small arrows) is minimally hyperintense. Also note the marked swelling of the spinal cord. B: Sagittal SE image shows that the epidural fluid collection is hyperintense. The margins around the herniated disc are better demonstrated (black arrow). Note the associated interruption of the ALL (white arrow). C: Axial 3DFT GE image in another patient shows a large extruded disc fragment (asterisk) that is compressing the right anterior margin of the thecal sac (arrows).

FIGURE 22.35 Large posttraumatic disc herniation with epidural hematoma. A: Sagittal CT MPR image shows a hyperdense soft tissue mound extending into the spinal canal and compromising the anterior epidural space (arrows). B: Sagittal intermediate-weighted MR image shows discontinuity of the posterior annulus at C4–C5 (black arrow) and an epidural tissue mound spanning the C4 and C5 vertebral bodies which compromises the spinal canal (white arrows). Note that disc material cannot be distinguished from hematoma. C: Off-midline sagittal T2-weighted MR image with fat suppression shows the herniated disc fragment that is not discernable on the other images. The remainder of the mound of tissue represents a combination of epidural hemorrhage and congested epidural venous plexus. Also note the complete disruption of the posterior paraspinal soft tissues (asterisk).

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FIGURE 22.36 Large epidural hematoma. A: Sagittal FSE intermediate-weighted image. There is a fracture of the T12 vertebral body with resultant kyphous deformity of the spine. The ALL is ruptured at the T12 level (white arrow). A large hyperintense fluid collection is present in the ventral epidural space that extends caudally to approximately the L3 level (asterisks). There is marked compression of the thecal sac (curved arrow). B: Axial T1-weighted image. The epidural hemorrhage is forcing the thecal sac dorsally and causing severe compression of the conus medullaris (arrows).

FIGURE 22.37 Large epidural collection following C2 fracture. A: Sagittal T1-weighted image shows a markedly widened ventral subarachnoid space. The spinal cord is displaced posteriorly (arrows). (B): Sagittal intermediateweighted image shows that the widened epidural space (asterisks) contains fluid that is somewhat hyperintense relative to CSF. The hypointense band (arrow) represents the ventral dura. (C): Sagittal T2-weighted image shows a large epidural fluid collection (asterisks) separate from normal CSF that is displacing the spinal cord dorsally (arrows). The collection is bounded by dura as the PLL appears intact. There is diffuse high signal intensity within the spinal cord parenchyma from edema. Note that the deformity of the odontoid process is very difficult to appreciate (curved white arrow). There is associated rupture of the interspinous ligaments between C1 and C2 (curved black arrow).

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FIGURE 22.38 Unusual dorsal thoracic epidural hematoma not associated with a fracture in a 32-year-old woman after a fall. A: Sagittal FSE T2-weighted image shows a dorsal hyperintense epidural fluid collection which spans multiple segments of the thoracic spine (arrows). B: Contrast-enhanced axial T1-weighted image shows the low– signal-intensity hematoma (asterisk) compressing the thecal sac.

FIGURE 22.39 Dorsal epidural hematoma in patient with ankylosing spondylitis. A: Oblique axial CT image through lower cervical spine shows a large biconvex hyperdense collection (asterisk) dorsal to the thecal sac. The theca is displaced anteriorly (arrows). B: Axial FSE MRI images confirm the presence of the epidural hematoma (asterisk) and the compression of the posterior dura (arrows). C: Sagittal FSE T2-weighted image shows the broad extent of the hemorrhage through the entire cervical region (arrows). The heterogeneous signal characteristics are secondary to heme in various stages of evolution. The accentuated configuration of the cervical spine is secondary to ankylosing spondylitis.

Vascular Injury The true incidence of associated posttraumatic dissection or thrombosis of the extracranial carotid and vertebral arteries following cervical spine injury is unknown because the vascular injury often remains clinically occult. Prior investigations have suggested that damage to the vertebral arteries can be demonstrated with angiography in up to 40% of patients following cervical subluxation/dislocation (74). Dissection of the vertebral artery is more frequent than carotid artery dissection following fracture/subluxation because a portion of the cervical vertebral artery is contained within the foramen transversarium. A fracture that extends through the foramen transversarium may compress the ipsilateral vertebral artery. Because the artery is fixed within the foramen, it may also be subject to severe stretching and torsional forces from cervical subluxation (Figs. 22.20C, and 22.40–22.42) (75,76). 1710

Early recognition of vertebral artery injury remains important because of its potential to produce significant neurologic comorbidity and permanent neurologic damage. Moreover, the secondary injury is potentially preventable with early institution of therapy (e.g., anticoagulation, embolization, or surgical ligation) (77). The incidence of isolated vertebral artery injury in the setting of cervical spine trauma is not well known because the patient is frequently asymptomatic at the time of injury (78). In a prospective study of 47 cervical spine trauma patients, Parbhoo et al. (78) reported that 26% (n = 12) of the patients showed vertebral artery damage on MRI/MRA; in 9 patients (19%), the vertebral artery was thrombosed. Most of the patients with vertebral artery injury (n = 10) had an associated unilateral facet dislocation (78). Willis et al. (79) prospectively selected 26 patients with bony injuries associated with vertebral artery injury and found vertebral artery thrombosis (VAT) in 9 patients (35%), normal VA in 14 patients (54%), and dissection in 3 patients (11%) by using angiography; SCI was present in half of the patients, and no neurologic sequelae were attributed to the arterial injuries.

FIGURE 22.40 Clinically occult vertebral artery thrombosis after unilateral facet dislocation (UID) at C5–C6 without spinal cord injury at C5–C6 without SCI. A: Sagittal T2-weighted fast spin-echo (FSE) image shows an injured disk at C5–C6 with increased signal intensity in the disk and probably avulsion of the anterior longitudinal ligament (dashed arrow). Prevertebral edema (arrowheads) and edema in the posterior paraspinal musculature (white arrows) are present. B: Nonvisualization of the right vertebral artery. MIP image (anterior view) from a 2D time-of-flight MRA acquisition shows absence of signal intensity in the expected course of the right vertebral artery (dotted line). C: Thrombus in the right foramen transversarium. Axial image from a 3D GRE acquisition shows an oval area of low signal intensity in the right foramen transversarium corresponding to thrombus in the right vertebral artery. Note the normal flow-related enhancement in the left foramen transversarium. D: Thrombus in the right vertebral artery. Axial FSE image obtained at a similar level to image in panel (C) shows a high–signal-intensity thrombus (arrow) in the right foramen transversarium indicative of a thrombosed vertebral artery. Note the normal flow void of the left vertebral artery. (From Torina PJ, Flanders AE, Carrino JA, et al. Incidence of vertebral artery thrombosis in cervical spine trauma: correlation with severity of spinal cord injury. AJNR Am Soc Neuroradiol 2005;26:2645–2651, with permission.)

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FIGURE 22.41 Crush injury from fork lift in a 49-year-old man. A: Sagittal fast spin-echo (FSE) T2-weighted image shows a massive hemorrhagic injury of the cervical spinal cord. The edema extends up to the level of the foramen magnum. A disc herniation is present at C4–C5 (white arrow) and there is offset of the cervical segments at that level. The ligamentum flavum is disrupted at the C4 level (black arrow). Note the sharp change in caliber of the spinal cord caudally (small black arrow). B: Axial FSE T2-weighted images at the C3–C4 level shows buckling of the lamina with encroachment on the posterior epidural space (open black arrow). The spinal cord is enlarged, deformed, and devoid of all normal internal anatomic features. Portions of the central gray matter are hypointense secondary to hemorrhage (long white arrows). Note the absence of normal flow void in the left vertebral artery (curved white arrow) and left internal carotid artery (open white arrow) suggestive of slow flow or occlusion (compare with normal right side). C: Axial computed tomographic image at the C4 level shows comminuted fractures of the lamina bilaterally with resultant narrowing of the spinal canal. D: Maximum intensity projection image from axial 2D time-of-flight MRA acquisition reveals normal flow-related enhancement of the right carotid artery and right vertebral artery with absence of the left carotid and vertebral arteries. E: Right posterior oblique view from arch arteriography confirms the traumatic occlusion of the left common carotid artery (open arrow) and left vertebral artery (curved arrow).

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FIGURE 22.42 Traumatic intimal injury of vertebral artery. A: AP radiograph from a left vertebral arteriogram shows irregularity of the lateral wall (arrows) of the contrast column secondary to distractive injury at C3–C4. (No associated fracture at this level.) B: Single projection from a 2D TOF MRA shows normal flow-related enhancement in all vessels. There is minimal irregularity of the left vertebral artery (arrow) but the intimal damage is not apparent. C: Axial 3DFT GE images in another patient with traumatic occlusion of the left vertebral artery. Hypointense acute clot is demonstrated within the lumen of the left vertebral artery (arrows). Compare with normal flow-related enhancement in the right vertebral artery (open arrows). Also note the massive hemorrhage in the spinal cord (curved arrow).

In another prospective MRI/MRA study, Friedman et al. (75) identified VAT in 9 (24%) of 37 consecutive cervical SCI patients. VAT was significantly more common in the motor-complete SCI patients than in the motor-incomplete patients. Using cerebral arteriography, Biffl et al. (80) found 47 vertebral artery injuries in 38 patients in a selected cohort derived from 7,205 consecutive patients (0.53%) admitted with blunt trauma to a single level I trauma center; 350 patients were selected for cerebral arteriography on the basis of mechanism of injury or the existence of acute cerebrovascular symptoms. The most frequent related injury associated with vertebral injury included spine fracture/dislocation (71%), followed by chest and extremity injury (45%). The actual frequency of VAT in the subgroup evaluated with angiography was 2.6%. These authors found no relationship between grade of vertebral artery injury, neurologic deficit, or neurologic outcome (80). Other investigators have shown a higher incidence of VAT on cerebral arteriography when selecting for patients with specific types of cervical injuries, such as facet joint dislocations (75%; unilateral or bilateral) and foramen transversarium fractures (88%) (3,6). The frequency of VAT was lower overall for similar studies that used MRA as the imaging technique: 33% for patients with foramen transversarium fractures and as high as 24% for multiple contiguous cervical spinal injuries (6,7,15). There is some disparity in the literature whether the severity of neurologic deficit has a relationship to the frequency of VAT. Giacobetti et al. (81) prospectively reviewed MRA examinations of 61 consecutive cervical spine injuries, finding VAT in 12 (19.7%). Twenty-eight of the 61 patients sustained some form of SCI. The frequency of VAT stratified by American Spinal Injury Association (ASIA) impairment scale included ASIA-A (n = 3), ASIA-B (n = 3), ASIA-D (n = 2), and ASIA-E (n = 4). This suggested that the severity of neurologic injury was not predictive of VAT. No permanent neurologic deficits related to the VAT were identified (81). Six of the patients were reimaged by MRA 12 to 26 months after injury. The vertebral arteries in five patients remained thrombosed on the subsequent MRA study (82). In the largest retrospective review that evaluated the association of VAT with severity of SCI, Torina et al. (83) assessed the vertebral arteries of 632 patients with nonpenetrating injuries using MRA/MRI. Eighty-three (13%) patients had VAT on the admission MRI/MRA. Fifty-nine percent (49/83) of VAT 1713

patients had an associated SCI. VAT was significantly more common in motor-complete patients (ASIA-A and ASIA-B, 20%) than in neurologically intact (ASIA-E, 11%) cervical spine–injured patients (p = .019). VAT incidence was not significantly different between motor-incomplete (ASIA-C and ASIA-D, 10%) and neurologically intact (ASIA-E, 11%) cervical spine–injured patients (p = .840). They concluded that the absence of neurologic symptoms from the SCI does not preclude VAT (Fig. 22.40). Therefore, MRA evaluation is warranted as part of the routine MRI evaluation of cervical injuries (83). The clinical significance of occult vertebral artery injury is not known; however, in some series the stroke rate has been as high as 54% for untreated vertebral artery injury (82). Biffl et al. (80) reported a posterior circulation stroke rate of 25% in his series of blunt vertebral artery injuries. It is noteworthy that no other published studies report a stroke rate of this magnitude. Both Miller and Biffl have advocated for prompt angiographic evaluation of selective patients at risk of vascular injury and aggressive management of vertebral artery injury (VAI) with anticoagulation; reporting significant protection from cerebral ischemia and improved neurologic outcomes (80,84). While their reported incidence of vertebral artery injury and secondary cerebral ischemia is substantial, other reports would suggest that the incidence is much lower and that secondary neurologic complications are unusual, particularly with VAT (83). There is empirical evidence that a 6-month course of anticoagulation offers some protective effect against thromboembolic events and cerebral ischemia from spontaneous carotid or vertebral dissection; however, no well-controlled studies have been performed to support routine use of anticoagulation in this setting (85). Since the proportion of patients with clinically symptomatic posttraumatic vascular injury is small, conventional angiography cannot be justified to evaluate all patients with cervical trauma for occult vascular injury. However, MRA or CT angiography (CTA) is an appropriate screening test to identify patients who may require subsequent catheter angiography. A 2D time-of-flight sequence used in conjunction with a walking superior saturation pulse used to suppress venous inflow is effective in screening the extracranial vasculature for occlusion. This technique is adequate to evaluate vascular occlusion or significant narrowing; however, resolution limits the effectiveness of detecting subtle intimal injuries associated with dissection (Fig. 22.42). In cases of vertebral artery occlusion, axial GE images reveal replacement of normal flow-related enhancement in the foramen transversarium by a hypointense clot (deoxyhemoglobin) (Figs. 22.40 and 22.42). In contrast, the acute clot appears hyperintense on routine T2-weighted cross-sectional images compared to the normal flow void in the normal artery (Figs. 22.41 and 22.42). The use of black-blood techniques is also advocated to improve detection of subintimal dissections without occlusion. This technique suppresses signal from flowing blood and the surrounding tissues through the use of multiple spatial and chemical saturation pulses which render flowing blood hypointense and subintimal clot as hyperintense (75,83). A comparison of test performance of MRI, MRA, and CTA in the diagnosis of carotid and vertebral artery dissection found relatively similar characteristics for MRI, MRA, and CTA (86). Biomechanics and Distribution of Injuries Most SCIs reported in any given year result in tetraparesis due to damage to the cervical spinal cord. The majority of victims of thoracic and lumbar spine trauma suffer no neurologic sequelae (70,87). The type of injuries that occur in the cervical, thoracic, and lumbar regions differs because of regional structural differences, biomechanical variations, and mechanisms of injury. Factors that may predispose to SCI include developmental or acquired spinal stenosis, degenerative spondylosis, and AS (57,62,73,88,89). The pathophysiology of spinal injury can be better understood in a biomechanical framework (90). The spine is made up of relatively rigid components (vertebral bodies and posterior elements) and flexible components (intervertebral discs and ligaments). All the spinal segments work in concert with the adjacent segments to allow for reasonable amounts of flexion, extension, and rotation. The response of any substance to stretching or compression by an external force is defined by its elastic modulus. The application of too great a force over a short period of time results in tissue stress and eventual failure. Bone and ligament have different failure characteristics (1). The dissipation of a force applied to the spine is well tolerated under the following circumstances: (a) the force is applied gradually over a prolonged period, and (b) the resultant motion of the spine by the force does not exceed the design specifications in terms of length of travel. If either of these rules is violated, then the elastic modulus of the tissues may be exceeded and tissue failure results. This phenomenon is well illustrated in the cervical region: the cervical spine supports a large free weight (the head) that allows for a full range of 1714

motion (flexion, extension, and rotation). During periods of rapid acceleration/deceleration, the head develops large amounts of kinetic energy that must be completely dissipated by the cervical spine. In this setting, a lower segment of the cervical spine may behave as a fulcrum against the relatively fixed thoracic spine, resulting in tissue failure. Tissue failure allows for focal dissipation of this kinetic energy; therefore, the osseous, ligamentous, and spinal cord damage tend to be in anatomic proximity (9,57,62). Classification systems have been developed to help simplify the description of spinal injuries as an aid in diagnosis, prognosis, and treatment (91,92). These systems are used to infer the amount of “invisible” soft tissue damage based on radiographic appearance. Some of these schema are based on mechanisms of injury, that is, hyperflexion, hyperextension, rotation, flexion–rotation, extension–rotation, axial loading, or lateral translation (90). A major limitation of this concept is that few injuries can be explained by “pure” mechanisms. Moreover, the biomechanics of the spine differ drastically by location and, therefore, the types of injuries produced by the same force vectors differ by location. A classification based on mechanism alone does not directly relate either to treatment or prognosis. Other classification schemes of spinal injury are based solely on the presence of stability or instability of an injury. Potential instability is an important determining factor in the use and type of surgical stabilization. Instability is defined as the loss of ability of the spine to maintain normal anatomic alignment under normal physiologic loads (70,92). The properties of spinal instability are based on the three-column model of thoracolumbar spine trauma suggested by Holdsworth and revised by Denis (91, 92). This model was devised so that inferences could be made about the status of soft tissue injury based solely on radiologic changes. In this model, the spine is represented by three columns: the anterior column, which is made up of the anterior one-half of the vertebral body, the anterior annulus fibrosus, and the ALL; the middle column, composed of the posterior half of the vertebral body and the PLL; and the posterior column, which contains the posterior neural arch, LF, facets, and ISP. Isolated disruption of the posterior column does not constitute instability; the structures of the middle column must also be involved to invoke instability in the thoracic and lumbar spines (91). This type of classification offers information that aids in the diagnosis and treatment of specific injuries, yet it is an oversimplification that is probably not valid biomechanically (70). Tears of the PLL, LF, ISL, and SSL, and facet joint disruption are potentially unstable (94). Some fractures that would be classified as stable can still harbor components that would render the injury unstable if not adequately treated (95). Furthermore, since MRI provides direct visualization of the integrity of the ligamentous complexes, MRI evaluation may supersede standard classification methods when MRI demonstrates unexpected soft tissue injuries.

FIGURE 22.43 Severe fracture from minor trauma in a 50-year-old with pre-existing diffuse idiopathic skeletal hyperostosis (DISH). A: Sagittal MPR CT image shows posttraumatic subluxation of the C3 segment on C4 with widening of the interspinous distance (arrow) and a large fragmented osteophyte anteriorly (dashed line). Note the extensive bony bridging elsewhere. B: Sagittal MPR CT image shows the associated unilateral interfacetal dislocation. C: Sagittal T2-weighted MR image shows extensive prevertebral edema (asterisk) as well as marrow edema within the C3 and C4 vertebral bodies. There has been damage to the posterior ligamentous complex as well (arrow). There is a small associated posterior epidural fluid collection. Note the absence of injury to the spinal cord. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

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Degenerative spondylosis alters the biomechanical properties of the spine by decreasing elasticity, thereby diminishing the ability of the tissues to uniformly dissipate applied force (Fig. 22.43) (62). The loss of spinal elasticity in AS is so severe that even minor trauma can result in a fracture-dislocation (89). In AS, lower cervical spine fractures predominate (75%) and hyperextension is the most frequent mechanism of injury. The loss of spinal elasticity associated with the disease augments fractures through both the anterior and posterior columns as well as the intervertebral disc space (Fig. 22.44) (89). As a result, spinal fractures in patients with AS are highly unstable and difficult to manage, with a high incidence of morbidity and secondary mortality, ranging from 35% to 50% (73,89). It is, therefore, essential to inspect both MRI and CT scanning with a particularly high index of suspicion in AS patients. Because of biomechanical differences, the pathophysiology of upper cervical spine injuries (C1–C2) (Figs. 22.13 and 22.45) differs from lower cervical spine injuries (C3–C7) (21,71). Upper cervical SCIs are more common in children than adults because the head size for children is proportionally larger than for adults (25). Furthermore, in adults, the probability of developing a permanent neurologic deficit is much higher in the lower cervical spine injuries. The classification system devised by Allen et al. (1) is the most widely used classification scheme for lower cervical injuries. Injuries are classified by major and minor injury force vectors and then are subclassified into degree of severity. The common classification groups are compressive flexion, vertical compression, distraction flexion, compressive extension, distraction extension, and lateral flexion (1). Most injuries to the cervical spine, however, are the result of hyperflexion mechanisms (79%) (96).

FIGURE 22.44 Classic extension type injury in ankylosing spondylitis. A: Midsagittal MPR CT image shows widening of the anterior aspect of the C5–C6 interspace (thick arrow). Note the bony ankylosis of the skull base to the upper cervical spine (thin arrow) and the ossification of the ligamentum flavum (dashed arrow). B: T2-weighted fatsuppressed sagittal MR image shows the disrupted intervertebral disc (arrow) and the extensive prevertebral edema (asterisk).

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FIGURE 22.45 Atlanto-occipital dislocation. A: Coronal CT reformatted image shows markedly increased distance between the superior articular process of C1 and the occipital condyles (arrows) without evidence of fracture. B: Midsagittal T2-weighted MR image with fat suppression shows distraction of the skull base and upper cervical spine with complete disruption of the ligamentous support structures between the apex of the dens and the foramen magnum (white arrow) with hematoma/fluid in the gap and prevertebral hematoma in the upper cervical spine (white asterisk). There is complete disruption of the posterior ligamentous complex with epidural hemorrhage interposed between the dura and the posterior ring of C1 (dashed black arrow). The posterior musculature is also edematous (black asterisk). C: Midsagittal T2-weighted MR image with fat suppression after surgery shows a massive prevertebral fluid collection from dural laceration that compromises the airway (asterisk). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

Although fractures of the thoracic spine are not unusual, they comprise only a small proportion of all fractures of the spinal column (16%) (70,97). The biomechanics of the upper thoracic spine (T1–T10) differ from the cervical spine as well as from the lower thoracic spine (T10–T12) and thoracolumbar junction. Most thoracic fractures occur at the thoracolumbar junction and remain neurologically intact (Fig. 22.46) (87). The thoracic cage offers a protective effect to the upper thoracic spine by adding stiffness and providing additional energy-absorbing capacity. The rib cage alters the moment of inertia of the spine and, therefore, imparts resistance to rotational forces. In addition, the facet joints have a coronal orientation in the upper thoracic spine that resists anterior translational forces. Considerable force is, therefore, necessary to fracture or dislocate the thoracic spine. It is estimated that these anatomic features increase the compression tolerance of the thoracic spine by a factor of four (70). These factors contribute to the lower overall incidence of fracture-dislocations in the upper thoracic spine compared to other areas (70). Since the thoracic spinal canal is relatively narrow in dimension, there is a high association of complete SCI (63%) with fractures of the upper thoracic spine (Fig. 22.47) (97). Most of these injuries occur via hyperflexion mechanisms (70,97). When there are associated bilateral fractures of the posterior elements with resultant auto-decompression of the spinal canal, the spinal cord sometimes escapes injury (70,97). In adults, SCIWORA is a well-recognized syndrome of the cervical spine that is thought to occur secondary to hyperextension dislocations or hyperextension sprain associated with cervical spondylosis (Fig. 22.48) (22,57,61,62,98). This type of mechanism is reproduced in rear-end motor vehicle collisions 1717

and direct anterior craniofacial trauma (57). In one report, 96% of patients over the age of 40 years with SCIWORA had severe cervical spondylosis (62). Common to this type of injury is momentary compression of the thecal sac between the edge of the dorsally displaced vertebral body or disc and the buckled LF (21,22,57,61,62). Minimal changes that may be appreciated on radiographs include prevertebral swelling, focal widening of the disc space anteriorly, or avulsion of a small portion of the vertebral endplate. MRI is of particular diagnostic value in this type of injury because it depicts abnormalities that are invisible on conventional radiographs, including separation of the intervertebral disc, rupture of the ALL and annulus, prevertebral hemorrhage, and parenchymal SCI (Figs. 22.26, 22.27, and 22.48) (21,58). Since SCIWORA was first described over 20 years ago, MRI has been central to improving our understanding the mechanisms of this syndrome, particularly in the pediatric population (24,98).

FIGURE 22.46 L1 burst fracture with failure of the middle column and compression of the thecal sac. A: Midsagittal T2-weighted MR image with fat suppression shows loss of height of the L1 vertebral body with disruption of the superior endplate. There is retropulsion of the posterior cortex into the anterior epidural space resulting in approximately 50% compromise of the spinal canal. Note that the conus medullaris (arrow) is above the level of injury. B: Axial proton density MR image through the L1 level shows epidural hemorrhage compressing the thecal sac (asterisk). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

FIGURE 22.47 T7 fracture dislocation from high-speed motor vehicle accident. A: Midsagittal CT MPR image shows severe comminution of the T7 vertebral body with multiple retropulsed fragments that obliterate the spinal canal and complete disruption of the posterior ligamentous complex (arrow) resulting in acute angulation. There is a noncontiguous fracture at C6 (dashed arrow). B: Sagittal T2-weighted MR image with fat suppression reveals the extent of soft tissue disruption which has occurred at this level. The retropulsed cortical fragments from T7 have obliterated the entire spinal canal (white arrows). The entire posterior ligamentous complex has been disrupted (black star). The thoracic spinal cord is distorted and edematous (white star). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

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FIGURE 22.48 Spinal cord injury without radiographic abnormality (SCIWORA) in a 48-year-old male who experienced hand weakness (central cord syndrome) following a motor vehicle accident. A: Midsagittal CT MPR image shows multilevel cervical spondylosis with pre-existing developmental stenosis. Note the absence of an obvious fracture or subluxation. B: Sagittal T2-weighted MR image with fat suppression shows the markedly stenotic spinal canal with effacement of the subarachnoid space. There is edema within the spinal cord at the C3–C4 level (arrow) and prevertebral edema (star) suggestive of an extension type injury. C: Axial T2-weighted MR image with fat suppression obtained at the C3–C4 level shows the compression of the spinal cord and intrinsic edema (arrow). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

Assessment of Spinal Instability The integrity of the spinal ligamentous complexes is paramount to the assessment of spinal instability. The occurrence of radiographically occult unstable cervical spine injuries, while rare, (estimated at 0.04 to 0.6% in some series) underscores the need for improved detection of soft tissue injuries (99). While MRI offers an unprecedented assessment of the ligamentous structures of the spine, MRI’s role in predicting mechanical instability remains in question. Clearly, a ligament does not need to be torn or disrupted in order to be mechanically incompetent. Any ligament that has been stretched or distorted beyond its normal elastic tolerance will no longer provide effective resistance to abnormal translation of adjacent vertebral segments even if it remains intact. Therefore, controlled physiologic testing of spinal mechanical stability has been the primary means of assessment of ligamentous incompetence and mechanical instability. Prior to the advent of MRI, the accepted method for testing spinal instability has been through the evaluation of lateral radiographs during controlled flexion and extension of the spine. Detection of abnormal translation or angulation between two adjacent vertebral segments (>3 mm or 11-degrees angulation) is considered an indication of mechanical instability, even in the absence of a fracture (93). When a patient has an altered level of consciousness, immobilization of the spine may be necessary until the patient alert enough to provide an adequate clinical examination. Alternatively, operatorcontrolled passive flexion and extension of the patient’s cervical spine is sometimes advocated in conjunction with radiography; however, this technique has important limitations including significant operator dependency, and diminished sensitivity to injury unless adequate motion is achieved. Many studies report an unacceptable false-positive and false-negative rates (100). In one study, 30% of the flexion–extension radiographs were evaluated as inadequate due to limited motion and a 12.5% falsenegative rate (101). Dynamic flexion radiography (DF) was completely normal for 276 patients who required cervical spine clearance as a result of TBI. Flexion–extension radiography did not offer any additional diagnostic value beyond that available with standard radiography and high-resolution CT (102). Moreover, the method is potentially dangerous to perform in the unconscious patient who may harbor an unstable injury (100–103). Since MRI offers a noninvasive method to visualize the spinal ligaments, it has been suggested that MRI can provide an objective assessment of ligament integrity (95,99,100–116). However, studies which rigorously assess the validity of MRI in this application are lacking (109). In a study which assessed the reliability of identifying intact ligaments on cervical MRIs in nontraumatic patients, Saifuddin et al. (59) found that complete ligaments were absent in a substantial proportion of normal subjects. Moreover, there were marked interobserver variation and identification varied by ligament type. The identification rate for a complete, intact ALL ranged from 74% to 79%; for an intact PLL, the range was 36% to 74%; and for the LF, the rate of identification range was poor at 63% to 65%. 1719

Moreover, the prevalence of normal discontinuous longitudinal ligaments was greater in patients with cervical spondylosis. The authors concluded that the ALL, PLL, and LF are not commonly visualized; therefore, discontinuity of the ligament alone cannot be used as a reliable measure of ligament integrity especially in the setting of superimposed spondylosis (59). A surprisingly high incidence of cervical soft tissue injuries was reported in a postmortem study of 10 cadaver spines who died from multisystem trauma. In this study, a comparison was made of cervical specimen radiographs, anatomic dissection, and MRI of the specimens. Twenty-eight distinct injuries were found in 8 of the 10 specimens; the majority of the injuries consisted of soft tissue processes including facet joint capsule lesions, ligament and disc injury, and SCI. Observers were only able to identify 11 of the 28 pathologic findings prospectively on MRI and 17 abnormalities were ultimately found retrospectively. The authors concluded that occult soft tissue lesions of the cervical spine are common in trauma victims and that MRI is limited in its ability to depict these injuries. An important limitation of this study was the absence of fat-suppressed T2-weighted MRI which may have diminished the detection of associated soft tissue injury. This study does suggest that, even in the best imaging conditions (i.e., motionless subject), the sensitivity of MRI in identifying traumatic soft tissue injuries may be limited (114). In order to define the role of MRI in the preoperative evaluation of the spinal ligaments, Lee et al. (112) prospectively evaluated 34 thoracolumbar fracture patients with fat-suppressed T2-weighted MRI and assessed the PLCs by palpation and direct inspection during surgery. The authors found that the accuracy of palpation for PLC injury was 53.6% and for plain radiography it was 66.7%. The performance of MRI was substantially better; the accuracy in the detection of injury to the SSL was 90.9%, the ISL—97.0% and for the LF, 87.9%. The authors concluded that a fat-suppressed T2-weighted sagittal sequence was highly sensitive, specific, and accurate in the detection of PLC injuries. A similar study by Haba et al. (108) determined the diagnostic accuracy of MRI in detecting injury to the SSL and ISL was 90.5% and 94.3%. T1-weighted images had a significantly great specificity than T2weighted images for detecting SSL injury. The kappa inter-rater values were 0.803 for PLC injury, 0.915 for ISL, and 0.69 for SSL injury. These authors concluded that MRI can reliably differentiate an inherently unstable three-column injury from a potentially stable two-column injury (108). Other studies have studied the reproducibility of soft tissue damage in identical types of injuries. In a retrospective review of 48 MRI studies performed on unilateral (UID) and bilateral (BID) cervical facet dislocations (without controls), Vaccaro et al. (115) found disruption to the PLC (68.2%), facet capsule, LF, PLL (56.5%), and ALL (65.2%) in a statistically significant number of patients with BID. Disruption of these structures was also found in UID patients with the exception of the PLL. Disruption of the ALL, PLL, and the left facet capsule were significantly more common in BID compared to UID. Intervertebral disc injury was associated with both UID and BID, but was more common in BID (115). A follow-up study by the same group of investigators which evaluated ligamentous integrity in 30 BID patients with MRI found a lower incidence of ligamentous disruption: ALL—26.7%; PLL—40%; PLC—96.7%. The authors noted that the PLL was rated as intact in the majority of these BID patients which contradicts accepted theory for the mechanism of this type of injury (105). The discrepancy in results between the two studies can be partially explained by dissimilar classification methods used for the two studies and the use of a separate category for mechanically compromised but intact ligaments (i.e., intact but elevated). The differences underscore the fact that ambiguities exist in classifying damage to the supporting spinal structures. While trauma centers typically employ MDCT as their main diagnostic tools in the evaluation of spinal injury, the indication for the use of MRI in the clearance of spinal injury (without neurologic injury) remains controversial. Several trauma centers have employed protocols which use MRI in conjunction with radiography and high-resolution CT. In one such study, 97 cervical injury patients were evaluated with MRI after CT. In 83 cases, the MRI study confirmed the findings of CT, yet did not offer any additional information. MRI reclassified fractures as degenerative changes in 12 cases and MRI identified a new injury that was not depicted on CT in only two instances. The overall negative predictive value of CT was 98%, positive predictive value was 78%, and the sensitivity and specificity were 94% and 91%, respectively. The findings suggested that the routine use of MRI as part of a standard trauma protocol is not warranted unless under specific circumstances such as patient obtundation or confounding physical/clinical findings (104). This conclusion was also supported by Hogan et al. (110) who assessed the added value of MRI in detecting occult cervical soft tissue injuries in 366 obtunded patients who also received high-resolution MDCT evaluation. The negative predictive value of MDCT was 98.9% for ligament injury and 100% for 1720

unstable cervical injury. Only 4 of the 366 patients with a negative MDCT study were subsequently found to have a ligament injury with MRI; none of these injuries were judged to be unstable. The authors concluded that a normal MDCT study alone will exclude unstable cervical injuries (110). Sliker et al. (113) reviewed the body of literature which addresses cervical spine stability in obtunded blunt trauma patients who were evaluated with MRI or dynamic fluoroscopy. The aggregate MR data from numerous studies yielded a frequency of ligamentous injury detected by MRI for the blunt trauma population at 22.7%; 80.8% of these injuries warranted treatment, with 5.6% requiring immobilization. For the subset of patients that were obtunded, MRI diagnosed ligament injuries at a lower frequency (19.5%), with 69.2% of these injuries requiring treatment, 12.8% needing surgery, and 2.5% receiving surgical stabilization. It is noteworthy that the MRI criteria for ligamentous injury and surgical indications were very inconsistent between studies. Several large trauma series have shown that MDCT alone offers excellent sensitivity for identifying spine instability. In a series of 2,854 cervical injuries, MDCT had a sensitivity of 99% and specificity of 100%. All obtunded patients with normal neurologic exams also had normal CTs and MRI examinations. The estimate for missing a cervical injury was estimated at 0.04%. The authors concluded that blunt trauma patients with normal motor examination and MDCT do not require any further examination to clear the cervical spine (117). In other trauma study, 115 cervical MRI exams were performed which uncovered 6 occult injuries: microfracture, ISL signal, cord signal abnormality, and epidural hematoma. None of these findings changed patients’ management, but as a result, six of the patients had complications from prolonged cervical collar use. The authors concluded that MRI may be unnecessary if CT is negative (118). A large comparative effectiveness meta-analysis study of 14,327 blunt cervical trauma patients derived from 17 studies confirmed that the sensitivity and specificity of MDCT to detecting unstable injuries in obtunded or intubated patients exceeded 99.9%. The negative likelihood ratio of unstable injury with a negative MDCT was less than 0.001. The authors predicted that a false-negative MDCT study would occur once every 14 years in a typical US Level I trauma center. During that same time period, up to 3,200 patients would sustain a complication from prolonged cervical collar use (119). The occipital–cervical and the atlantoaxial junctions contain a complex of multiple nonparallel ligaments that confer stability to this area. Imaging assessment for rotatory instability has also traditionally been accomplished with rotational dynamic radiography or fluoroscopy. Today, MRI is often relied upon to exclude ligamentous strain or disruption of this area, despite the relative paucity of data which validates MRI for this application (Figs. 22.49 and 22.50). Wilmink and Patijn (116) evaluated the alar ligaments at the atlantoaxial junction of patients with whiplash-associated disorders (WADs) using 0.5-T MRI. They were unable to identify a reliable set of imaging criteria which differentiated WAD patients from control subjects. Moreover, the level of agreement between observers in grading the ligaments was poor. Kaale et al. (111) applied an MRI grading system to the alar and transverse ligaments, as well as the tectorial and posterior atlanto-occipital membranes for 92 symptomatic WAD patients and 30 control subjects. The authors demonstrated a significant relationship between pain–disability scores and the grade of ligamentous damage; the highest association was found with alar ligament damage and the number of structures showing changes on MRI. One principal shortcoming of this study was the use of only a single observer to grade the ligaments; therefore, the validity and reproducibility of the grading system remain in question. Although MRI is significantly more costly than radiography or CT, judicious use of MRI in the appropriate circumstances can be cost-effective. At one pediatric center, incorporation of routine MRI into their pediatric spinal clearance protocol for obtunded patients resulted in a significant decrease in time-to-clearance (5.1 to 3.2 days), average stay in the intensive care unit (9.2 to 7.3 days), and an overall decrease in hospital stay. Taking these factors into account, they realized an average cost savings of $7,700 per patient by using MRI as an integral part of their spinal clearance protocol (106).

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FIGURE 22.49 Absence of expected ligamentous injury in a rotatory subluxation of C1–C2 in a 16-year-old who presented with the head fixed in rotation after trauma. A: Sagittal MPR-reformatted CT image shows abnormal configuration and orientation of the skull base and atlas (C1) relative to the axis (C2) (arrow). B: Surface-rendered CT-reformatted image of the C1–C2 articulation shows the rotational malalignment of the lateral mass of C1 and C2 (arrow). C: Sagittal T2-weighted MR image with fat suppression obtained at the midline shows the absence of any significant soft tissue damage including the transverse/alar ligaments (asterisk) and posterior ligamentous complex (arrow). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188– 253, with permission.)

FIGURE 22.50 Use of MRI to assess ligamentous instability; C1–C2 instability in an elderly female after a fall. A: Midsagittal MPR image of the cervical spine shows thinning of the anterior arch of C1 and dystrophic bone formation between the apex of the odontoid process and the anterior margin of the foramen magnum (white arrow) from a prior occult injury. There is abnormal increased distance between the odontoid process and the anterior arch of the atlas (asterisk). There is also anterior subluxation of the C3 vertebral body relative to C4 (black arrow). B: Sagittal T2weighted MR image with fat suppression shows fluid in the predental space (arrow) indicative of instability. Note that the subluxation at C3–C4 has reduced and there are no associated signal changes of ligamentous injury at this area. This represents a degenerative subluxation rather than an acute traumatic episode. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

While it is often assumed that MRI provides the most accurate assessment of spinal ligamentous instability, the current body of literature on this topic would suggest otherwise. The literature fails to use a consistent grading scheme and definition of ligamentous injury or disruption and most published studies lack validation of results. While true discontinuity or avulsion of a ligament is likely an indicator of ligamentous failure, the significance of the MR signal changes seen in intact ligaments or surrounding soft tissues remains unclear; differentiation between a simple strain from a mechanically incompetent but intact ligament is unproven. Moreover, the absence of a signal change in a ligament on MRI may not always be predictive of mechanical stability (Fig. 22.49). Finally, with minimal exception, there are no studies which gauge the ligament soft tissue changes with physical disability and loss in range of motion. All of these factors underscore the need for controlled prospective trials to prove the complementary value of MRI in assessing soft tissue injury in blunt spinal trauma. Even the recent Eastern Association for the Surgery of Trauma (EAST) practice management guidelines for identification of cervical spine injuries after trauma acknowledge that while MRI is more sensitive for the detection of 1722

soft tissue injuries than CT, it is not clear if all of the injuries identified with MRI are clinically significant and that the risk of significant injury with a negative MDCT approaches zero. No broad recommendation was offered with the caveat that MRI should be used at the discretion of the institution (118). This discordance in demonstrating MRI values with ligamentous injury is an opportunity to develop new MRI techniques that augment signal from the ligaments. One method that has received some interest is ultrashort TE imaging (UTE) which has the capability of extracting signal from structures that normally elicit little to no signal using conventional pulse sequences (107). Standard MR pulse sequences are typically capable of receiving signals from tissues that have T2 relaxation properties greater than 10 ms. However, the intrinsic T2 relaxation of ligaments is typically less than 1 ms and this is the reason why ligaments are low in signal on conventional MR images. The typical echo times of the UTE sequence are on the order of 0.08 ms and are therefore capable of capturing signal from less conspicuous structures (Fig. 22.51).

FIGURE 22.51 Ultrashort TE imaging of the transverse ligament of C1. Axial UTE image obtained at the level of C1 depicts the entire transverse ligament as a high signal intensity structure (arrows). The transverse ligament is usually difficult to identify using standard clinical MR sequences. (Image courtesy of Graham Bydder, Ph.D., of the University of California in San Diego). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

SPINAL CORD INJURY MRI Findings of SCI Probably MRIs’ greatest asset in imaging of spinal trauma is in the depiction of the injured spinal cord. The clarity with which MRI is able to depict the internal architecture of the spinal cord is unmatched by any other imaging modality. Moreover, the depiction of parenchymal SCI on MRI not only correlates well with the degree of neurologic deficit, but it also bears significant implications in regard to prognosis and potential for neurologic recovery (6,9,11,44,45,65,69,120–127). Although the spinal cord can be reliably visualized with conventional MRI, it is often difficult to distinguish spinal gray matter from white matter as readily as the brain. This is particularly true in the sagittal plane, in which the spinal cord is uniform in signal intensity on all pulse sequences. Spinal gray and white matter have very similar T1 and T2 relaxation characteristics, and therefore, the cord parenchyma appears relatively uniform in signal intensity (123,128–130). In vitro imaging of spinal cord specimens shows that the central gray matter is uniformly hyperintense relative to white matter on all pulse sequences. This is attributed to the higher spin density of gray matter (123,128–130) (Fig. 22.52). The gray–white matter interface is often best demonstrated in the cross section on long–TR SE and GE axial images. The tissue imaging characteristics are usually lost after SCI due to accumulation of edema and hemorrhage within the substance of the cord parenchyma. Despite these limitations, the basic MRI features of SCI that correlate with the pathologic changes of SCI are reliably demonstrated (Fig. 22.52) (131). The foundation for understanding MRI patterns of SCI was developed initially in animal models (3,6,44,71,132). It has been shown in a rat model of SCI that the areas of low and high signal intensities in the cord on T2-weighted images were confirmed histologically as foci of intramedullary hemorrhage and edema, respectively (3,71,129,133). Several investigators have been successful in quantifying the volume of injured parenchyma and the 1723

spatial/temporal evolution of the injury in experimental SCI (45,128,130,134,135). Decreased motor function was associated with lesions that had greater longitudinal and cross-sectional involvement of the spinal cord and evidence of central hemorrhage (44,128,130). In experimentally induced injuries, the typical MRI abnormalities were readily identifiable shortly after injury and were clearly manifest 1-day postinjury. The abnormal signal pattern reached maximum intensity within 3-day postinjury. Histologic preparations revealed the presence of hemorrhage, necrosis, and macrophages dispersed in the gray matter. The initial changes were attributed to the primary mechanical and vascular injury mechanism, whereas the prolonged growth in lesion size and intensity was related to the superimposed secondary or biochemical cascade which continued to expand the lesion for several days after the actual injury (135). MRI provides excellent definition of intramedullary hemorrhage and edema in animal models (3,43,71,128,134). The combination of MRI lesion length, cord caliber, and degree of preservation of white matter in MRI cross section has a significant relationship to functional status in animals and the pathologic findings at autopsy (128,130,136). The MRI appearance of experimentally induced SCI has been used to explain the variability in functional deficit among animals subjected to identical injuries (128). A significant shortcoming of MRI is its limited capability in demonstrating functionally preserved white matter tracts at the level of injury; this observation becomes significant in estimating preserved functional capacity (130,135,136). With the advent of diffusion techniques and tractography algorithms based upon diffusion parameters, MRI now has the capacity to assess the integrity of spinal white matter. Several MRI classification schemes of human SCI have been proposed by prior investigators (4,6,11). Kulkarni et al. (11) first described three basic patterns of acute SCI with MRI. Schaeffer et al. (8,65) described a four-tiered classification system. Common to these schemes are three imaging observations: spinal cord hemorrhage, spinal cord edema, and spinal cord swelling (4,6,9,11,12,17,65,124). Each of these characteristics can be further defined by their rostral–caudal location in the spinal cord and the length or span of parenchyma that is involved. The typical SCI lesion on MRI is spindle-shaped, containing an epicenter of hemorrhage surrounded by a halo of edema; the latter has a greater rostral– caudal extent than the central hemorrhage (Fig. 22.53). These MRI findings have a direct relationship to the degree of neurologic deficit. Spinal Cord Hemorrhage Posttraumatic spinal cord hemorrhage (i.e., hemorrhagic contusion) is defined as the presence of a discrete focus of hemorrhage within the substance of the spinal cord after an injury. The most common location is within the central gray matter of the spinal cord, and centered at the point of mechanical impact (Figs. 22.54–22.58) (3,8,9,11,44,137). Drawing from experimental and autopsy pathologic studies, the underlying lesion most often will be hemorrhagic necrosis of the spinal cord. True hematomyelia will be rarely encountered (44).

FIGURE 22.52 Cervical spinal cord specimen with hemorrhage in the posterior columns. A: Axial T1-weighted image at 1.5 T shows a large focus of hemorrhage (asterisk) that involves the posterior columns bilaterally, with greater involvement on the right. B: The same lesion imaged in a 7-T magnet shows far greater resolution of gray matter, white matter, and the hemorrhage in the posterior columns. (7-T image courtesy of E. Wirth, M.D., Ph.D., University of Florida School of Medicine.)

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FIGURE 22.53 Graphic representation of spinal cord injury. A central focus of hemorrhage (red oval) is identified at the epicenter of the injury with a longer segment of edema (yellow oval) which spans the cord for a variable length. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

In the acute phase following injury, deoxyhemoglobin is the most common species generated (3,8,9,12,44,71,138). Thus, the hemorrhagic component of the SCI on high–field-strength scanners is depicted as a discrete area of hypointensity on the T2-weighted and GE images (Figs. 22.55, 22.57, and 22.58) (4,6,7,8,9,11,16,65,137,138). This represents the imaging manifestations of hemorrhagic necrosis of the spinal cord (9,11,17,139). The oxidative process in which deoxyhemoglobin evolves to methemoglobin is prolonged in the injured spinal cord. Methemoglobin appears approximately 3 to 5 days after an initial hemorrhage in the brain; however, conversion to intracellular methemoglobin may be delayed for 8 days or more in the spinal cord following injury (Figs. 22.56 and 22.57) because degradation of deoxyhemoglobin is delayed due to local hypoxia/hypoperfusion of the injured segment (8,9,11,71). Early investigations in animal and human SCI suggested that identification of acute hemorrhage was unusual and that methemoglobin was the most prevalent species (8,9,11,44). The low overall incidence of detecting deoxyhemoglobin in these early reports was most likely due to the use of low–static-field strength magnets (6–9,44).

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FIGURE 22.54 Hyperacute hemorrhage in high cervical-cord trauma. A: Sagittal T2-weighted magnetic resonance (MR) on admission. B: Sagittal T2-weighted MR 2 days later. C: Axial gradient-echo images from cervicomedullary junction to midcervical spine. Initial MR (A) of cervical cord injury in football player showed small focus of hyperacute hemorrhage at C1–C2 (arrow) and very subtle high-intensity edema. Two days later (B), more obvious edema extending down to C4 and clear hemorrhage in deoxyhemoglobin state is seen, particularly on axial GRE (C), where hemorrhage is noted within central portion of spinal cord.

FIGURE 22.55 Hemorrhagic spinal cord injury. A: Sagittal SE T1-weighted image shows a flexion deformity centered at the C5–C6 interspace (white arrow). There are fractures that extend through the inferior endplate of C5 and superior endplate of C6. Disc material is retropulsed into the anterior epidural space (black arrow). B: Sagittal SE T2-weighted image shows that the compressed marrow space of C5 reverts to hyperintensity (open arrow). A large hypointense focus of spinal cord hemorrhage (deoxyhemoglobin) is present extending from C4 to T1 (white arrow). The upper margin of spinal cord edema is indistinct (black arrow). C: Sagittal FSE T2-weighted image shows the injury with improved clarity due to increased matrix size and improved signal. This image shows interruption of the inferior endplate at C5 (black arrow). The upper and lower boundaries of the spinal cord edema are very distinct (white arrows). Note that the spinal cord hemorrhage is not as hypointense as it is in the SE image because of

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decreased magnetic susceptibility effects. D: This sagittal section of the cervical spine and cord was taken from a patient who died 3 hours after trauma. The odontoid process is fractured and displaced posteriorly (arrow). The cord is transected just caudal to the fracture with obvious tissue distortion and fresh hemorrhage (asterisks). Additional blood can be seen tracking centrally for several centimeters rostral and caudal to the transection. (Material courtesy of R.O. Weller M.D., University of Southampton, UK, and Harvey Miller Publishers.)

FIGURE 22.56 Methemoglobin in a 9-day-old spinal cord injury. A: Sagittal SE T1-weighted image demonstrates a markedly swollen spinal cord that effaces the surrounding subarachnoid space. There is associated herniation of disc material at C5–C6. The large hyperintense focus within the spinal cord at the level of injury is methemoglobin. B: Cervical spinal cord from another patient who sustained a C6 lesion 1 week before demise. Dorsal view of the cord reveals a hematoma (arrow). C: Cross sections of the cord shown in B demonstrate extension of the contusion into the dorsal spinal white and gray. (D): Serial axial T2-weighted SE images (3,000/100/2 NEX) at 1.5 T of specimen in B and C show well-demarcated areas of hypointense hemorrhage involving the central gray matter (arrow) as well as the surrounding white matter (curved arrows).

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FIGURE 22.57 Evolution of intramedullary hemorrhage (18-year-old man). A: Sagittal T1-weighted image (500/11/2 NEX) shows fracture deformity of C5 (arrow) with loss of height anteriorly. Extensive spinal cord swelling is present

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with effacement of the subarachnoid space. Note the lack of cord signal abnormality. B: Sagittal T2-weighted image (2,000/80/2 NEX) shows a long segment of signal abnormality in the spinal cord. The hyperintensity that extends from C2 to T1 represents spinal cord edema (open arrows). The central focus of hypointensity centered at the C5 level is intramedullary hemorrhage (deoxyhemoglobin) (curved arrow). C: Sagittal FSE T2-weighted image (2,500/102Ef/4 NEX, ETL 8) also depicts the spinal cord signal abnormalities. Note that the intramedullary hemorrhage (asterisk) is not as hypointense as it is in (B). Acquisition time was half that of (B). D: Four 1.5-mm thick continuous axial images from a 3DFT GE sequence through the epicenter of the injury show discrete hypointense foci of hemorrhage within the central gray matter of the spinal cord. E: Sagittal T1-weighted image obtained 2 months after injury shows a welldefined area of cavitation within the still swollen spinal cord. The central portion of the cavity is now hyperintense (asterisk) from retained hemorrhagic breakdown products. The cavity is surrounded by a rind of myelomalacia/gliosis (arrow). F: Sagittal FSE T2-weighted image shows the persistent swelling of the spinal cord. The necrotic cavity and malacic tissue are all hyperintense. Several discrete foci of low signal intensity are noted within the cavity (arrow) from hemorrhagic residue. G: Sections of cervical spinal cord taken from a patient who died 6 days following a neurologically complete C6–C7 anterior dislocation that did not come to medical attention immediately. Note that the hemorrhage occupies the complete extent of gray and white matter over several centimeters of spinal cord. H: Micrograph of spinal cord from case illustrated in (G). Even in this histologic preparation, the hemorrhage has distorted the spinal anatomy almost beyond recognition. For orientation, note preserved anterior spinal artery (arrowhead) (H and E). I: Impregnation for axons (Bodian stain). The axonal profiles (arrows) have been destroyed by the mechanical force of the cervical dislocation. Axonal profiles that would normally stain as black dots in white matter are not seen. Hemorrhage stains green in this preparation.

FIGURE 22.58 Brown-Séquard syndrome. A: Sagittal T1-weighted image shows an obliquely oriented hypointense

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band that traverses the width of the spinal cord between C3 and C4 (arrow), which represents the path of a knife blade. There is a mild degree of cord swelling at this level. B: Axial GE 3DFT in another patient shows a discrete hypointense focus in the central gray matter of the spinal cord on the left side (arrow) representing deoxyhemoglobin. C: Serial axial T1-weighted images of a human spinal cord specimen at 1.5 T with a Brown-Séquard lesion. A focal area of hyperintensity is noted within the central gray matter on the left side secondary to hemorrhage (methemoglobin). D: Serial axial intermediate-weighted FSE images show abnormal morphology of the central gray matter on the left (asterisks). Tissue damage extends into the ventral white matter approximating the spinothalamic tracts (arrow). (Multiple magnetic susceptibility artifacts are present surrounding the specimen presumably from air bubbles in solution during preparation.) E: Gross specimen of (C) and (D). Note the asymmetrical hemorrhagic lesion involving the gray matter (arrow). F: Photomicrograph of a stained section taken from the case illustrated in (E). Note the area of tissue destruction in the left dorsal horn and dorsal columns (arrows). Although the lesion was hemorrhagic, the blood pigments fail to show with this method (Luxol fast blue).

Parenchymal hemorrhage develops rapidly in the spinal cord after injury. In experimentally induced SCI models, hemorrhage was found in 12.5% of the cross-sectional area of the lesion epicenter initially, increasing exponentially to approximately 25% of the epicenter cross section within hours of injury. The rate of change in volume of hemorrhage is initially 0.15% per minute, with a maximal rate of 45% per minute within 5 hours after injury (140). The MRI identification of hemorrhage in the spinal cord following trauma has significant clinical implications. It was originally thought that detection of intramedullary hemorrhage was predictive of a complete injury. However, the increased sensitivity and spatial resolution of current MRI techniques have shown that even small amounts of hemorrhage are identifiable in incomplete lesions. Boldin (141) reported in a series of 29 SCI patients that an injury featuring a central focus hemorrhage measuring less than 4 mm in length or less was more likely to have an incomplete neurologic deficit than patients with hemorrhages measuring greater than 4 mm in length. The anatomic location of the hemorrhage closely corresponds to the NLI and the presence of frank hemorrhage implies a poor potential for neurologic recovery (8,9,11,69,121,137,138). Spinal Cord Edema Spinal cord edema is defined on MRI as a focus of abnormal high signal intensity on T2-weighted images (16). This signal abnormality presumably reflects a focal accumulation of intracellular and interstitial fluid in response to injury (3,4,6–9,11,12,16,44,65,71). Edema is usually well defined on the midsagittal long-TR image (Figs. 22.12, 22.18, 22.20, 22.22, 22.23, and 22.25–22.28). Axial T2weighted images offer supplemental information in regard to involvement of structures in cross section. Edema involves a variable length of spinal cord above and below the level of injury, with discrete boundaries adjacent to uninvolved parenchyma. Spinal cord edema is invariably associated with some degree of spinal cord swelling; however, it can occur without MRI evidence of intramedullary hemorrhage. Simple edema within the spinal cord in the setting of trauma has been referred to as a contusion by some investigators or as a hemorrhagic contusion when blood products are identified on MRI (17,65,71,124,137). The length of spinal cord affected by edema is directly proportional to the degree of initial neurologic deficit (9,65). Posttraumatic spinal cord hemorrhage always coexists with spinal cord edema; however, the converse is not always true; edema alone may be observed on MRI following an injury. Cord edema alone connotes a more favorable prognosis than cord hemorrhage (11,96,121,124,137). Spinal Cord Swelling Spinal cord swelling is the most nondescriptive imaging finding associated with SCI. It is defined as a focal increase in caliber of the spinal cord centered at the level of an injury. By itself, swelling does not specifically describe any signal changes in the spinal cord. Spinal cord swelling is best demonstrated on the T1-weighted sagittal images (9,11,17,65); the parenchyma may be normal to slightly hypointense (9,65). The normal spinal cord is relatively uniform in caliber, although it increases slightly in diameter at the lower cervical and lower thoracic areas. This normal enlargement may be difficult to discern on MR images. The change in caliber of the injured spinal cord is usually maximal at the level of trauma and tapers gradually cranially and caudally from the epicenter of the injury (Figs. 22.20, 22.22, 22.26, 22.28, 22.41, 22.55, and 22.57). In some instances, the swelling abruptly begins at the level of impact and progresses cranially only. Spinal cord swelling may be difficult to appreciate at a level of acute compression or when superimposed spinal canal stenosis is present. In this instance, the surrounding subarachnoid space is completely effaced, obscuring the upper and lower borders of the swelling. 1730

Although identification of spinal cord swelling alone is an indicator of spinal cord dysfunction, it does not predict the extent of the parenchymal injury (9,68). Clinical Measures of Spinal Cord Injury The ASIA has devised standards for both neurologic and functional classification of spinal injuries (142). These have been adopted as the International Standards for Neurologic Classification of Spinal Cord Injury (ISNCSCI) by the International Spinal Cord Society (ISCOS). A standardized set of examination procedures allows the determination of sensory/motor deficits and a spinal level for the lesion. From these, a clinical spinal cord syndrome and an impairment scale are derived, including a measure of functional independence. The ASIA impairment scale is modified from Frankel (143,144) and is used to grade the patient’s overall degree of neurologic impairment due to the spinal lesion. Thus, complete (grade A) impairment connotes paralysis in the lower extremities and the absence of both sensation and motor function in the sacral segments S4–S5. Incomplete impairment (grades B–D) ranges from preserved sensation without motor function below the level of the lesion (grade B) to preserved sensation with motor function approximating normal below the level of the lesion (grade D). Normal sensory and motor function is graded E. Lesions of the spinal cord have been classically divided into five classic neuroanatomic syndromes: anterior cord, central cord, Brown-Séquard, conus medullaris, and cauda equina. Anterior cord syndrome most commonly results from occlusion of the anterior spinal artery (Fig. 22.59) (145–148). In the setting of trauma, processes that collapse a vertebral body with resultant canal compromise and compression of the cord may also result in this syndrome, probably on the basis of vascular insufficiency either from interruption of the arterial supply or from intrinsic changes to the vascular supply due to secondary injury. Patients experience profound loss of motor function and interruption of pain and temperature sensation below the level of lesion. There is relative preservation of vibration and position sense. Since the anterior two-thirds of the spinal cord is supplied by the anterior spinal artery, this syndrome correlates anatomically with damage to the corticospinal and lateral spinothalamic tracts with relative sparing of the posterior columns.

FIGURE 22.59 Anterior cord syndrome. The ventral aspect of the spinal cord shows infarction with necrosis (arrowheads). In this case, the most medial portions of the anterior horns bear the brunt of the injury with relative preservation of the remainder of the anterior circulation. Quite often, the area of damage spreads more laterally to involve the entire anterior horn and the white matter comprising spinothalamic and corticospinal tracts. (Luxol fast blue–periodic acid Schiff. Material courtesy of A. Hirano, M.D., Division of Neuropathology Montefiore Medical Center, Bronx, N.Y. and Igaku-Shoin Publishers.)

The central cord syndrome (149–151) is characterized by greater weakness in the arms than the legs, with sparing of sacral sensation. Patients with cervical spondylosis/stenosis are predisposed to central cord injuries (Figs. 22.27 and 22.48) (21). The proposed mechanism of injury suggests that the spinal cord is pinched between a dorsally displaced vertebral body and a buckled LF during hyperextension (152). Other authors describe central cord syndrome in association with disc herniations (63). The underlying pathology consists of contusion, hemorrhage, and/or necrosis of the central cervical gray matter. Since both the corticospinal and spinothalamic tracts in primates and probably in man are laminated such that the most rostral projections are most medial, central damage in the cervical cord would predict injury to the cervical laminations with sparing of the sacral laminations, resulting in the characteristic pattern of deficit. Recent work questions this traditional view. One study described 11 cases of acute central cord syndrome, 9 of which had MRI correlation and 3 of which had pathologic 1731

examination (3). In none of these cases was blood or blood products found by imaging or pathology. In all cases, the most severe changes occurred in the white matter and included demyelination with or without axonal loss. No necrotic lesions were reported in the central gray matter. Since these findings are at variance with what has been previously accepted, they challenge other investigators to attempt independent confirmation. The Brown-Séquard syndrome is due to a purely unilateral transverse lesion above midlumbar spinal cord levels. Probably the most common type of trauma associated with this syndrome is penetrating injury to the spinal cord (Figs. 22.58 and 22.60) (153,154). The resultant loss of proprioception and motor control ipsilateral to the lesion reflects damage to the corticospinal tract and posterior columns on the side of the lesion, whereas contralateral loss of sensitivity to pin and temperature is due to damage to the crossing spinothalamic tracts. Traumatic lesions of the lower spinal canal rarely affect the sacral spinal cord or conus medullaris exclusively, but they may also damage the surrounding cauda equina (155,156). Damage to the sacral spinal segments alone produces a pure conus medullaris syndrome resulting in an areflexic bladder, fecal incontinence, and saddle anesthesia (Fig. 22.61). Additional cauda equina injury may result in a variable degree of flaccid paralysis in the legs with accompanying multimodal sensory loss. Lesions that occur higher in the sacral cord may effectively isolate the distalmost cord and thus these injuries exhibit preservation of bowel, bladder, and genital reflexes with loss of motor function in the lower extremities. Injuries below the level of the sacral segments cause a pure cauda equina syndrome (Fig. 22.62). Damage to lumbosacral nerve roots results in flaccid paralysis of the bowel, bladder, and legs. All forms of sensory input are also affected. The cauda equina is said to be more resistant to trauma than the spinal cord and certainly shows a greater propensity for recovery. The fact that it is composed of peripheral nerve roots rather than central nervous system (CNS) tissue may account for its resistance to injury. Nerve roots are ensheathed by a substrate that includes fibrous tissue; this covering renders them more resistant to trauma than the spinal cord. The fact that peripheral axons are myelinated by Schwann cells rather than the oligodendrocytes found in the spinal white matter is a major factor that accounts for the unique ability of peripheral nerves to regenerate following trauma. Following injury to the cauda equina, Schwann cells provide a substrate for axonal elongation, thus setting the stage for restitution of the peripheral nerves and neurologic recovery.

FIGURE 22.60 Chronic Brown-Séquard injury from stab wound to neck 32 years prior. A: Sagittal T1-weighted MR image shows a well-defined, low signal intensity cleft which obliquely traverses the left half of the spinal cord (arrow). B: Lesion reverts to hyperintensity on this corresponding T2-weighted, fat-suppressed image. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

Atypical mechanisms of SCI produce different patterns of MRI including penetrating trauma (e.g., knife wounds or gun shot injuries) (Figs. 22.58, 22.60, and 22.63). While physiologic transection of the spinal cord is typical of severe blunt injury, complete mechanical transection (i.e., separation of the spinal cord into two or more pieces) is uncommon and is usually secondary to a high-velocity motor vehicle accidents which produce marked translocation at a segmental level (Fig. 22.64). Aside from the mechanical separation of the spinal cord fragments, the degree of injury to the preserved adjacent parenchyma is often less than observed with injuries associated with intact spinal cords. 1732

The functional independence measure or FIM (143,157,158) more fully defines the impact of SCI on the daily activities of the individual and serves as a benchmark against which to evaluate spontaneous or treatment-associated changes in overall function. By focusing on 18 items in 6 areas of function (selfcare, sphincter control, mobility, locomotion, communication, and social cognition), a seven-point scale is constructed ranging from complete independence (7) to total assistance (1) for each item. The total score summed across all items gives a more complete estimate of total disability. A variant of the FIM that is now in common use is the SCIM (spinal cord independence measure) and the WISCI or walking index for SCI. All of these instruments are designed to evaluate level of function by assessing capacity to perform real tasks rather than measuring strength alone.

FIGURE 22.61 A 33-year-old male presenting with a conus medullaris syndrome from a L1 burst fracture. A: Sagittal intermediate-weighted image shows loss of stature of the L1 vertebral body secondary to a burst fracture. There is failure of the middle column and buckling of the posterior cortex into the spinal canal (arrow). B: Sagittal T2 weighted, fat-suppressed image shows a subtle focus of signal abnormality in the distal thoracic spinal cord (arrow) representing subacute, posttraumatic edema. C: Axial T2-weighted, fat-suppressed image obtained at the L1 level shows the oblique fracture line (curved arrow). There is a subtle increased signal intensity originating from the central gray matter of the conus medullaris (paired white arrows) indicative of posttraumatic edema. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

FIGURE 22.62 Cauda equina syndrome from translocation at the L3 level resulting from a high-speed motor vehicle accident. A: Sagittal T2-weighted, fat-suppressed image shows complete disruption of the L3 vertebral body and adjacent interspaces (asterisk) with translocation of the L3 and L4 vertebral segments. There is complete loss of continuity of the spinal canal (double arrow). B: Axial T2-weighted, fat-suppressed image obtained at the L3–L4 level shows the markedly distracted left L4 superior articular process (s) and the inferior articular process of L3 (i). A large amount of hemorrhage fills the potential space. No recognizable components of the cauda equine are visible in the canal (arrow). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

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FIGURE 22.63 High cervical SCI secondary to gun-shot wound which has traversed the spinal canal. A: Lateral digital radiograph shows an intact bullet fragment lodged in the posterior cervical soft tissues whose trajectory has passed through the upper cervical canal. B: Sagittal T2-weighted MR image with fat suppression shows a linear focus of signal abnormality traversing the cervical spinal cord at the C3 level (arrow). C: Axial intermediate-weighted MR image obtained at the C3 level shows a markedly enlarged spinal cord with loss of internal features related to diffuse edema (arrow). D: Sagittal gradient-echo MR image reveals a focus of low signal intensity at the injured level (arrow) as a result of the paramagnetic effects of hemorrhage. Note the relative absence of artifact from the bullet fragment on all imaging sequences. Also recognize that the severity of the injury on MRI is disproportionately small in spite of the amount of direct trauma to the spinal cord. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

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FIGURE 22.64 Mechanical transection of the spinal cord. A: Sagittal T2-weighted MR image of the cervical spine shows a complete disassociation of the C6 and C7 segments with disruption of the intervertebral disc and elevation of the ALL (arrow). The bulbous segments of the separated spinal cord are identified showing minimal intrinsic edema (dotted arrows). The entire posterior ligamentous complex is disrupted as well (asterisk). B: Midcervical translocation. Sagittal CT MPR image in another patient shows complete separation of the C4 and C5 vertebral segments with complete obliteration of the spinal canal secondary to the degree of subluxation (dotted line). C: Sagittal T2-weighted MR image corresponding to (B) confirms the mechanical transection of the spinal cord by the corner of the dorsally displaced C5 fragment which obliterates the spinal canal (arrow). (D) Midthoracic translocation in another patient who was thrown from a motorcycle. Sagittal T2-weighted MR image with fat suppression shows the acute angulation and malalignment of the T7 and T8 segments with disruption of the all of the ligamentous complexes. The severed ends of the spinal cord are widened and edematous (arrows). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

Clinical Significance of the Spinal Cord MRI Findings Many clinical investigations have reported that the MRI patterns of SCI correlate with the neurologic deficit at presentation (8,9,11,65,69,72,124,137). Kulkarni et al. initially proposed three MRI injury patterns for SCI and correlated these with the five-part ASIA impairment scale and total motor scores. Intramedullary hemorrhage (type I pattern of injury) equated with a severe neurologic deficit and a poor prognosis. Cord edema alone (type II pattern of injury) was found in patients with mild to moderate initial neurologic deficits who subsequently showed neurologic improvement (8,9,11,72,124,137). Schaefer et al. (65) refined the MRI patterns of SCI by including the size of the injured segment. Cord edema that extended for more than the span of one vertebral segment was associated with a more severe initial deficit than smaller areas of edema. Cord hemorrhage was associated with the most severe neurologic abnormalities (65). Flanders et al. (9) demonstrated that spinal cord hemorrhage in the cervical region was a strong predictive finding for a complete neurologic injury. The location of the hemorrhage corresponded anatomically to the level of neurologic injury. Although the location of spinal cord edema related 1735

imprecisely to the neurologic level, the proportion of spinal cord affected by edema was directly related to the severity of initial neurologic injury. The presence of vertebral body fractures, disc herniation, and ligamentous injury was not predictive of the neurologic deficit; however, the presence of residual spinal cord compression by bone, disc, or fluid was predictive of a hemorrhagic spinal cord lesion located at the level of the compression. This relationship is a rationale for early decompressive surgery in acute SCI (7,9,67). The imaging changes observed in the spinal cord parenchyma with MRI show a close correlation with the initial neurologic deficit. Furthermore, substantial evidence suggests that these MRI changes offer prognostic information regarding neurologic recovery (8,11,19,45,69,96,121,124,126,127,137,138,159,160). Yamashita et al. (160,161) showed that poor recovery from SCI was associated with severe cord compression, cord swelling, and abnormal signal on T1-weighted and T2-weighted images. Moreover, patients with persistent signal changes in the spinal cord on follow-up MRI examinations demonstrated little or no clinical improvement whereas prognosis was improved for patients who demonstrated resolution of signal abnormalities (160,161). The authors categorized MRI SCI patterns into five types. Signal patterns that correlated with the best prognosis include normal spinal cord signal or hyperintensity on T2-weighted images (intramedullary edema). Hypo- or hyperintensity on T1-weighted images with hyperintense parenchyma on T2-weighted images is a poor prognostic indicator (45,69,124,126,160,161). In two very similar studies, Shimada et al. (45,126) showed that persistent signal changes in the spinal cord on serial MRI studies was associated with no significant clinical improvement whereas marked improvement in neurologic status was found in the subset of patients whose MR studies became normal. In an experimental model of SCI which included serial MRI studies, Ohta et al. (122) demonstrated results which validated similar results reported in clinical studies. Two types of paralysis were induced in rats using a weight-drop model (20 and 35 g, respectively) resulting in a transient and persistent motor paralysis. The animals were imaged and motor strength was tested 2 and 28 days after induction of the injury. The animals with the milder injury showed significant improvement in motor function after 28 days. Spinal cord edema was identified on the initial and final MRI studies which corresponded histologically to edema and reactive gliosis. The subset of animals with the severe injury featured a central focus of hemorrhage surrounded by edema on the T2-weighted images on the initial MRI study. Low signal was observed on the T1-weighted images on the final study suggesting cavitation. Histologically, this injury resulted in hemorrhages, cavitation, and reactive gliosis (122). This supported the observation that identification of hemorrhage on MRI after SCI is an indicator of poor recovery. Silberstein et al. (69) found that the presence of associated spinal fractures, subluxation, ligamentous injury, prevertebral swelling, and epidural hematoma was associated with a more severe clinical deficit at presentation and a poorer prognosis. All these associated imaging features suggested that residual spinal cord compression may be an important factor in determining poor neurologic recovery (69). Not all investigators have not found a relationship between residual spinal cord compression and initial neurologic deficit or neurologic recovery (63). Schaefer et al. (125) correlated the MRI appearance of the spinal cord on admission to the change in total motor index score (MIS) in 57 patients. Patients with hemorrhagic spinal cord lesions showed no statistical improvement in MIS at follow-up. The group of patients with small areas of edema (less than one vertebral segment in length) demonstrated the largest improvement in MIS (72% recovery), whereas larger areas of edema showed intermediate recovery of MIS (42%) (125). In a similar study, Marciello et al. (121) compared the presence or absence of intramedullary hemorrhage to change in individual motor scores for the upper and lower extremities in 24 subjects. For patients with spinal cord hemorrhage, only 16% of muscles in the upper extremities and 3% of muscles in the lower extremities improved to a useful grade (>3/5) at follow-up and only 7% improved one or more motor levels. For patients without MRI evidence of spinal cord hemorrhage, 73% of upper extremity and 74% of lower extremity muscles improved to useful grade, and 78% of subjects improved one or more motor levels (121). In a subsequent comprehensive study, Flanders et al. (120) assessed the prognostic capabilities of MRI in forecasting motor recovery in 104 cervical SCI patients. Individual manual muscle test scores were compiled for the upper and lower extremities both at the time of admission and 12 months after injury. A motor recovery rate for the upper and lower extremities was also determined. The injured spinal cord segment on MRI was measured using a unique method which quantified spinal cord hemorrhage and edema by length and location relative to known anatomic landmarks. Lesion length was directly proportional to neurologic impairment at the time of injury (p < .001). In addition, spinal cord 1736

hemorrhage was associated with the most severe injuries (p < .001). While improvement in motor function after 1 year was observed in all patients, subjects with spinal cord hemorrhage on MRI had lower initial motor scores and had less improvement than those without hemorrhage. Nonhemorrhagic MRI lesions were associated with significantly higher motor recovery rates in the lower and upper extremities and had a higher proportion of useful muscle function. Multiple regressions were used to determine the contribution of MRI in predicting the outcomes parameters of motor function independent of the initial clinical evaluation. Initial motor scores, the presence of hemorrhage, and the length of edema were independent predictors of final motor score and the proportion of muscles with useful function at 1 year. The addition of the MRI parameters to the initial clinical information improved the statistical power of the SCI model by 16% for the upper extremities and 34% for the lower extremities (120). In a similar study of 55 cervical SCI patients, Selden et al. (159) identified four MRI characteristics that were significant negative prognosticators of neurologic recovery as measured by the ASIA grades that were independent from the initial clinical examination: presence of spinal cord hemorrhage, length of spinal cord hemorrhage, length of spinal cord edema, and spinal cord compression. In a subsequent prognostic study, Flanders et al. (162) compared the MRI parameters of edema and hemorrhage to a standardized measurement of disability (FIM). Four distinct motor scales from the FIM assessment were determined at the time of admission to rehabilitation and subsequently at discharge from rehabilitation. The individual motor scales included tasks related to self-care, sphincter control, mobility, and locomotion. Patients without spinal cord hemorrhage on MRI had significant improvement in self-care and mobility scores compared to patients with hemorrhage. The upper limit of the lesion (edema) correlated with admission and discharge self-care, admission mobility, and locomotion scores. Edema length correlated negatively with all FIM scores at admission and discharge. Moreover, at the time of admission to rehabilitation, all patients were completely dependent on equipment or caregivers to perform the FIM tasks. At the time of discharge, only patients with nonhemorrhagic MRI lesions improved to a modified dependence category (162).

FIGURE 22.65 Transient ascension in neurologic level of injury (NLI) and therapeutic recovery correlated with MRI in a 68-year-old SCI patient. A: Sagittal T2-weighted MR image at the date of injury shows the upper boundary of spinal cord edema approximating the C5–C6 interspace (C5 NLI). B: Spontaneous ascent in NLI to the C3 level, three days after admission. Repeat T2-weighted MR image shows that the edema now extends cephalad to approximately the C3–C4 interspace and caudad to the T2–T3 interspace. Note the disc herniation at the C6–C7 level (dotted arrow). C: Marked reduction in lesion length after administration of high-dose methylprednisolone. Sagittal T2-weighted image obtained 10 days after steroid administration shows improvement in spinal cord lesion which now is improved from the initial study. Patient’s NLI also descended to C6 commensurate with the MRI findings. (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

Another clinical parameter which has bearing on neurologic function and potential for recovery is the NLI. The NLI is determined by assessing the motor power and sensory function for myotomes and dermatomes which are innervated by adjacent spinal cord segments. By definition, the most caudal intact myotome or sensory dermatome is used to determine the NLI. Due to the linear organizational structure of the spinal cord, the NLI by clinical examination determines (by inference) the location of 1737

the lesion in the spinal cord. Since abnormal spinal cord tissue on MRI correlates with physiologic dysfunction, the anatomic location of the MRI relates to the NLI; the higher the signal changes on MRI extends up the spinal cord, the higher the NLI (Fig. 22.65). Boghosian et al. (163) correlated the NLI with the anatomic location of the spinal cord lesions on the MRIs of 109 cervical spinal cord injured patients. The authors found a statistically significant correlation between the location of the upper margin of spinal cord edema and hemorrhage as well as the lesion epicenter. The upper boundary of hemorrhage showed a stronger correlation than either edema or lesion epicenter. The lesion length showed no statistical significance with NLI. Multiple regression showed that the combination of lesion epicenter and edema length were the best predictors of NLI. Therefore, MRI measures may be used as an objective measure of the NLI when determination by clinical examination is either inaccurate or unavailable. Recently, Boldin et al. (141) published a small prospective series of 29 SCI patients which compared an absolute measurement of the size of the injured segment on a postoperative MRI to the initial clinical examination and changes in long-term neurologic status. The authors also found that the presence of intramedullary hemorrhage had a higher association with a complete neurologic deficit and that patients with hemorrhages which measured greater than 4 mm in cranial–caudal length showed no clinical improvement at follow-up. Both the lengths of edema and hemorrhage were shown to be predictive variables for complete injuries. Patients with hemorrhages measuring less than 4 mm had incomplete injuries upon admission and showed clinical improvement at follow-up. While their patient cohort was small and the authors were unable to control for time to clinical follow-up or time to imaging, their data suggest that there may be an absolute threshold for lesion size that predicts neurologic recovery (141). In the only major study which minimizes the value of MRI in predicting neurologic recovery after SCI, Shepard and Bracken (164) compared the results of MRI studies in 191 cervical SCI patients from multiple institutions to motor and sensory evaluations obtained at admission and 6 weeks after injury. The authors reported no statistical difference in the presence of contusions or edema between complete and incomplete injuries. MRI studies that featured hemorrhage or contusion were more likely to be associated with lower initial motor, pin, and touch scores. Motor function recovery parameters were less in patients showing hemorrhage, contusion, and edema on MRI; however, the differences were not statistically significant. After controlling for the results of the initial clinical assessment, the authors found no added value of the MRI findings (cord hemorrhage, contusion, and edema) in predicting neurologic recovery (164). The validity of this ambitious study is questionable, especially in consideration of the number of other investigations that contradict these results. While data from a large cohort of patients were collected for this study, there was no actual central review of any of the MRI examinations. The imaging protocol, scanner field strength, and overall image quality were not controlled for. Moreover, there was no central review of the images. Therefore, the definitions or criteria of contusion, edema, and hemorrhage were never established. Although there is an apparent relationship between spinal cord compression and neurologic injury, the methods for characterizing spinal cord compression, reduction in canal diameter following injury, and their relationship to neurologic deficit are inconsistent. Rao and Fehlings (165) provided a critical, evidence-based analysis of existing radiologic literature which correlated the degree of posttraumatic spinal cord compression to neurologic deficit. The studies that were evaluated contained both quantitative and qualitative assessments of spinal canal and spinal cord dimensions. Pre-existing midsagittal canal stenosis (developmental or congenital stenosis) was generally associated with more severe neurologic deficit following injury, notably when the midsagittal diameter of the spinal canal was 10 mm or less. There was a direct relationship between the severity of congenital stenosis (as defined by the Torg ratio) and the degree of neurologic function after injury in at least one study. The anteroposterior diameter of the spinal canal was significantly smaller in patients with complete injuries (10.5 mm) and in incomplete injuries (13.1 mm) compared to canal diameters in patients with no deficits (165). The sensitivity and specificity of canal diameter measurements to neurologic symptoms was high. In another study, Hayashi et al. (19) found that 30% of patients with severe spinal cord compression (defined as a 2/3 reduction in spinal cord diameter) had a complete motor deficit at the time of injury compared to 20% of patients with mild spinal cord compression (defined as less than 1/3 reduction in spinal cord diameter). More importantly, 90% of patients with mild spinal cord compression improved by one or more ASIA grades compared to 30% for patients with severe spinal cord compression. Fehlings et al. (165) developed a standardized method for measuring midsagittal spinal canal 1738

compromise and spinal cord compression that is applicable to both CT and MRI. The authors found excellent agreement with CT and T1-weighted MRI images in determining canal compromise following injury. T2-weighted sagittal MR images provided the most reliable assessment of spinal cord compression. CT alone was a relatively poor predictor of spinal cord compression (98% specificity and 72% sensitivity). Overestimation of canal compromise occurred with MRI; however, agreement between CT and MRI in assessing canal narrowing in patients with pre-existent spondylosis was excellent. Spinal canal compromise on CT by 25% or more was 100% specific for spinal cord compression on MRI. The authors also identified a statistically significant difference in neurologic deficit for patients with and without spinal cord compression or spinal canal compromise. Effects of Methylprednisolone on the MRI Findings of SCI The only sanctioned medical therapy for SCI has been the administration of high-dose methylprednisolone (MPS) given within an 8-hour window after injury (166–168). While the efficacy of MPS for SCI remains controversial, the drug is currently used empirically at many trauma centers in the United States for this purpose. Moreover, while there is some experimental evidence that MPS can decrease the development intraparenchymal hemorrhage in a rodent model, there has been no direct evidence that a similar effect occurs in humans (169). Leypold et al. (170) recently compared the MRI findings of two cohorts of patients with ASIA type A injuries (motor and sensory complete); one group had received MPS within the therapeutic window prior to imaging and the other group did not receive steroids. The two groups were compared for the presence or absence of hemorrhage, the size of the hemorrhage, and the size of the surrounding edema. Multiple regression was used to control for the effects of patient age, level of injury, and time period between injury and MRI as all three of these variables were found to have significant effects on edema length (Fig. 22.66). After correcting for these factors, it was determined that MPS administration did not have a significant effect on the mean length of spinal cord edema between treated and untreated subjects. However, there was a statistically significant difference in hemorrhage length between the treated and untreated groups and a larger proportion of treated patients had no evidence of hemorrhage in their lesions compared to the untreated group (not statistically significant). MPS could reduce the length of hemorrhage (on average) the equivalent of one-half of a vertebral body height.

FIGURE 22.66 Difference in lesion morphology for two SCI patients with similar neurologic deficit (C5 ASIA-A) A: T2 weighted sagittal MR image in a 20-year-old male not treated with MPS. B: T2-weighted sagittal MR image in a 29year-old, MPS-treated SCI patient. Note that the overall lesion length and hemorrhage length is less in the MPS treated patient (dotted lines). (From Flanders AE. Magnetic resonance imaging of acute spinal trauma. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:188–253, with permission.)

Several additional observations were derived from this dataset: Age was noted to have a significant effect on presence/absence of intramedullary hemorrhage and on edema length, that is, the findings were more prevalent in younger patients. Alternatively, age had minimal effects on hemorrhage length. In addition, there was a significant dependency between edema length and the time elapsed from injury (the injury to imaging time interval) such that a lesion would enlarge the equivalent of one-third of a vertebral body height for every 8 hours after injury. This suggests that the MR lesion created in SCI is dynamic. This may be due in part to the evolution of the secondary phase of injury (171). 1739

Limitations of Conventional MRI in the Evaluation of Spinal Cord Injury Conventional MRI pulse sequences can indicate the presence of hemorrhage, length of contusioninduced edema, level of injury, spinal cord swelling, and cord compression. This information has proven valuable in early diagnosis and treatment planning. These techniques are limited; however, in that their contrast primarily reflects changes in water content or presence of hemorrhage. This limitation is demonstrated in experimental research that attempts to correlate edema and hemorrhage with neurologic and histologic severity. One study using a rat spinal cord contusion model showed that the degree of neurologic recovery following contusion injury did not correlate either with volumetric lesion size as evaluated by T2 weighted abnormal signal (edema) or T2 hypointensity (hemorrhage) (134). Another study with the rat contusion model demonstrated that the water content and average T2 may not change significantly in areas of acute injury (172); therefore, conventional MRI techniques may underestimate the degree of injury. Additionally, some areas of hemorrhage may be too small to be visible on T2* images. While MRI is the best imaging modality for the evaluation of spinal cord parenchyma at this time, conventional MR techniques do not appear to differentiate edema from axonal injury and are therefore limited to providing anatomic information about the spinal cord parenchyma, including the degree of spinal cord compression, amount of hemorrhage, and injury localization. The water content or hemorrhagic content does not necessarily reflect the status of the white matter tracts, and consequently, the functional status of the spinal cord is not well assessed. Follow-up imaging of chronic SCI has also been limited to assessment of spinal cord morphology, and the development of posttraumatic syringomyelia and myelomalacia (173–178). Other methodologies are needed for identifying appropriate patient populations for treatment delivery; optimal therapy may need to be delivered in the first few hours or days, yet neurologic examination may require a week’s delay before providing an accurate prognosis (179,180). The remainder of the chapter will review the MRI techniques that have the most potential for impacting the diagnosis and treatment of SCI, with the greatest emphasis on diffusion-weighted and diffusion tensor MRI (DWI and DTI). Other promising techniques will be introduced as well, including MR spectroscopy (MRS), magnetization transfer imaging (MTI), functional MRI (fMRI), and techniques for tracking cells following neurotransplantation. Diffusion-Weighted MRI (DWI) and Diffusion Tensor MRI (DTI) of the Spinal Cord As with white matter tracts in the brain, anisotropy in the spinal cord appears to be due to diffusion barriers encountered as water moves in the direction perpendicular to the fibers. These barriers are believed to be cellular membranes and myelin sheaths, which result in a low transverse apparent diffusion coefficient (tADC). As water diffuses longitudinally in the spinal cord, these diffusion barriers are not encountered, and the longitudinal apparent diffusion coefficient (lADC) is, therefore, large in comparison to tADC. Using either DWI or DTI techniques, the preferred direction of anisotropic water diffusion in spinal cord white matter tracts has been shown in numerous ex vivo (172,181–188) and in vivo (189–197) experimental studies, as well as in vivo human studies (198–204), to be parallel, or longitudinal, to the long axis of the axons (Fig. 22.67). A critical goal of spinal cord imaging research is a noninvasive quantification of axons. Experimental studies have shown that the natural variation of differing axon morphometric parameters (including axon density, axon spacing, axon diameter) between normal spinal cord tracts significantly correlates with different directional water diffusion values (185,205). What makes this technique relevant has been its early successful application to human subjects (200–202,204,206–215). However, there are technical difficulties associated with in vivo imaging of the spinal cord that are not as problematic in brain imaging. These difficulties include susceptibility artifacts from surrounding bony structures, motion from CSF pulsations, pulsation from carotid/vertebral arteries, respiratory motion, and the intrinsic small size of the spinal cord resulting in signal contamination from surrounding CSF (215,216). These challenges have limited development of spinal cord DWI and DTI; however, advances in pulse sequence development and hardware, including application of parallel imaging technology (Fig. 22.68), have improved image quality (211,217–221). Many of these initial studies have confirmed what was learned with experimental data, suggesting that this technique is valid and applicable to human spinal cord disease. While studies have demonstrated anisotropic diffusion within the white matter, the situation in gray matter is not as clear. Two studies of fixed rat spinal cord have shown slight anisotropy in the gray matter, with a larger lADC than tADC (172,222), while fixed cat spinal cords showed a slightly elevated 1740

tADC as compared to lADC (181). High-resolution DTI of rodent spinal cords showed variability within the gray matter that appeared to correspond to anatomic fiber orientation (190,223). More rapid longitudinal diffusion was seen in the substantia gelatinosa where small fibers from the tract of Lissauer are ascending and descending, whereas there was left–right anisotropy in the gray commissure where these axons cross (Fig. 22.69). An ex vivo study of human cervical spinal cord has shown that collateral fibers connecting the spinal cord white with the gray matter can be visualized with DTI (224).

FIGURE 22.67 Normal cervical spinal cord section stained with Nissl–myelin staining (A, black bar = 1 mm) with corresponding T2-weighted axial image (B) and color-coded diffusion tensor image (C) of ex vivo normal rat cervical spinal cord. A color sphere is provided adjacent to the diffusion tensor image in order to indicate the preferential direction of water diffusion seen in the spinal cord. The diffusion tensor image shows white matter to be blue, indicating, as shown with the color sphere, preferential water diffusion to be perpendicular to the plane of the image, in the expected rostral–caudal direction. Another method of presenting anisotropic and directional information is to create a three-dimensional ellipsoid for each pixel for each pixel in the DTI image. The central portion of the spinal cord with representative ellipsoids for each pixel (D) shows how the ellipsoids in the gray matter are more rounded and larger than those in the white matter, indicating less anisotropy and increased trace diffusion. An enlarged image of the ventral white matter (E) demonstrates the expected “cigar shape” ellipsoids for white matter, indicating strong rostral–caudal anisotropy. (Adapted from Schwartz ED, Duda J, Shumsky JS, et al. Spinal cord diffusion tensor imaging and fiber tracking can identify white matter tract disruption and glial scar orientation following lateral funiculotomy. J Neurotrauma 2005;22(12):1388–1398, with permission.)

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FIGURE 22.68 Sagittal color-coded diffusion tensor image of the normal human cervical spinal cord in vivo at 1.5 T using parallel imaging technology (A) demonstrates expected rostral–caudal anisotropy, indicated by blue. Axial color coded diffusion tensor image in the upper cervical human spinal cord (B) shows greater diffusional anisotropy in the white matter as compared to the gray matter. Fiber tractography (C) shows expected continuity of fiber (fiber tractography performed with DTIstudio, http://lbam.med.jhmi.edu/, Johns Hopkins University). (From Schwartz ED. Experimental techniques of spinal imaging. In: Schwartz ED, Flanders AE, eds. Spinal Trauma: Imaging, Diagnosis, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:373–407, with permission.)

FIGURE 22.69 An enlarged view of the central and lateral gray matter of the normal spinal cord with lines for each pixel indicating the direction of primary (λ1) diffusivity. The central gray matter, surrounding the central canal which is black, appearing to be a combination of red and green; this finding indicates left–right diffusional anisotropy which is seen with the left–right orientation of the primary diffusivity and may be expected due to left–right orientation of crossing axons and glial processes. Histologic image (B) shows the glial processes (white arrowhead—stained green for GFAP, a glial marker), and axonal fibers (white arrow—stained red for RT-97, an axonal marker), confirm their left– right orientation in the midline. Also note that the lines of principal diffusivity also appear to track axons that exit ventrally through the white matter (A, arrowheads). (Adapted from Schwartz ED, Duda J, Shumsky JS, et al. Spinal cord diffusion tensor imaging and fiber tracking can identify white matter tract disruption and glial scar orientation following lateral funiculotomy. J Neurotrauma 2005;22(12):1388–1398, with permission.)

DWI and DTI of Spinal Cord Injury Ford et al. (172) showed that alterations in ADC values were more sensitive than conventional MR techniques in detecting experimental SCI. Following injury, tADC values increased and lADC values decreased in both normal- and abnormal-appearing white matter. These changes resulted in decreased anisotropy. These results imply that there are consequences of SCI that dramatically alter axon structure without changing water content or T2, and therefore would not be detected by conventional MRI. Nevo et al. (186) has shown that measurement of ADC values and anisotropy can be used to quantify SCI and neuroprotection following treatment with T cells specific to the CNS self-antigen myelin basic protein, an intervention that has been shown to be neuroprotective (225). Changes in apparent diffusion coefficients in spinal cord white matter have been correlated with behavioral recovery following cervical lateral funiculus lesion and transplantation of fibroblasts genetically modified to express brain1742

derived neurotrophic factor (BDNF) (182). In a follow-up study, the tract tracer biotinylated dextran amine (BDA) gave a quantitative measure of axon survival and dieback following partial cervical hemisection and fibroblast transplantation (183), providing the first evidence that ADC values can quantitate the degree of axonal pathology following injury. Fraidakis et al. (189) used a standard diffusion-weighted SE sequence in a 4.7-T magnet with a surface coil to obtain in vivo images 2 to 6 months following transection of rat spinal cords. In this study, diffusion anisotropy was seen to progressively decline toward the cut ends of the spinal cord. Banasik et al. (226) performed in vivo DWI in three orthogonal directions following a weight-drop injury to the rat spinal cord, with some animals receiving treatment with a glutamate receptor antagonist that is thought to decrease excitatory amino acid toxicity following SCI. At 48 hours postinjury, they found that transverse ADC values in white matter at the injury level were elevated only in the surgical control animals, while the MPEP-treated animals had values similar to normal controls. Deo et al. (227) used implantable coils and a 7-T magnet to perform serial in vivo DTI up to 56 days postcontusion SCI. They found that FA values, as well as individual directional diffusivities, could evaluate endogenous tissue recovery and remyelination. Recent studies have shown that DTI can identify spared and functional white matter following acute experimental SCI that correlates with subsequent histologic and behavioral recovery (228–230). In a report of DWI in acute human SCI, and it was noted that diffusion values decreased acutely at the site of injury, potentially due to cellular and axonal swelling (231). In a case report of a patient with syringomyelia, DTI was able to identify spared white matter around the periphery of the syrinx, underscoring the potential for visualizing spared white matter following trauma (232). In patients with spondylosis and spinal cord compression, it has been seen that diffusion MRI improves sensitivity to cervical myelopathy (233); however, there have been conflicting reports of both increased and decreased ADC values, and it may be that the age and clinical severity of a lesion may be important in relating the imaging finding to pathophysiology (208,215,234). Although the majority of published works on the application of DTI in SCI utilize animal models, there are limited published series that illustrate the utility of DTI in human SCI (235–244). Ellingson et al. (237,239) reported significant decreases in FA and MD in a group of chronic spinal cord–injured patients compared to normal controls. MD was measurably lower throughout the spinal cord in the injured group and FA reduction was indirectly related to clinical severity. In a small clinical series, Shanmuganathan et al. (241) demonstrated the feasibility of clinical DTI in acute SCI by reporting a consistent change of DTI parameters in 20 SCI patients compared to normal controls using a standard clinical MRI unit. Whole-cord ADC values were significantly lower in patients and both the ADC values and fractional anisotropy (FA) values were decreased at the site of injury compared with controls (Fig. 22.70). Interestingly, the authors reported a decrease in regional ADC values remote from the site of injury suggesting that the DTI parameters can vary in normal-appearing spinal cord on conventional MRI. This supports the concept that DTI may have greater value in mapping the full extent of injury in conjunction with features from conventional MRI. In a subsequent study, Cheran et al. (237) found statistically significant differences in mean diffusivity (MD), FA, radial diffusivity (RD), and longitudinal diffusivity (AD) for hemorrhagic and nonhemorrhagic SCI patients compared to controls. For nonhemorrhagic SCI, the investigators found strong correlations between admission motor scores (total MIS) and average MD, FA, RD, and AD at the injury site. This same relationship did not hold for hemorrhagic SCI. In a small cohort of human cervical SCI patients, Chang (236) found that DTI indices correlated better than conventional anatomic MRI.

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FIGURE 22.70 DTI parameters mapped along the length of the cervical spinal cord in spinal cord injury. A: Sagittal T2 STIR image of a high cervical spinal cord injury (C3 ASIA-A—motor complete). There is edema spanning the upper cervical cord between the levels of C2 and C5 (horizontal dashed bars). The lesion center is at the C3/C4 interspace (red circle). B: The upper graph and lower graph depict the FA and ADC values, respectively, relative to anatomic location in the cervical spinal cord. Note that the FA value is maximal and the ADC value is minimal at the anatomic level of the injury center and remains abnormal in the area bound by edema (vertical dashed bars).

Evaluation of Gray Matter and Transplants In a rat model of posttraumatic syringomyelia, ADC maps could detect regions of cavitation in the gray matter at 1 week; however, conventional T1- and T2-weighted images showed cystic changes only at 4 and 8 weeks (222). DWI has also been shown to differentiate between functioning and nonfunctioning transplants, with lower ADC values seen in grafts that secrete BDNF and result in greater ingrowth of axons (182). DTI may also be able to determine the degree and directionality of glial scarring in the gray following injury, which may go undetected with conventional MRI (223) (Fig. 22.71). As some therapies may focus on decreasing the degree of glial scarring following injury, DTI may provide an important noninvasive outcome measure. DTI and White Matter Fiber Tractography In the spinal cord, fiber tractography may be used to evaluate integrity and continuity of white matter following injury. This fast method of graphically presenting DTI data may be important in the clinical setting when rapid decisions need to be made. In a study with ex vivo spinal cords following experimental partial hemisection and transplantation, fiber tractography could accurately demonstrate disruption (and sparing) of the axons on the affected side (223). In vivo DTI of experimental hemisection SCI also shows similar findings (Fig. 22.72) (205,245). White matter tractography also appears to be feasible in the clinical setting (Fig. 22.68) (197,199). Ducreux et al. (246) have shown that DTI and white matter tractography can be used to evaluate the effects of astrocytoma infiltration in the spinal cord. Q-Space MRI of the Spinal Cord Q-space imaging is a diffusion-based MR technique that is analogous to observing the diffraction of light waves traveling through an aperture. Instead of observing light waves, however, the diffraction pattern of water molecular spins provides morphologic information based on water displacement profiles that can detect diffusion to a few microns. The potential importance of the q-space imaging technique is that this approach provides indirect measurement to assess the structural integrity of spinal cord at the cellular level resolution, which is beyond any other available MRI method. Using a combination of computer simulations and high-resolution ex vivo imaging in a 9.4-T magnet, researchers have shown that q-space imaging could provide quantitative morphometric data such as mean axonal diameter in different spinal cord tracts (247–249). Nossin-Manor et al. (250) used q-space imaging to evaluate injury in the rat spinal cord; the mean displacement of water molecules perpendicular to the long axis of 1744

the spinal cord increased with injury and that the probability for zero displacement of water molecules decreased. Their findings were, therefore, felt to reflect decreased restriction to water diffusion secondary to structural damage. They point out that these findings were more sensitive to injury than conventional T1- and T2-weighted images. Anaby et al. and Farrell et al. (251,252) have utilized q-space imaging to characterize the diffusion characteristics of white matter in animal models of dysmyelination and axonal degeneration. Although this technique has been applied to the brain in patients with multiple sclerosis (253,254), the need for long b-values makes imaging in a small, motion-prone structure like the spinal cord challenging. Fast acquisition techniques such as echo-planar imaging will likely be necessary (255).

FIGURE 22.71 Nissl–myelin-stained section of cervical rat spinal cord section following partial hemisection (A) with corresponding ex vivo T2-weighted image (B) and color-coded diffusion tensor image (C). Although the right-sided white matter adjacent to the injury site appears to have normal signal on the T2-weighted image, the diffusion tensor image shows increased left–right diffusional anisotropy (indicated by green, refer to color-coded sphere in C) as compared to normal animals (Figure 1). This finding is confirmed in the enlarged image (D) with lines indicating the principal direction of diffusivity in each pixel. E: Histologic image shows a left–right orientation of reactive glial processes in the gray matter adjacent to the transplant and extending to the midline (arrow, glial processes are stained green for GFAP, a glial marker). Arrowhead indicates blue-stained nuclei of a fibroblast transplant that was placed in the partial hemisection cavity. (Adapted and reproduced from Schwartz ED, Duda J, Shumsky JS, et al. Spinal cord diffusion tensor imaging and fiber tracking can identify white matter tract disruption and glial scar orientation following lateral funiculotomy. J Neurotrauma 2005;22(12):1388–1398, with permission.)

Contrast-Enhanced MRI: Evaluation of the Blood–Spinal Cord Barrier 1745

Disruption of the blood–spinal cord barrier (BSCB) following traumatic SCI may be an important cause of propagating injury following spinal cord trauma, and is therefore a potential target for therapy (256). MRI may provide a method for serial and in vivo analysis of the BSCB disruption and subsequent restoration (257). In a model of contusive injury, Runge et al. (258) used contrast enhancement to demonstrate early breakdown of the BSCB. As they followed the animals over time, no significant enhancement could be seen by 28 days. Berens et al. (259) also saw no evidence of BSCB disruption in a contrast-enhanced MRI at 17 to 24 days postinjury in a rodent model of posttraumatic cavity formation. The lack of enhancement 4 weeks postinjury would appear to correspond to the expected timing of the BSCB postinjury. In a series of papers, Bilgen et al. (260,261,262) have looked at dynamic contrastenhanced MRI in experimental SCI. Proposing a multi-compartmental pharmacokinetic model, they used this MRI technique to quantify the integrity of the BSCB; they saw early disruption of the BSCB with subsequent restoration corresponding to behavioral recovery over the next few weeks. Cohen et al. (263) looked and dynamic contrast-enhanced MRI (DCE-MRI) up to 56 days following experimental SCI. They showed that BSCB may stay compromised as late as 56 days postinjury, and that decreased BSCB permeability correlated with improved locomotor recovery.

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FIGURE 22.72 In vivo spinal cord fiber tractography at 4.7 T shows intact white matter in a normal rat (A). An end-on view of the fiber tracking (B) shows how the fibers are confined to the white matter. A corresponding color-coded diffusion tensor image from the normal spinal cord (C) indicates strong rostral–caudal anisotropic diffusion in the white matter, again seen as blue. In a rat with a complete hemisection, fiber tractography clearly indicates disruption of the white at the site of injury (arrow, D). The corresponding axial diffusion tensor image at the level of injury (E) shows decreased anisotropy on the side of the hemisection (arrow) as compared to the intact side (arrowhead); this finding is confirmed with a toluidine blue-stained histologic image (F). Another method of presenting data includes volume rendering of the DTI maps. Volume rendered image of the FA maps (G) of an in vivo spinal cord at 1-month posthemisection injury is viewed on end from the caudal aspect of the spinal cord (volume rendering performed with Medinria software, http://www-sop.inria.fr/asclepios/software/MedINRIA/, Asclepios research project). The volumerendered FA map shows that the right-sided white matter has decreased anisotropy (black arrow, G) consistent with degeneration following the right-sided hemisection in a tract that has both ascending and descending white matter fibers. However, note that the dorsal columns (black arrow, G) are not as affected as these are predominantly ascending tracts; this is expected as we are viewing caudal to the site of injury.

Magnetic Resonance Spectroscopy (MRS) While MRS has been successfully applied to the brain, applications to the spinal cord have been limited, likely due to technical challenges in performing MRS in the spinal cord (264,265). Salomon et al. (266) looked at metabolite changes in the spinal cord associated with cervical spondylosis and demonstrated elevation in the choline–creatine ratio in those patients with spinal cord T2 signal abnormality, and they also found that higher choline–NAA ratios correlated with worse neurologic outcome. Other researchers have used MRS to evaluate changes in the brain following SCI. Pattany et al. (267) evaluated patients with SCI and paraplegia, and found that patients with chronic neuropathic pain had decreased NAA and increased myo-inositol in their thalami (Fig. 22.73). They hypothesize that the decreased NAA may be due to dysfunction of inhibitory neurons due to deafferentation. The increased myo-inositol, a glial marker, may be due to gliosis in the thalami. The authors suggest that MRS may be used to predict and to evaluate effectiveness of treatments for managing pain in SCI patients. Puri et al. (268) reported increases in NAA within the motor cortex following incomplete SCI. The authors suggest that the increased NAA may be due to neuronal adaptation and point out that MRS could be used noninvasively to monitor recovery following SCI. Experimentally, there have also been only a few publications that utilize MRS to evaluate SCI. Although application to an animal model is technically difficult, two studies have shown the feasibility of in vivo MRS within the rat spinal cord by utilizing implantable radiofrequency coils (191,195). Erschbamer et al. (269) performed in vivo MRS of the rat spinal cord and brain following SCI and demonstrated that glutamate/glutamine levels in the spinal cord increased following injury but decreased in the cortex. Vink et al. (270,271) also used phosphorus (31P) MRS, which is used to evaluate energy metabolites, such as ATP. They performed 1H and 31P MRS in vivo following experimental SCI in the rabbit and showed that there were early elevations in lactic acid and loss of high-energy metabolites in regions that progressed to necrosis and cavitation, suggesting that MRS could evaluate changes in metabolism and predict irreversible tissue damage.

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FIGURE 22.73 Axial T1-weighted image (left) shows the location of the 2 cm × 2 cm × 2 cm voxel in the region of the left thalamus and the corresponding location of the right thalamus. MRS data were separately acquired from each voxel for the three groups: SCI patients with pain, SCI patients without pain, and healthy control subjects. Typical MRS spectrum (right) from a healthy control subject with peaks representing cerebral metabolites: N-acetyl (NA), total creatine (Cr), choline compounds (Cho), glutamate (Glu), Glutamine (Gln), Glu and Gln (Glx), and myo-inositol (Ins). In spinal cord–injured patients with neuropathic pain, the NA is decreased and the Ins is increased. (Reproduced from Pattany PM, Yezierski RP, Widerström-Noga EG, et al. Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury. AJNR Am J Neuroradiol 2002;23(6):901–905.)

Magnetization Transfer MRI (MTI) In a weight-drop model of experimental SCI, McGowan et al. (272) imaged ex vivo spinal cords 4-week postinjury in a 1.9-T magnet. The authors found that the degree of magnetization transfer ratio (MTR) alterations correlated with histologic measures of myelin and neurofilament damage, however, not as well with edema, suggesting that edema did not contribute as much to the MTR reduction. This distinction is important as edema contributes strongly to conventional MRI findings, such as T2weighted images, and may indicate that MTR provides more specific information concerning spinal cord pathology. Gareau et al. (273) studied MTI in vivo following clip compression injury in rats utilizing a 4.0-T magnet. They found that the average MTR in white matter could discriminate between mild and severe SCI at 1 day following injury, with lowest MTRs seen in severe SCI, as opposed to proton density imaging which did not allow for discrimination of injury severity. Forgione et al. (274) also suggest that MTR values can be used to evaluate neuroanatomy and myelin content in an experimental model of SCI. These studies suggest that MTI may visualize changes in myelin and neurofilament structure that may go unseen with conventional MRI. Cohen-Adad et al. (275) imaged patients with chronic SCI and found MTR parameters in dorsal spinal cord correlated with sensory disability while MTR parameters in the lateral spinal cord correlated with motor disability. Functional MRI (fMRI) fMRI is an imaging technique that has been used extensively as a tool for mapping brain activity in vivo. The most utilized fMRI technique is the blood oxygen level–dependent (BOLD) pulse sequence (276,277). Although the vast majority of fMRI is brain-related, there has been some interest in applying this technique to the spinal cord. Unfortunately, BOLD imaging of the spinal cord is limited by the small size of the spinal cord, by spinal cord motion, and by nearby location of large pial vessels; all of these factors can result in poor localization of the BOLD signal. Additionally, the magnetic susceptibility of the surrounding vertebral bodies and ligaments can also result in distortions to the MRI signal. Due to these significant challenges and limitations, there have been relatively few clinical studies investigating BOLD fMRI applied to the spinal cord. Following a unilateral hand closing task, Yoshizawa et al. (278) noted a 4.8% change in BOLD signal intensity in the ipsilateral cervical spinal cord utilizing a 1.5-T magnet and Backes et al. (279) noted localized spinal cord activation (8% to 15% BOLD signal increase) following median nerve stimulation and hand clenching although lateralization was not visualized. Stroman et al. (280) used a 3-T magnet to evaluate the lower cervical spinal cord following hand exercises and found a 7.0% increase in BOLD signal that corresponded to the expected location of both motor and sensory activation. Madi et al. (281) used a series of different exercised to determine if they could demonstrate a task-dependent change in the spinal cord BOLD signal at 1.5 T (Fig. 22.74). They found that BOLD signal increased at 1748

the expected spinal cord level; elbow flexion showed activation at C5 and C6, wrist extension at C6 and C7, and finger abduction at T1 and T2. They also reported a linear dependence of the fMRI signal with the force applied by the muscle group. Stroman et al. (282) also showed that following sensory stimulation, the distribution of spinal cord activity with fMRI matched the expected location of neuronal activation; however, a separate report by Stracke et al. (283) also showed consistent activation at higher cervical levels as well which they attribute to synaptic transmissions at interneurons.

FIGURE 22.74 BOLD fMRI of the human spinal cord. In a subject performing isometric exercises with the arm, sagittal BOLD fMRI image shows first-order activation in the expected C5–C6 region of the spinal cord; this finding suggests a linear relationship between BOLD signal and applied force. (Image courtesy of Adam Flanders, MD, Thomas Jefferson University.)

It has been suggested, however, that the changes seen in fMRI of the spinal cord may not be due to the BOLD effect. Changes in proton density may actually predominate, which can be then be imaged with a proton-density SE sequence, eliminating much of the susceptibility artifacts that limited spinal fMRI (284,285). The mechanism for the signal changes on proton density imaging appears to be due to water protons in the extravascular space, and not due to water protons in the blood where the BOLD effect takes place; this effect has been termed by Stroman et al. (286,287) as Signal Enhancement by Extravascular water Protons (SEEP). It has been proposed that the underlying mechanism for the SEEP effect is that hemodynamic changes in regions of activated neurons result in increased perfusion and movement of water molecules from the vascular to the extravascular spaces. Additionally, the swelling of glial cells following neurotransmitter release may also contribute to the SEEP effect. This technique has been optimized to perform spinal fMRI, both in the cervical (285) and lumbar spine (288). One advantage of this technique is that it can be performed on low–field-strength magnets, such as 0.2 T, whereas the BOLD technique relies on susceptibility changes which are best seen with higher-strength magnetic fields (289,290). The SEEP fMRI technique has been applied to patients with SCI. Graded thermal stimuli were applied to normal controls and SCI patients below the level of injury. Lumbar spinal cord activity is seen in both controls and patients; however, the pattern of activation is altered in the injured patients. Also preserved in SCI patients is a stimulus response pattern similar to uninjured subjects, as the signal changes increased with more noxious (colder) stimuli (284,291,292). Spinal fMRI was also applied to ASIA-A through D patients, and was able to detect neuronal activity caudal to the SCI site, both passive and active lower limb movement; the pattern of activation seen with this study suggests that fMRI could help with assessment of injury and subsequent rehabilitation (Fig. 22.75) (293). Spinal fMRI may also demonstrate plasticity of sensory neuronal networks in patients with chronic incomplete SCI (294). There have been a number of studies exploring fMRI in the spinal cords of animals. These studies have shown activation in the cervical (295) and lumbar (296,297) spinal cord of rats following noxious stimuli. Confirming the robustness of fMRI, Lawrence et al. (298) demonstrated agreement between the areas of activation seen with fMRI and C-fos (upregulated in neurons following repeated stimuli) expression seen on immunochemistry. BOLD fMRI of brain activation following spinal and peripheral nerve injury has shown that there is reorganization, expansion, and shifting of motor cortical representations in nonaffected limbs (299–301). Interestingly, Sabbah et al. (302) demonstrated that in patients with complete SCI, activation could be seen in the motor regions of the brain with both an attempt to move as well as 1749

mental imagery of movement in affected limbs. These findings suggest that the cortical networks involved with motion and sensation remain intact despite complete injury. Komisaruk (303) used fMRI to demonstrate that women with complete SCI could use the vagus nerve to provide a spinal cord– bypass pathway for vaginal–cervical sensation, and that the degree of sensation was sufficient to achieve orgasm. In a rodent model of SCI, fMRI showed the expected expansion of cortical representation of nonaffected limbs as well as loss of sensory cortical representation in the affected limb; in mild SCI, there was recovery of sensory function detectable with fMRI, as opposed to moderate SCI (304).

FIGURE 22.75 Image orientation: two sagittal slices and nine axial slices from each ASIA classification are shown. Each sagittal slice spans the spinal cord with the lumbar segments approximately midimage. The slice on the left is taken from the right side of the cord (R) and the slice on the right is taken from the left side of the cord (L). The dorsal aspect is toward the left of the image (D) and the ventral aspect is on the right of the image (V) as indicated by the spinous processes and vertebral bodies, respectively. Sagittal images are oriented with rostral toward the top of each slice, caudal toward the bottom. The axial slices are oriented with the right side of the cord to the left of the image, the left side of the cord to the right of the image, dorsal toward the bottom of the cord, ventral toward the top, rostral to caudal displaying left to right. The level at which the axial slices correspond to the sagittal slices are indicated by green lines. Results from an ASIA-A and ASIA-B volunteer during passive participation are shown on the top row. Results from an ASIA-C volunteer during active and passive participation are shown in the middle row. Results from an ASIA-D volunteer during active and passive participation are shown on the bottom row. The ASIA-A patient shows activity caudal to the injury site on passive activation, within both the left and right sides of the spinal cord, in the dorsal and ventral areas. The ASIA-B, -C, and -D patients show some laterality to their activation which may be due to development of clonus in the ASIA-B patient and asymmetric injury in the ASIA-C and ASIA-D patients. (Reprinted with permission from Kornelsn J, Stroman PW. Detection of the neuronal activity occurring caudal to the site of spinal cord injury that is elicited during lower limb movement tasks. Spinal Cord 2007;45:485–490.)

Two experimental studies have shown that fMRI of the brain may be used as a noninvasive test of recovery following experimental treatment. Hofstetter et al. (305) showed fMRI could detect sensory recovery in rats treated with modified neural stem cells following contusion injury and Liebscher et al. (306) demonstrated that fMRI could detect the recovery of sensory function in rats that were treated with Nogo-A antibody following a surgically induced lesion to the dorsal columns. In both studies, no recovery was seen in untreated surgical controls. A pilot study in human SCI ASIA-A subjects showed increased sensorimotor cortex activation, possibly due to functional reorganization, following continuous intrathecal baclofen pump implantation to relieve spasticity (307). These findings, both clinical and experimental, suggest that fMRI may be a noninvasive technique of 1750

evaluating the effects of SCI and treatment, both within the spinal cord and the brain. MRI Tracking of Magnetically Labeled Neurotransplants Recently, there has been interest in using noninvasive methods for the tracking of engrafted cells into the injured spinal cord. One technique utilizing MRI is performed by magnetically labeling the cells, prior to transplantation, with super paramagnetic iron nanoparticles. MRI will then show the labeled cells to be hypointense as compared to the remainder of the spinal cord. Bulte et al. (308) have shown the feasibility of this technique in the spinal cord by labeling oligodendrocyte precursors and injecting these cells into the spinal cord of myelin deficient rats; there was a close correlation between the hypointense regions seen with ex vivo MRI and histologic confirmation of cell location and myelination. This technique can be used for tracking the migration of cells following neurotransplantation (Fig. 22.76) (309). More recent studies have shown that this technique is feasible in vivo, with Lee et al. (310) demonstrating that labeled olfactory ensheathing cells could not cross an experimental spinal cord transection site following neurotransplantation. In an experimental model of compressive SCI, Amemori et al. (311) transplanted labeled neural stem cells which were imaged serially prior to and following the injury and transplantation. This technique has also demonstrated that labeled bone marrow stromal cells and embryonic stem cells will migrate to a site of injury in the brain or spinal cord following either direct implantation into the CNS or intravenous injection (312,313). MRI has also been used to confirm that intrathecally injected mesenchymal stem cells labeled with superparamagnetic iron oxide nanoparticles could be guided to SCI site using an implantable magnet (314). One of the disadvantages of this technique, however, in that the labeled cells cannot be reliably differentiated from blood products (which also appear hypointense), thus adding a confounding factor when imaging an injury that also contains hemorrhage; however, recent reports suggest that newer pulse sequences and labeling techniques have potential to overcome this limitation (315,316). MRI has matured from a scientific curiosity to an essential part of the clinical armamentarium for assessment of the spinal injured patient. While the traditional radiographic assessment and classification systems of spinal injury remain useful, MRI has eclipsed these other imaging methods because of its unique ability to demonstrate the soft tissue components of injury. In this regard, MRI is still the only imaging method that provides an objective assessment of the damaged spinal cord’s internal architecture. As we look to the future, with implementation of novel medical and surgical therapies for SCI, MRI will continue to play an intimate role in the assessment of the SCI patient.

FIGURE 22.76 Neural restricted precursor stem cells (NRPs) and glial restricted precursor stem cells have been labeled with iron oxide (Ferridex; Berlex Laboratories, Wayne, NJ), and then grafted into the intact rat spinal cord. Ex

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vivo axial (A) and sagittal (B and C) MR images obtained 5-week posttransplantation show the grafted cells as dark areas. Histologic image stained with the iron stain Prussian Blue (D) shows a correspondence between the MR and iron-containing cells. The grafted cells were from a transgenic alkaline phosphatase (AP) rat, and a histologic image stained for AP (E) shows that the dark areas in the MRI correspond to grafted cells. Note that this technique is able to detect grafted cells that have migrated rostral and caudal to the implantation site. There is less MRI–histology correspondence at the central portion of the graft site (asterisk) due to high degree of cell proliferation that dilutes the iron oxide label. (Adapted from Lepore AC, Walczak P, Rao MS, et al. MR imaging of lineage-restricted neural precursors following transplantation into the adult spinal cord. Exp Neurol. 2006;201(1):49–59.)

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ACKNOWLEDGMENTS We thank John F. Ditunno M.D., Anthony S. Burns, M.D., Ralph J. Marino, M.D., James S. Harrop, M.D., Alexander Vacarro, M.D., Marion Murray Ph.D., and Mary Patrick R.N. for their critical input and the Regional Spinal Cord Injury Center of the Delaware Valley for clinical support.

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23 Vascular Disorders of the Spine and Spinal Cord Anton Valavanis and Robert W. Hurst

Vascular diseases of the spine and spinal cord comprise a rare but important group of conditions affecting this critical portion of the central nervous system (CNS). Among the group of neurovascular pathologic conditions, the group of vascular disorders of the spine and spinal cord comprises approximately 2% and includes spinal cord ischemia of various etiologies and a spectrum of vascular malformations. In addition, hemangioblastomas of the spinal cord are highly vascularized neoplasms which may mimic morphologically an arteriovenous malformation (AVM) of the spinal cord. Complete evaluation of patients with potential spinal vascular disease is a significant and often difficult task for all physicians involved in the diagnosis and treatment of disease of the spine. Magnetic resonance imaging (MRI) including magnetic resonance angiography (MRA) represents the most important single source of diagnostic information regarding spinal anatomy and pathology and is particularly important in the evaluation of the patient with possible spinal vascular disease. However and despite its invasiveness, spinal digital subtraction angiography (DSA) is an essential, additional tool for the detailed angioarchitectonic evaluation, classification and treatment planning in cases with AVMs of the spinal cord. A thorough familiarity with the normal vascular anatomy of the spine and spinal cord is essential for complete understanding and proper interpretation of MRI in spinal vascular disease. Just as critical is an appreciation of the varieties of vascular pathology that may afflict the spine and cord and an acquaintance with clinical situations that warrant consideration of these entities. Finally, an understanding of the strengths and limitations of MRI and MRA in spinal vascular disease aids in formulating a diagnostic evaluation plan and assists in determining which patients require additional evaluation including spinal DSA.

VASCULAR ANATOMY Knowledge of the complex vascularization of the spinal cord and its surrounding tissues including the arterial supply and the venous drainage is essential for the interpretation of spinal MRI and MRA as well as for the performance and diagnostic analysis of spinal DSA when evaluating patients with suspected vascular disease of the spine and/or spinal cord. The supply of the spine and spinal cord is provided by a bilateral, symmetrical, longitudinally arranged segmental system of arteries, that is, the segmental arteries. These segmental arteries originate at the cervical level from the vertebral, ascending, and deep cervical arteries, at the thoracic level from the thoracic aorta as the intercostal arteries, at the lumbar level from the lumbar aorta as the lumbar arteries and at the sacral level from the internal iliac arteries as the iliolumbar arteries. Each segmental artery provides distinct branches for the supply of the vertebral bodies, the paraspinal musculature, the dura, the nerve roots and the spinal cord. The nerve roots, the dura and the cord are supplied from the spinal radicular branch, which courses through the intervertebral foramen. The spinal cord receives its blood supply from the longitudinal anterior spinal artery (ASA) and the paired posterior spinal arteries (PSAs). The ASA results from the midline fusion of the paired ventral paramedian located longitudinal neural arterial axes, which takes place during embryonic development. The most cranial extent of the ASA originates as separate lateralized branches from the intradural vertebral arteries at the cervicomedullary junction. A single-midline ASA is formed, which courses along the ventral surface of the spinal cord adjacent to the anterior median fissure. The longest artery in the body, the ASA is usually continuous along the entire length of the spinal cord. 1763

Predictable variations in caliber of the ASA occur along the length of the cord reflecting variations in metabolic requirement of the various cord regions. The relatively large amounts of gray matter found within the cervical and lumbar enlargements require a larger blood supply than the white matter tracts of the cord. Consequently, the larger size of the ASA in the lower cervical and lumbosacral regions, often exceeding 1 mm in diameter, reflects this relatively large blood flow requirement. The ASA often narrows to less than 0.5 mm in diameter in the thoracic region between T2 and T9, where the cord is largely composed of white matter tracts and the metabolic demand is correspondingly low (1,2). Each spinal nerve root receives its blood supply from a radicular artery, which follows the root within the neural foramen. The radicular artery supplies the root sleeve and spinal dura and also gives supply to the vertebra at each level (Fig. 23.1). The majority of the radicular arteries give no supply to the spinal cord itself. At various locations along the length of the cord, however, branches from the radicular arteries contribute to both the ASA and PSA. Radicular artery branches contributing to the ASA are referred to as “radiculomedullary” arteries, and those giving supply to a PSA are known as “radiculopial” arteries (Fig. 23.2). From six to eight radiculomedullary arteries arise from radicular arteries along the length of the cord. Radiculomedullary arteries follow the nerve root through the neural foramen and bifurcate on the ventral surface of the cord near the midline into ascending and descending branches that join the ASA (3). The locations of radiculomedullary arteries along the cord follow general guidelines based on the cord blood flow requirements at various levels. Nevertheless, considerable individual variation exists in the location of radiculomedullary arteries.

FIGURE 23.1 Diagram of the intercostal arterial system. (1) Arteries to the vertebral body, (2) anterolateral anastomotic artery, (3, 4) pretransverse anastomoses, (5) dorsospinal artery, (6, 8) ventral muscular branches, (7) ventral branch, (9, 10) dorsal muscular branches, (11) radicular artery, (12, 14) epidural anastomoses, (13) dural branch. (From Lasjaunias P, Berenstein A. Surgical Neuroangiography. Volume 3: Functional Vascular Anatomy of Brain, Spinal Cord, and Spine. New York: Springer-Verlag, 1990, with permission.)

Clinical consideration of the spinal cord blood supply is aided by the concept of three major regions of supply to the ASA axis (4) (Fig. 23.3). The three regions include the cervicothoracic, midthoracic, and thoracolumbar regions. Hemodynamic watershed areas occur at the margins of each region as flow through the ASA in one region encounters opposing ASA flow from the adjacent region. Little net flow normally occurs across the border zone, resulting in relative hemodynamic isolation of the ASA supply of each region from its neighbor. Although the ASA is usually continuous anatomically along the length of the spinal cord, adequate collateral flow across border zones is not always available. This is especially frequent in the midthoracic region, where the ASA may be relatively small. The spinal cord is, therefore, vulnerable to infarction in the event of compromise of a radiculomedullary feeding vessel or of hypotension affecting the ASA (5). In the cervicothoracic region, radiculomedullary contributions to the ASA may originate from the vertebral artery as well as from branches of the costocervical or thyrocervical trunks. In most cases, the ASA receives a radiculomedullary branch from the vertebral artery at approximately the C3 level. In addition, a relatively constant radiculomedullary vessel, the artery of the cervical enlargement, is usually found accompanying the C6 nerve root.

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FIGURE 23.2 Superficial arteries of the spinal cord: (1) radicular artery, (2) radiculomedullary artery (to anterior spinal artery), (3) radiculopial artery (to posterior spinal artery), (4) anterior spinal artery, (5) posterior spinal artery, (6, 7) circumferential pial arterial plexus, (8) sulcocommissural arteries. (From Thron A. Vascular Anatomy of the Spinal Cord. New York: Springer-Verlag, 1988:114, with permission.)

FIGURE 23.3 Diagram of the arterial regions of the spinal cord. (I) Superior or cervicothoracic region, (II) intermediate or midthoracic region, (III) lower or thoracolumbar region. (1) Anterior spinal artery, (2) artery of the spinal enlargement (variable), (3) posterior spinal artery, (4) artery of the lumbar enlargement (artery of Adamkiewicz), (5) anastomotic loop of the conus medullaris with continuation of the anterior spinal artery as the artery of the filum terminale. (From Lazorthes G, Gouaze A, Zadeh JO, et al. Arterial vascularization of the spinal cord: recent studies of the anastomotic substitution pathways. J Neurosurg 1971;35:253–262, with permission.)

The midthoracic region, consisting of the next six or seven cord segments, has a lower metabolic demand and demonstrates a correspondingly smaller blood supply. Often only one radiculomedullary artery, usually accompanying the T4 or T5 root, occurs in this region. The thoracolumbar region, extending from the T8 segment to the conus medullaris, is provided with a relatively rich blood supply, usually originating from a single large radiculomedullary artery. This vessel, described by Adamkiewicz as the “arteria radicularis anterior magna,” is also known as the artery of Adamkiewicz (Fig. 23.4). In 75% of cases, the artery of the lumbar enlargement enters the spinal canal at a level from T9 through T12, most commonly on the left, whereas in 10%, the vessel accompanies the first or second lumbar nerves. The artery has a high origin in 15%, entering at levels from T5 through T8. Although general guidelines exist for the location of this important radiculomedullary artery, the location in a given patient is variable, ranging from the upper lumbar through midthoracic levels. Like the ASA, the cranial extent of the paired PSAs usually originates from the intradural vertebral arteries. The PSAs, whose caliber is more uniform and usually smaller than that of the ASA, course on the dorsal surface of the cord adjacent to the dorsal roots. These features of the PSAs reflect their area of spinal cord supply, which includes mostly the dorsal white matter tracts and demonstrates little variation in size or metabolic requirement from one cord level to another. Frequent intercommunications connect the two PSAs across the dorsal cord surface. In contrast, collaterals around the lateral surface of the cord are infrequent and too attenuated to function reliably as anastomoses between the territories supplied by the ASA and PSAs. The absence of adequate collaterals results in functional and anatomic isolation between these two major territories of spinal cord vascular supply. 1765

FIGURE 23.4 Variations in the location of the artery of the lumbar enlargement. (1) Ascending branch of the anterior spinal artery, (2) artery of the filum terminale, (3, 4) artery of the lumbar enlargement, (5) sacral arteries. Percentages refer to the occurrence of the artery of the lumbar enlargement at specific spinal levels. (From Lazorthes G, Gouaze A, Zadeh JO, et al. Arterial vascularization of the spinal cord: recent studies of the anastomotic substitution pathways. J Neurosurg 1971;35:253–262, with permission.)

At variable locations along the length of the cord, the PSAs receive contributions from radiculopial branches of the radicular arteries. From 10 to 20 radiculopial arteries may be present, each one joining a PSA but making no contribution to the ASA. Intrinsic Spinal Cord Supply Two distinct groups of arteries, the sulcocommissural arteries and the rami perforantes, provide blood supply directly to the neural tissue of the cord (Fig. 23.5). The sulcocommissural arteries, a lateralized, centrally directed system of perforating arteries, originate from the ASA. The sulcocommissural arteries course dorsally within the anterior median fissure before turning left or right to enter the cord in the region of the anterior white commissure (Fig. 23.6). Dense capillary networks from the sulcocommissural arteries originate within the cord substance to supply the gray matter of the anterior, intermediate, and basal dorsal horns as well as most of the white matter within the anterior and lateral funiculi. A separate system of centripetally directed arteries known as rami perforantes receives its supply mainly via the PSAs. The rami perforantes supply the peripheral structures of the cord including the posterior columns and the apices of the dorsal horns. A minimal amount of gray matter is supplied by the rami perforantes in comparison to that supplied by the sulcocommissural arteries (Fig. 23.7). The inadequate anastomoses between the ASA and PSA territories result in anatomic and functional separation between the two intrinsic cord vascular distributions. The anterior 60% to 80% of the spinal cord receives supply exclusively from branches of the ASA, whereas the posterior 20% to 30% is fed by rami perforantes originating from the PSA. The intrinsic veins of the spinal cord collect blood in a radially symmetric pattern. On reaching the surface of the cord, venous blood collects into the longitudinally directed anterior and posterior spinal veins (Fig. 23.8) (6). Both longitudinal venous systems, that is, the anterior and posterior, are interconnected by a circumferential, superficial pial venous network as well as by direct transmedullary venous anastomotic channels. The transition from a median spinal vein into a radicular vein has the same hairpin configuration as the corresponding radiculomedullary artery. At multiple levels, radicular veins drain the anterior and posterior spinal veins into the epidural venous plexus which is connected to the azygos and hemiazygos venous systems.

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FIGURE 23.5 Superficial and intrinsic arteries of the spinal cord. (1) Anterior spinal artery, (2) posterior spinal arteries, (3) sulcocommissural arteries, (4) circumferential pial arterial plexus. (From Lazorthes G, Gouaze A, Zadeh JO, et al. Arterial vascularization of the spinal cord: recent studies of the anastomotic substitution pathways. J Neurosurg 1971;35:253–262, with permission.)

FIGURE 23.6 Sulcocommissural branches (4–7) of the descending branch of the anterior spinal artery (3) penetrate the cord in the anterior median fissure. Both the descending and ascending (2) branches of the anterior spinal artery are supplied by a radiculomedullary artery (1). The axial (8, 10, 11) and longitudinal (9) distribution of the sulcocommissural arteries is shown. (From Lasjaunias P, Berenstein A. Surgical Neuroangiography. Volume 3: Functional Vascular Anatomy of Brain, Spinal Cord, and Spine. New York: Springer-Verlag, 1990, with permission.)

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FIGURE 23.7 Territory of the intrinsic arterial systems of the spinal cord. Cross sections at cervical (top), thoracic (middle), and lumbar (bottom) spinal levels. The gray zone corresponds to the area supplied by the anterior spinal artery (about two-thirds of the entire cross-sectional area), and the dorsal white zone is supplied by branches of the posterior spinal arteries. (From Thron A. Vascular Anatomy of the Spinal Cord. New York: Springer-Verlag, 1988:114, with permission.)

FIGURE 23.8 Intrinsic and extrinsic veins of the cord. (1–3) Intrinsic venous anastomoses, (4) sulcal vein, (5) transmedullary anastomoses, (7) ventral spinal cord vein, (6, 8, 9) extrinsic anastomoses, (10) radial vein. (From Lasjaunias P, Berenstein A. Surgical Neuroangiography. Volume 3: Functional Vascular Anatomy of Brain, Spinal Cord, and Spine. New York: Springer-Verlag, 1990, with permission.)

Evaluation of Vascular Lesions of the Spine and Spinal Cord MRI permits noninvasive evaluation of spinal cord anatomy and many types of spine and spinal cord pathology. Although spinal angiography remains the best method for detailed visualization of the spinal vasculature, both MRA and computed tomography angiography (CTA) using multi-detector CT have been able reliably to detect the normal artery of the lumbar enlargement (artery of Adamkiewicz) (1,2,4,7–12). Nijenhuis et al. (11) evaluated 15 patients having suspected spinal cord vascular pathology with both spinal contrast-enhanced MRA (CE-MRA) and selective spinal DSA. Localization and spatial configuration of the artery of Adamkiewicz by CE-MRA agreed with DSA findings in 14 of 15 cases. Comparison of image quality revealed that DSA was superior to CE-MRA concerning vessel continuity, sharpness, and background homogeneity (p < .001). Overall vessel conspicuity and contrast were 1768

judged to be similar. Advances in both MR and CT promise to provide increasingly reliable information on both normal spinal vascular anatomy and spinal vascular pathology. Information from noninvasive imaging is often extremely helpful in planning evaluation and treatment of disorders involving the spinal vasculature. Nevertheless, spinal angiography remains indicated when specific information regarding the vascular supply of the spine, cord, or adjacent tissue is required. Evaluation and endovascular treatment of spinal vascular malformations and some vascular neoplasms are the major indications for spinal angiographic examination. In most cases, MRI findings suggestive or diagnostic of a spinal vascular malformation mandate further evaluation with spinal angiography, particularly for planning surgical or endovascular therapy. In contrast, the role of angiography is limited in the evaluation of infarction or ischemia involving the spine, except in cases of aortic occlusion.

CLASSIFICATION OF SPINE AND SPINAL CORD VASCULAR LESIONS Vascular malformations of the spine and spinal cord comprise a heterogeneous group of abnormalities, which are reported to make up approximately 3% to 16% of spinal mass lesions. The classification or delineation of distinct, relatively homogeneous subgroups of spinal vascular malformations is important to permit useful characterization of the lesions with regard to clinical behavior and therapeutic options. The widespread use of selective angiographic examination and MRI has resulted in improved definition of the angioarchitecture and hemodynamics of spinal vascular lesions, features implicit in useful classification. Additional aspects of spinal vascular lesions important for classification include specific imaging features; anatomic localization with regard to the dura and the spinal cord; the type of shuntinvolved fistula or nidus; and potential relationships with genetics, vascular biologic features, and angiogenesis (13). Various classification systems and eponyms for spinal vascular lesions have been used over the years with resultant confusion and difficulty in comparing and evaluating the various types and subgroups (13–16). Anson and Spetzler (14) proposed a widely used, relatively simple classification that distinguishes four types of spinal vascular malformations associated with arteriovenous shunting: type I, spinal dural arteriovenous fistulas (SDAVFs); type II, intramedullary glomus AVMs; type III, juvenile or combined AVMs; and type IV, intradural perimedullary AVFs. Spetzler et al. (17), in a recently proposed modification of this classification system, divided spinal vascular lesions into three primary or broad categories: neoplasms, aneurysms, and arteriovenous lesions. Arteriovenous lesions are further subdivided based on their angioarchitecture into AVFs and AVMs. TABLE 23.1 Spinal Vascular Malformations

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Under the modified classification, AVFs are subdivided into extradural and intradural lesions, with the latter being classified as either “dorsal” or “ventral.” Intradural AVFs occur far more frequently, with the “dorsal” type representing the most common spinal vascular lesion, the (SDAVFs) (type 1). The “ventral” type of intradural AVF, previously referred to as spinal cord AVF or perimedullary AVF (type IV), occurs much less frequently. Spinal AVMs, characterized by the presence of a nidus as the site of arteriovenous shunting, are divided into extradural–intradural and intradural. Extradural–intradural AVMs, also referred to as “juvenile” arteriovenous confirmations (type III), are uncommon lesions. Intradural AVMs, previously referred to as “glomus” type (type II), have been newly subdivided into intramedullary and intramedullary–extramedullary based on their relationship to the spinal cord. In addition, conus medullaris AVMs comprise a newly proposed category. Table 23.1 relates the terminology of these two most widely utilized classification systems to the various spinal vascular lesions. A number of features of this modified classification system remain controversial, including its classification of cavernous malformations (CMs) as neoplasms (18). Nevertheless, familiarity with these two most widely used classifications is useful for understanding, evaluating, and communicating information regarding this important group of spinal vascular lesions. With regard to the spinal dura, which represents a topographical landmark for localization of spinal vascular malformations, these lesions can be classified as follows: A. Spinal extradural AVMs 1. Paraspinal arteriovenous shunts. These are very rare lesions characterized by a direct fistulous connection between a segmental artery or a branch of it and the corresponding segment of the paraspinal venous system at this level. They may occur at any level along the spinal notochord but the majority occurs at the thoracic level. They may drain through a radicular vein into the perimedullary venous system causing significant venous ectasias with cord compression and venous congestion of the spinal cord. In addition, arterial steal phenomenon may occur in cases with a high-volume arteriovenous shunt. 2. Spinal epidural arteriovenous shunts These are also extremely rare and small lesions located within the spinal epidural space and draining into epidural veins. They may cause intradural venous congestion or present with an acute epidural hematoma. B. SDAVMs or shunts These are the most common spinal vascular malformation with arteriovenous shunting. They are acquired lesions located within the dura, most commonly within the dural sleeve of a nerve root in the intervertebral foramen, are fed by a radiculomeningeal artery and drain through a radicular vein in a retrograde direction into the perimedullary venous system. Intramedullary venous congestion with progressive myelopathy is the pathophysiologic and clinical hallmarks of the disease. C. Spinal intradural AVMs Spinal intradural AVMs may be located in the subarachnoid space surrounding the spinal cord, along the intradural course of a nerve root, in the spinal cord itself with or without extramedullary extension, or in the filum terminale. Topologically, intradural AVMs are, therefore, classified into four types: 1. Perimedullary AVFs 2. Intramedullary AVMs 3. Radicular AVMs 4. Filum terminale AVFs In addition, spinal intradural AVMs may have or lack a genetic association. Depending on the hereditary or nonhereditary type of genetic association, or the absence of a genetic link, spinal intradural AVMs are classified into three types: 1. Single arteriovenous shunts associated with a genetic hereditary disorder. The great majority of these patients have hereditary hemorrhagic telangiectasia type I (HHTI) or Rendue–Osler–Weber disease. The arteriovenous shunt is typically a perimedullary arteriovenous macrofistula. TABLE 23.2 Spinal Vascular Malformations 1770

2. Multiple genetic, nonhereditary arteriovenous shunts a. with a metameric distribution affecting the cord, the dura, the vertebral body, the paraspinal musculature and the skin. A typical representative of this group is the Cobb syndrome. b. without an evident metameric link. In the majority of these patients, the intradural arteriovenous shunt is co-existent with a vascular malformation of a limb corresponding to the Klippel–Trenauney or Parks–Weber syndrome. 3. Single, sporadic spinal intradural AVMs. This is the most common type of a spinal intradural arteriovenous shunt. It may affect the cord, a nerve root, or the filum terminale. Angiomorphologically, the shunt is either of the plexiform (nidus) type or a small AVF. D. Spinal cord CMs This chapter will emphasize imaging evaluation of major groups of nonneoplastic spinal vascular lesions including: a. the major angiomorphologic types of spinal arteriovenous shunts, that is, the spinal dural arteriovenous shunts, the plexiform (nidus) type spinal cord AVMs, and the perimedullary AVFs; b. the spinal cord CMs; c. spinal cord ischemia and infarction; and d. spinal hemorrhage (Tables 23.1 and 23.2). It has to be noted that neither developmental venous anomalies (DVAs) nor capillary telangiectasias occur in the spinal cord and will therefore not be discussed here. Spinal Dural Arteriovenous Fistula SDAVFs, also known as type I or dorsal intradural AVFs, are the most common spinal vascular malformation, with some estimates ranging as high as 80% of the total (23,24). The use of MRI has resulted in more frequent diagnosis of these lesions, which are often undetectable by other noninvasive imaging modalities. In contrast to spinal cord AVMs, SDAVFs are believed to be acquired lesions, possibly resulting from thrombosis of the extradural venous plexus. Evidence for their acquired nature includes their virtual absence in young patients and predominance in later life; the lack of association of SDAVF with other vascular anomalies; and their predilection for a location below the midthoracic spine, where increased venous pressure exists in a standing position (25,26). Anatomy and Pathophysiology SDAVFs are arteriovenous (AV) shunts that occur within the dural covering of the spinal cord (Fig. 23.9). Usually adjacent to the intervertebral foramen or within the dural root sleeve, the shunts are most often tiny, usually receiving arterial supply from a dural branch of a single radicular artery. This most common type, with a single feeding artery, has been designated type A, and the much less common type, which receives multiple feeding arteries, has been termed type B in the modified classification. An intradural vein drains directly into the pial veins of the cord, most prominently over 1771

the dorsal aspect (27). The result is venous engorgement and venous hypertension involving the spinal cord. SDAVFs may occur at any level of the spinal cord, from the foramen magnum to the sacrum, but most commonly occur at thoracolumbar levels, usually between T5 and L3. Most often, no direct arterial supply to the spinal cord itself originates from the radicular artery feeding an SDAVF. In 10% to 15% of cases, however, the SDAVF is fed by a radicular artery that also supplies the spinal cord via a radiculomedullary or radiculopial branch (28,29).

FIGURE 23.9 Diagram of spinal dural arteriovenous fistula, illustrating the single dural branch of a radicular artery supplying the cluster of small vessels within the root sleeve that forms the fistula. The fistula drains into an enlarged intradural vein that communicates with and engorges the pial venous plexus of the spinal cord. (From Anson J, Spetzler R. Classification of spinal arteriovenous malformations. BNI Q 1992;8:2–8, with permission.)

Venous drainage from the SDAVF results in increased pressure and engorgement of the pial veins of the spinal cord. The increased venous pressure is transmitted to the intrinsic veins of the cord, reducing the intramedullary AV pressure gradient. A decrease in tissue perfusion results in hypoxia of the cord. Intramedullary vasodilation and loss of autoregulatory capacity may also occur resulting in cord edema, stagnation of blood flow, and disruption of the blood–CNS barrier (30). The longitudinal extent of cord dysfunction from the venous hypertension may be very extensive and may progress over time. Poor correlation between the location of the AV shunt and the clinical level of spinal dysfunction is a frequent finding. The chronic effects of this longstanding venous hypertensive myelopathy results in a “subacute necrotizing myelopathy” which is clinically identical to the syndrome described by Foix and Alajouanine in 1926 (31). SDAVF is, therefore, the underlying pathology in the disorder referred to as Foix– Alajouanine syndrome (23,32). The elevated pressures in spinal pial veins draining SDAVFs vary in association with arterial pressure elevations, possibly accounting for the clinical worsening reported with exercise (33). The venous hypertensive myelopathy induced by SDAVFs is reversible if treated early but may become irreversible in later stages. Clinical Presentation SDAVF, the most common spinal vascular anomaly in the older adult, afflicts males in 80% to 90% of cases. The lesions usually present after the fourth or fifth decade; however, patients from the third through the ninth decade have been reported. The progressive spinal venous hypertension resulting from SDAVF results in a chronic progressive myelopathy with both motor and sensory deficits (20,23,26,34–36). Progressive lower extremity weakness, often characterized by both upper and lower motor neuron deficits, is the most common symptom (23,36). Because of the location of the abnormal AV shunt and venous drainage, the upper extremities are not affected. Weakness is followed in frequency by localized or radicular back pain. Sensory deficits as well as bowel, bladder, and sexual dysfunction also develop in the majority of patients prior to diagnosis. Chronic progression of symptoms often exacerbated by exercise characterizes the clinical course in greater than 80% of SDAVF patients. The slowly progressive clinical course, often exceeding 2 to 3 years from presentation to the time of diagnosis, is unusual in most vascular diseases and often delays diagnosis. Progressive deficits with occasional remission or acute development of paraparesis or 1772

paraplegia are less frequent clinical courses. Hemorrhage has not been associated with SDAVF. The characteristic picture of chronic myelopathy that results from SDAVF is in marked contrast to the acute onset of symptoms, often associated with hemorrhage, that frequently occurs in the presence of a spinal cord AVM (see later discussion) (Table 23.3) (26,36–40). The nonspecific clinical picture of chronic progressive myelopathy, usually in an older man, that characterizes SDAVF requires consideration of more common disorders in the differential diagnosis. Longstanding demyelinating disease, cervical spondylosis, and amyotrophic lateral sclerosis represent the most common causes of chronic progressive myelopathy and may often be differentiated by specific clinical features. Neoplasms, syringomyelia, degenerative processes, and infectious or inflammatory myelopathy such as that associated with AIDS are less common but may present and progress in a fashion similar to SDAVF (41). The lack of specific clinical features suggesting SDAVF means that suspicion of this entity is the most important factor in early diagnosis (42). TABLE 23.3 Features of Spinal Dural Arteriovenous Fistulas (SDAVFs) and Spinal Cord Arteriovenous Malformations (SCAVMs) (type II, Intradural Arteriovenous Malformations)

Magnetic Resonance The MR characteristics reflect the pathophysiologic features of SDAVF including cord edema and venous hypertension with engorgement of the pial veins. Very uncommonly in patients with SDAVF, MR may be normal or may demonstrate only signal abnormality within the cord without dilated pial veins (43,44). Abnormal intramedullary cord signal intensity on T1, proton density, T2 FLAIR, and T2weighted images is identified in nearly all cases of SDAVF (Figs. 23.10–23.13). Cord signal abnormality was reported in 96% of patients from a series of definitively diagnosed cases in a recent review by Lindenholz et al. (45). The conus and lumbar enlargement of the cord are affected almost uniformly; however, the abnormal signal may extend into upper thoracic cord levels. Diffuse enlargement of the cord may be present (46). These MR findings are still nonspecific, because many of them may be seen in inflammatory, demyelinating, and even neoplastic conditions involving the cord. In these disorders, however, the cord parenchymal abnormalities are usually more focal than is the case in SDAVF, in which signal abnormality involving the cord from conus through thoracic levels is common. A more specific feature is the demonstration of dilated pial (i.e., intradural, perimedullary) veins of the cord, most commonly along the dorsal surface. The dilated pial veins may be seen best on T2-weighted images as areas of flow void admixed within surrounding high-signal cerebrospinal fluid (CSF). This finding was identified in 100% of cases in a recent review (45). Special care must be taken, however, to differentiate true flow void indicating engorged veins from artifacts arising from CSF pulsatile flow. This particularly is true when the veins are relatively small with slow but high-pressure flow. In such cases, the venous flow may appear isointense or even hyperintense, especially if flow compensation methods are used. Administration of gadolinium is very useful and may reveal the slow-flow veins as areas of high signal intensity (Fig. 23.14). Occasionally, gradient-echo images can be used to clarify such findings because these images do not suffer from the flow-related artifactual signal loss that plagues T2-weighted fast spin-echo in the thoracic region. If a high signal abnormality in the cord is 1773

absent despite the visualization of what appear to be dilated perimedullary veins, then the presence of a SDAVF is highly unlikely and the prominent perimedullary veins most probably represent a normal anatomic variation. Intrinsic spinal cord enhancement in SDAVF is another very frequent finding, reported to occur in over 90% of cases by the Toronto group (45); when present, it often is ill defined and patchy, and it should be taken as a manifestation of venous hypertension causing edema and with time ischemia and breakdown of the blood–cord barrier. Spinal cord enhancement is moderate in the early postinjection period and becomes more prominent after 30 to 45 minutes following injection of gadolinium. The enhancement in SDAVF usually is more accentuated in the area of the conus and its pattern is very different from that seen in intramedullary neoplasms, which tends to be more focal.

FIGURE 23.10 Spinal dural arteriovenous fistula (SDAVF). A,B: Sagittal T1- and T2-weighted magnetic resonance images demonstrate enlarged pial veins (arrow) along the dorsal surface of cord. Increased intrinsic cord signal on T2-weighted images extends from conus into thoracic levels. C: Early-phase angiographic film (anterior–posterior view) of intercostal artery injection at left T10 level. SDAVF (arrow) fills from the radicular artery with early arteriovenous shunting into the pial venous system (open arrow). D: Late phase shows extensive filling of pial veins outlining the cord from the thoracic levels to the conus (open arrows). Arrowhead at catheter tip.

FIGURE 23.11 Spinal dural arteriovenous fistula (SDAVF). A: Contrast-enhanced, T1-weighted sagittal image demonstrates flow voids along the dorsal cord representing enlarged pial veins in a patient with an SDAVF. Intrinsic cord enhancement is present. B: Sagittal T2-weighted fast spin-echo image shows abnormally increased intrinsic cord signal extending from the conus to upper thoracic levels. Dorsal flow voids are visible (arrows).

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FIGURE 23.12 Spinal dural arteriovenous fistula. A,B: Sagittal enhanced T1- and T2-weighted fast spin-echo images show enlarged pial veins as high-intensity slow flow and flow voids along the ventral (arrows) and dorsal surfaces of the cord. Patchy intrinsic cord enhancement and T2 signal abnormality extend from thoracic levels to conus medullaris.

FIGURE 23.13 Spinal dural arteriovenous fistula (SDAVF) with intramedullary enhancement. A,B: Sagittal enhanced T1- and T2-weighted images with dorsal flow voids on the cord surface. Intramedullary, patchy spinal cord enhancement and signal abnormality are present. C: Anterior–posterior view of angiographic injection of the left T6 intercostal artery. SDAVF (arrow) fills from the radicular artery with immediate shunting into pial veins of the cord (open arrow). Arrowhead at catheter tip.

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FIGURE 23.14 Spinal dural arteriovenous fistula (SDAVF), postoperative, clarified by magnetic resonance angiography (MRA). A: Sagittal contrast-enhanced T1-weighted magnetic resonance image. B,C: Rotational views of spinal three-dimensional time-of-flight (3DTOF) MRA, contrast-enhanced lumbar region. Note the suggestion of enhancing intradural vessels along the conus on the sagittal image (panel A), which is partially obscured by ferromagnetic artifacts from prior surgery. 3DTOF MRA (panels B and C) clearly demonstrates enlarged spinal arteries and markedly enlarged draining intradural and lumbar veins.

Recent observations indicate that T2 hypointensity involving the cord periphery may be a reliable imaging feature of venous hypertensive myelopathy resulting from either SDAVF or intracranial dural AVF with spinal drainage (Fig. 23.15) (47). However, other causes of superficial spinal cord hypointensity on T2-weighted images, including flow-related phase dispersion at interfaces of flowing CSF and spinal cord and spinal cord superficial hemosiderosis (Fig. 23.16), can appear similarly. It also should be noted that after treatment of SDAVF, the MR abnormalities may or may not regress completely (43,48–51).

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FIGURE 23.15 Spinal dural arteriovenous fistula. A: Sagittal T1-weighted, enhanced image demonstrates enlarged pial veins over the surface of the cord. B: Sagittal magnetic resonance angiography (MRA) also demonstrates enlarged pial veins (arrowheads). C: Sagittal MRA demonstrates a radicular artery originating from the aorta (arrowhead). D: Axial MRA demonstrates an enlarged radicular feeder to the spinal dural arteriovenous fistula (arrow). Unsubtracted (E) and subtracted (F) views from anteroposterior angiogram demonstrate injection of intercostal artery with enlarged radicular feeder (arrow) supplying the spinal dural arteriovenous fistula with pial veins over the cord surface (arrowheads).

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FIGURE 23.16 Superficial hemosiderosis involving the spinal cord. A: T2-weighted axial gradient-echo magnetic resonance demonstrates marked hypointensity over the surface of the spinal cord and within the central canal. (Courtesy of Dr. S. Galetta, Hospital of the University of Pennsylvania, Philadelphia, PA.) B: Serial axial sections at postmortem showing superficial hemosiderin deposition as depicted by positive blue Perl staining.

Spinal MRA techniques also can be used to identify enlarged intradural draining veins from SDAVF (Fig. 23.14). Newer contrast-enhanced techniques have also proven to be valuable for identifying the level of the radicular artery supply to a SDAVF (Fig. 23.15) and aiding considerably in planning angiographic evaluation and endovascular treatment of SDAVF (Fig. 23.17) (43,52–57). Luetmer et al. (57) used CE-MRA and DSA to evaluate 31 patients with suspected SDAVF. At angiography, SDAVFs were diagnosed in 22 of 31 patients, and MRA depicted a SDAVF in 20 of those 22 patients. Of the 20 true-positive MRA results, the level of the fistula was included in the imaging volume in 14. In 13 of these 14 cases, MRA results correctly predicted the side and the level of the fistula to within one vertebral level. Because many patients with SDAVF have atherosclerotic disease of the aorta, which may increase the difficulty of spinal angiography, the use of MRA can substantially reduce study time, radiation dose, and volume of contrast agent needed. Similar results have been also reported by Lindenholz et al. (45).

FIGURE 23.17 SDAVF at level T10 right side. Contrast-enhanced time-of-flight MRA (left) demonstrates SDAVF with vascular anatomy matching the selective catheter DSA (right).

Appropriately performed CE-MRA is able to correctly localize the SDAVF in over 80% of cases. Nevertheless, it does not substitute spinal DSA but due to the information it provides, it facilitates and expedites the technical execution of the angiographic procedure. Spinal angiographic examination, therefore, clearly still remains the gold standard for confirming the diagnosis, localizing the level of the abnormal AV shunt, and providing sufficient information to plan and perform treatment (Fig. 23.18). On rare occasions, drainage from intracranial pial or dural AVMs located in the posterior fossa may engorge the pial veins of the spinal cord and result in spinal venous hypertensive myelopathy (58–62). In such cases, signal abnormalities involving the brainstem and cervical cord may be present, and 1778

angiographic evaluation for intracranial lesions may reveal an otherwise occult source of engorgement of the spinal venous system (Fig. 23.19). The presence of symptoms in SDAVF is an indication for treatment because the benefits are multiple and the risks minimal (63). First-line treatment of SDAVF is usually accomplished with endovascular techniques. Endovascular occlusion of SDAVF is possible in greater than 80% of cases and can be accomplished at the same time as the diagnostic angiogram by using permanent liquid embolic agents such as N-butyl cyanoacrylate (NBCA) (64) or Onyx. For the embolization to be effective, the liquid embolic agent must reach and obliterate the initial segment of the draining radiculomedullary vein. Otherwise the embolization must be regarded as a technical failure and the patient should be submitted to surgical disconnection of the draining radiculomedullary vein. In contrast, the use of particulate emboli for occlusion of SDAVF results in nearly 100% recanalization with progression of neurologic deficits and is of only temporary benefit and therefore ineffective as a curative treatment technique (40,65,66). If endovascular therapy is unsuccessful or contraindicated as is usually the case in SDAVFs in which the radiculomedullary artery arises from the same radicular artery as the feeding radiculomeningeal branch, surgical identification and ligation of the initial segment of the draining vein with or without coagulation or resection of the shunt and surrounding dura can be safely performed in nearly all cases (24,67–69).

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FIGURE 23.18 A 78-year-old woman with progressive myelopathy and pathologically proven changes of Foix– Alajouanine syndrome. Sagittal T2-weighted image (A) shows abnormally increased intrinsic cord signal throughout the thoracic cord extending into the conus. No intradural flow voids are present. Axial T1-weighted (550/16) unenhanced (B) and enhanced (C) scans at the same thoracic level illustrate diffuse intramedullary enhancement. Unsubtracted (D) and subtracted (E) anteroposterior angiographic views demonstrate early filling of a spinal pial vein (arrows) indicating the presence of a spinal dural arteriovenous fistula (open arrow at catheter tip). Histologic sections of spinal cord biopsy showing subacute ischemic myelopathy: F: Hypocellular white matter with several small hyalinized vessels. G: Pathologic changes in blood vessels within cord parenchyma including severe sclerosis of vessel walls and obliteration of lumen. H: Trichrome staining highlights the collection of subpial, angiomatous, thickened-wall hyalinized vessels. I: Patchy loss of myelin within the cord is shown with Luxol fast blue myelin staining. J: Immunohistochemical staining with antineurofilament antibodies exhibits severely decreased neurofilament expression that appears focally in clumps. K: Immunohistochemical staining with antiglial fibrillary acidic protein antibodies shows severe gliosis. (Panels F–K: Courtesy of Dr. E. Lavi, Hospital of the University of Pennsylvania, Philadelphia, PA.)

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FIGURE 23.19 Posterior fossa dural arteriovenous fistula with drainage into veins of the cervical spinal cord. A 62year-old man with acute quadriparesis and lower cranial nerve palsies. A: Sagittal, unenhanced, T1-weighted image demonstrates high signal along the course of the anterior pontine vein with extension along the ventral surface of the medulla. B,C: Sagittal and axial T2-weighted images showing high signal throughout the cervicomedullary junction with expansion of the upper cervical cord. D: Lateral view of selective injection of the right ascending pharyngeal artery (arrow at catheter tip) shows dural arteriovenous malformation of the right jugular fossa with venous drainage inferiorly into the veins of the cervical cord.

FIGURE 23.20 Spinal cord arteriovenous malformations (SCAVMs). A: Glomus-type SCAVM with a nidus located on and within the spinal cord. B: Juvenile-type SCAVM with a nidus involving the cord as well as extending into adjacent tissue. (From Anson J, Spetzler R. Classification of spinal arteriovenous malformations. BNI Q 1992;8:2–8, with permission.)

Spinal Cord Arteriovenous Malformations In contrast to SDAVF, intradural spinal cord AVMs are congenital lesions resulting from a defect in early vascular embryogenesis. The nidus of the SCAVM is within the substance of the spinal cord itself or in the subpial space on the surface of the cord or within both, the spinal cord itself and the subpial space. The arterial supply of SCAVM arises from arteries that also directly supply the cord, that is, the radiculomedullary and/or the radiculopial arteries (Fig. 23.20). The angioarchitecture of SCAVM differs significantly from that of SDAVF. Consequently, SCAVMs display significant differences in pathophysiology, clinical behavior, and imaging findings in comparison to SDAVF (Table 23.3). 1782

Anatomy and Pathophysiology SCAVMs most frequently occur in the thoracolumbar region but may develop at any level of the cord, including the filum terminale and the intradural segment of a spinal nerve root. The arterial supply to SCAVMs arises from ASA or PSAs that also supply the spinal cord. The high flow through the nidus is thought to predispose to the formation of feeding artery aneurysms, which may occur in up to 20% of cases and constitute a significant risk factor for spinal hemorrhage (23,70,71). The actual AVM nidus may be located within or on the surface of the spinal cord. Dilated ascending and descending venous drainage is usually present located both dorsal and ventral to the spinal cord. Subtypes of SCAVM have been described based on the extent of AVM nidus. A nidus involving only the spinal cord characterizes the “glomus-type” SCAVMs, also known as type II, or intradural AVMs. The modified classification subdivides this group of intradural AVMs into those with a compact (intramedullary) and those with a more diffuse (intramedullary–extramedullary) nidus. The nidus in the much less common “juvenile-type” SCAVM (type III, extradural–intradural) also involves the spinal cord with additional extramedullary and often extraspinal extension into adjacent bone and soft tissue structures with a metameric distribution. SCAVM may result in neurologic dysfunction from a number of potential pathophysiologic mechanisms. Steal of blood from normal neural tissue with resultant ischemia is possible because of the high flow through the nidus and the common supply to both the spinal cord and the SCAVM. Venous hypertension may result from the increased pressure in the veins draining both the lesion and normal cord tissue. Thrombosis of draining veins or enlargement and venous varix formation with resultant mass effect may also be present. Hemorrhage, a particularly common symptom in SCAVM, may arise from arterial aneurysms, the nidus itself, or the draining veins. Hematomyelia, spinal subarachnoid hemorrhage, or both may result. In most cases, a combination of pathophysiologic mechanisms probably causes the development of neurologic dysfunction with resultant deficits. Clinical Presentation Large series of SCAVMs have noted a slight predominance of male patients and an average age at diagnosis in the second or third decade. At the time of presentation, however, nearly half of the patients are younger than 16 years of age (23,26,36). Greater than 30% of patients experience weakness as the initial symptom of SCAVM; however, nearly all patients develop some significant loss of motor function during the course. Back pain accompanies the onset in nearly one-fifth of patients and actually diminishes as a significant symptom later as sensory deficits, developing in greater than 70%, become more prominent. In addition, the characteristically progressive course usually involves compromise of bowel, bladder, and sexual functions. The result is confinement to bed or a wheelchair in nearly half of untreated patients within 3 years of symptom onset (72). Less frequent features include a bruit or cutaneous angioma over the location of the nidus. In contrast to SDAVF, spinal hemorrhage constitutes a prominent feature in the clinical course of greater than half of patients with SCAVM. Occurring in either subarachnoid or intramedullary locations, hemorrhage is associated with both high mortality (up to 30%) and high rates of rebleeding, which may reach 40% within the first year (72,73). However, it has to be emphasized that a spontaneous clinical recovery following intramedullary hemorrhage from a SCAVM is observed in the majority of patients (greater than 70% of patients) indicating that the prognosis following hemorrhage is significantly more favorable than previously assumed. Therefore, early aggressive treatment in the acute phase following hemorrhage from a SCAVM does not seem to be justified SCAVM may represent part of a more widespread systemic vascular disorder such as Rendu–Osler– Weber or Klippel–Trenauney syndrome (69). A complex metameric vascular malformation, Cobb syndrome, involves all embryonic layers from the spinal cord to the skin and may be present in 5% of SCAVM patients (74,75). Imaging MR provides the best noninvasive imaging information regarding spinal cord AVMs (Figs. 23.21 to 23.24). Kyphosis or scoliosis may accompany SCAVM and may be so severe as to make positioning problematic. Flow voids representing enlarged arterial feeding vessels and intramedullary nidus are well seen, although flow artifact may interfere in some cases with anatomic detail. Evidence of recent or past intramedullary hemorrhage is frequently present, although determining the presence of 1783

subarachnoid hemorrhage on MRI is difficult. Increased intramedullary signal on T2-weighted images adjacent to the nidus is also frequent and most likely indicates gliosis, edema, or areas of infarction. Flow voids of draining veins in the subarachnoid space may show areas of ectasia, mass effect, or thrombosis (77,78). In genetic, nonhereditary AVMs with a metameric link (also called juvenile SCAVMs), the multifocality of the nidus affecting in addition to the spinal cord also extramedullary structures, particularly vertebral bodies and paraspinal soft tissue structures, is also well seen on MR. Intramedullary enhancement is frequently present and has been shown to decrease after embolization therapy (56). Although MRA has not developed to the point at which specific feeding and draining vessels can be identified reliably (Fig. 23.22), it can confirm the vascular nature of signal voids and therefore can be useful as an adjunctive scanning sequence.

FIGURE 23.21 Spinal cord arteriovenous malformation (SCAVM). A: Sagittal unenhanced T1-weighted image shows intrinsic cord signal abnormality at the T7–T8 level. High signal dorsal to the cord suggests a thrombus or very slow flow in the veins. B: Enhanced T1-weighted image (400/15) reveals serpentine vascular structures within and along the surface of the cord. C: T2-weighted, fast spin-echo sagittal image illustrates intrinsic cord signal abnormality with flow voids within and along surface of the cord. Anterior–posterior angiographic injection of left T7 (D) and T9 (E) intercostal arteries show filling of the SCAVM nidus (arrows) via enlarged posterior spinal arteries. Open arrow at catheter tip.

In some cases, hemangioblastoma may mimic the presence of a SCAVM on contrast-enhanced MRI. This is particularly the case with smaller, nodular, noncystic hemangioblastomas which may exhibit contrast enhancement similar to that of a compact nidus AVM and be associated with enhancing perimedullary tubular, serpentine veins similar to the draining veins of an AVM. Angiographic evaluation of SCAVM is mandatory for planning and performance of treatment. Delineating all feeding vessels, identifying pre- or intranidal aneurysms or pseudoaneurysms, which are 1784

reliable angioarchitectural markers of a previous hemorrhagic event, locating the nidus within the cord, and mapping the size and location of draining veins are important goals to be accomplished angiographically. In addition, the normal blood supply to the cord above and below the lesion must be studied. In cases of extramedullary extension, the entire extent of the nidus and its feeding vessels must be evaluated.

FIGURE 23.22 Spinal cord arteriovenous malformation (SCAVM) (glomus type). A,B: Sagittal T2-weighted magnetic resonance (MR). C,D: Axial T2-weighted MR. Sagittal (panels A, B) and axial (panels C, D) T2-weighted images of the upper cervical spinal cord demonstrate complex intramedullary signal abnormality with cord expansion at the C3 and C4 cord levels. Mixed signal within the cord is consistent with blood storage products from previous hemorrhage and is suspicious for vessel-related flow void. Note the linear signal void anterior to the upper cervical spinal cord in the midline (panel C) resulting from the enlarged anterior spinal artery (vertebral arteries are out laterally). Intradural signal voids posterior and superior to the cord on sagittal images (panels A, B) represent prominent draining veins. E,F: Anterior-posterior right vertebral catheter angiogram. G: Three-dimensional, contrast-enhanced time-of-flight MR angiography. Catheter angiogram (panels E, F) and MR angiography (panel G) confirm findings of SCAVM. Arterial supply arises from the anterior spinal artery and from a branch of the distal right vertebral artery to feed the focal nidus (making the lesion a glomus type). Note the tortuous superiorly draining vein that is well depicted on MR angiography (panel G) and catheter angiography (panel F).

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FIGURE 23.23 Spinal cord arteriovenous malformation (SCAVM). A,B: Sagittal, T1-weighted unenhanced and enhanced images demonstrate intrinsic cord signal abnormality and adjacent flow void of the SCAVM. Abnormal signal involving vertebral bodies indicates extensive paraspinal involvement by this juvenile-type SCAVM. C: T2weighted fast spin-echo image demonstrates hemosiderin and blood storage products from prior hematomyelia. D,E: Lateral angiographic view of left and right vertebral arteries.

Treatment of symptomatic SCAVM is clearly indicated in the great majority of these patients because of the poor outcomes in untreated patients. Due to the improvements in the understanding of the pathophysiology and angioarchitecture of SCAVMs and the progress achieved in neuroendovascular technology, embolization is nowadays the preferred type of treatment for the majority of patients with a SCAVM, while microneurosurgical resection is reserved for cases in which embolization failed. The most effective embolic agent is NBCA. More recently, the liquid nonadhesive agent Onyx has also been used for embolization of SCAVMs but the experience with it is still limited. Microparticles of polyvinyl alcohol (PVA) may also be used for supplementary embolization of residual small and slower-flow compartments following embolization of the dominant compartments with NBCA.

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FIGURE 23.24 A,B: Sagittal and axial T1-weighted magnetic resonance images demonstrate high–signal-intensity hematomyelia (open arrow) of the lower thoracic cord. Adjacent flow void (arrows) represents pseudoaneurysm adjacent to hematoma. C: Anterior–posterior injection of the left T7 intercostal artery fills the anterior spinal artery axis, which supplies the arteriovenous malformation nidus (arrows) via sulcocommissural arteries. D: Injection of the right T8 intercostal artery fills the posterior spinal artery with large pseudoaneurysm (arrows).

In a significant and increasing number of cases, complete obliteration of SCAVM is achievable using endovascular techniques with an acceptably low morbidity rate. However, partial embolization selectively targeted toward angiographically identified vascular elements of the nidus responsible for the clinical manifestations, such as nidal compartments responsible for venous congestion of the cord, or compartments associated with stenosis and varix formation of their draining vein, or compartments harboring a pseudoaneurysm, which reliably point to the rupture site of the AVM, achieves the establishment of a new and more favorable hemodynamic equilibrium between the residual AVM and the surrounding parenchyma of the spinal cord providing stabilization or even improvement of the symptoms and protection from a recurrent hemorrhage. The morbidity of partial, targeted embolization of a SCAVM is lower than the morbidity of complete embolization. Therefore, complete embolization of a SCAVM is not always required in order to achieve a good or satisfactory clinical outcome (13). Additional goals of endovascular treatment may include presurgical devascularization, prevention of recurrent hemorrhage, or palliation in extensive lesions (70,71,73). Surgical resection in SCAVM also aims for complete obliteration of the lesion whenever possible. In selected lesions, good outcomes have been reported in a number of series using both methods (23,26,40,74). Close coordination between the surgeon and interventional neuroradiologist is critical for proper management of these difficult-to-treat and complex lesions (80,81). Spinal Cord Arteriovenous Fistula

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Spinal cord AVFs (also known as perimedullary AVFs, type IV, or ventral intradural AVFs) consist of direct AVFs located subpially on the surface of the spinal cord and fed directly by arteries that also supply the cord, most frequently the ASA. They have been subdivided into small (type A), medium (type B), and large (type C) based on the size of the lesion. SCAVFs constitute a small group of spinal AVMs that have been found in 8% to 19% of patients in large series of spinal vascular malformations (21,23,26). They are frequently associated with hereditary hemorrhagic telangiectasia type I. The intradural location of the shunt, constant involvement of arteries supplying the spinal cord, typical location ventral to the cord, and lack of intervening nidus are angioarchitectural features that differentiate SCAVF from both SDAVF and SCAVM (Figs. 23.25 and 23.26) (35). Believed to be congenital lesions, SCAVFs usually present in patients in their second through fourth decade. The most common neurologic presentation is one of progressive asymmetric radiculomedullary signs involving the lower extremities, reflecting the most common location of SCAVF in the lower thoracic or lumbar region. Spinal subarachnoid hemorrhage is also common and has been noted in nearly one-third of patients at presentation. Three subtypes of SCAVF have been identified based on the size and number of vessels involved and on the hemodynamics of the shunt (14,82). MRI is the noninvasive imaging modality of choice. Flow voids depict the enlarged feeding and draining vessels of SCAVF. Mass effect of the enlarged vascular structures with displacement or distortion of the cord by a large venous varix may occur. Intrinsic cord signal abnormality and evidence of hemorrhage may also be present. The small size of some lesions and lack of nidus may make differentiation from SDAVF or even detection by MRI difficult. Abnormal enhancement of the cord may be present. Angiographic evaluation of SCAVF remains necessary for complete delineation of the angioarchitecture, particularly determining the exact location of the arteriovenous shunt. In general, smaller lesions are best treated surgically, whereas larger SCAVFs are best approached by endovascular methods (83). The goal of endovascular treatment is occlusion of the fistula itself and the most proximal portion of the draining vein, preserving the ASA axis. This is best achieved with liquid embolic agents such as NBCA or detachable coils delivered in the venous side of the fistula following superselective microcatheterization of the shunt. Following complete occlusion of the SCAVF, contrast enhancement and signal abnormality within the cord may persist.

FIGURE 23.25 Diagram of a spinal cord arteriovenous fistula shows the direct fistula between the anterior spinal artery and an adjacent vein. (From Anson J, Spetzler R. Classification of spinal arteriovenous malformations. BNI Q 1992;8:2–8, with permission.)

Cavernous Malformation Unlike the spinal AVMs previously discussed, CMs are slow-flow vascular malformations without AV shunting. The widespread use of MR has resulted in an increase in diagnosis of CMs throughout the CNS, including lesions involving the spine. Although uncommon, the true incidence of spinal CMs is difficult to establish because most autopsy studies do not include the spinal cord. The reported incidence of CMs involving all regions of the CNS has been reported to be between 0.02% and 4%. Based on the spinal component weight and volume, it would be expected that 3% to 5% of CMs involve the spine. When the lesions do affect the spine, they are most often intramedullary and occur proportionally throughout the cord. Involvement of the cauda equina and filum terminale has also been described 1788

(84–86). In contrast to the equal male-to-female ratio reported in their intracranial counterparts, CMs of the spine have been noted preferentially to affect females. Kindreds have been described with multiple CMs throughout the CNS, including spinal involvement (87). CMs can occur as sporadic or autosomal dominant inherited conditions and have been attributed to mutations at three gene loci (88). Although rare, de novo development of the lesions has been described both intracranially and in the cord after trauma or radiation (89–91). The clinical presentation of CMs involving the spinal cord is variable. Although symptoms may begin at any age, patients most often present in the fourth decade. Discrete episodic neurologic dysfunction with variable recovery between episodes has been described most commonly; however, monophasic acute or chronic deterioration of spinal cord function may also occur. The acute presentation is probably secondary to hemorrhage either within the vascular spaces of the malformation or into the surrounding parenchyma (hematomyelia). Back pain is a frequent accompaniment, with the neurologic deficit beginning later and evolving over several hours to days. The pace of clinical deterioration tends to differentiate these patients from the more rapid course associated with hemorrhage from SCAVMs. Progressive myelopathy may result from growth or enlargement of the lesions by several mechanisms, including vessel dilation, repeated hemorrhage, and capillary proliferation (92,93).

FIGURE 23.26 Spinal cord arteriovenous fistula. A: Sagittal T1-weighted, enhanced image shows extensive areas of flow void both ventral and dorsal to the cord. B: Axial T1-weighted, enhanced image demonstrates flow voids along cord surface (arrows) and intrinsic cord enhancement. C: T2-weighted fast spin-echo image shows serpentine flow voids with intrinsic cord signal abnormality. D,E: Anterior–posterior views of angiographic injection of the right L2 lumbar artery in early and later phases, respectively. The enlarged anterior spinal artery supplies the direct arteriovenous fistula located on the conus with a superiorly flowing enlarged vein.

CMs of the spine are pathologically identical to intracranial CMs (also known as occult 1789

cerebrovascular malformations) and vary in size from several millimeters to greater than 1 cm in diameter. Most commonly they are well-demarcated lesions surrounded by hemosiderin-stained gliotic neural tissue. The constant presence of blood storage products suggests episodic diapedesis of blood or low-grade hemorrhage from the lesions. Acute hemorrhage within or adjacent to the lesions may be present in some cases. Histologically, blood-filled cysts are present composed of closely packed sinusoidal vascular channels with very slow blood flow. The channels have variable wall thickness ranging from a single cell layer to hyalinized, thickened walls containing densely packed collagen but no elastic or smooth muscle fibers. The gliotic tissue adjacent to the CM demonstrates constant hemosiderin staining and occasional collections of inflammatory cells. Calcification, seen in up to 15% of intracranial lesions on CT scan, is rare in spinal CMs (94).

FIGURE 23.27 Spinal cord cavernous malformation (CM). Sagittal T1-weighted (A) and (B) gradient-echo images demonstrate focal low signal intensity within the spinal cord with associated intramedullary mass. Intraoperative photograph (C) confirms an intramedullary CM extending to the surface of the spinal cord, seen as a “cluster of grapes,” after exposure of the intradural space.

MRI findings are often characteristic and usually permit a relatively specific diagnosis. A rim of low signal intensity representing iron storage products completely surrounds the lesion. Intrinsic heterogeneous signal abnormality is present on both T1- and T2-weighted images representing blood products of various ages (Fig. 23.27). Gliosis, edema, or syrinx adjacent to the lesion may cause abnormal signal in the surrounding cord parenchyma. After acute hemorrhage, the MRI appearance may be less specific, and other differential considerations for hematomyelia may need to be considered (87,95). Although most reported cases of spinal CMs are single, multiple lesions involving the spinal cord have been reported (96). In cases with characteristic MRI features, angiographic evaluation is unnecessary. Management of spinal CMs depends on the patient’s age and clinical features. No treatment is currently advised for asymptomatic lesions. Surgical exploration and resection is the treatment of choice for symptomatic lesions because of the potential morbidity of future neurologic deficits (93,97). Spinal Cord Ischemia and Infarction Although frequently devastating, spinal cord ischemia is an uncommon cause of myelopathy. The exact incidence of the disorder is difficult to ascertain, however. Some studies suggested that spinal ischemia may represent from 1% to 2% of all cases of stroke (98). In contrast, an autopsy study of 3,737 patients 1790

over a 50-year period found only 7 incidences of nontraumatic ischemic or hemorrhagic myelopathy (99). In cases of suspected ischemic damage to the spinal cord, MRI is the diagnostic study of choice. As is the case throughout the CNS, imaging evaluation of ischemia and infarction of the spinal cord is best approached with a thorough understanding of the vascular distributions supplying the involved region. The large intramedullary distribution of the ASA and the dependence of most cord gray matter and major white matter tracts on ASA supply are important features. The relative isolation of the ASA distribution from PSA collaterals and the frequent dependence of the ASA, especially in the thoracic and lumbar regions, on a single radiculomedullary feeding vessel are also important in determining both the clinical and MRI features of spinal cord ischemia. First described by Spiller in 1909, ischemia involving the ASA distribution is most often characterized clinically by the abrupt onset of flaccid paralysis associated with decreased or absent pain and temperature sensation below the level of the lesion. Bowel and bladder dysfunction are also present. In contrast, posterior column functions are usually preserved because of the intact PSA supply to these cord structures. The result is a dissociated sensory deficit with loss of pain and temperature in the face of intact posterior column functions including vibratory sensation and proprioception. The initial cord deficits are often incomplete and may be unilateral, reflecting the lateralized distribution of the sulcocommissural branches of the ASA. The sparing of posterior column function often permits clinical differentiation from a Brown-Sequard syndrome resulting from cord hemisection. Particular susceptibility of the thoracic and lumbar cord regions to ischemia results from the poor collateral flow via adjacent segments of the ASA in the event of compromise of a major radiculomedullary artery. In contrast, the multiple collateral routes to the cervical ASA seem to provide some protection from infarction at these levels, at least in cases of proximal or radiculomedullary artery obstruction. As in spinal shock associated with traumatic lesions, the initially flaccid areflexic paralysis often develops into spasticity with Babinski signs and a return of some degree of sphincter control. Although a pattern of clinical deficits referable to the ASA distribution suggests a vascular etiology, ischemia may involve both ASA and PSA distributions, resulting in the less specific picture of complete loss of cord function. Ischemia confined to the PSA distribution has been described but is recognized very rarely. Several clinical situations have been associated with infarction of the spinal cord and should prompt consideration of the diagnosis when present in the clinical history. Spontaneous aortic dissection may be the most common cause of ischemic damage to the spinal cord and has been associated with spinal infarction in nearly 2% of cases. Dissections involving the descending aorta (i.e., types I and III) are most often associated with the complication, whereas those confined to the ascending aorta (type II) manifest cord ischemia only rarely. The clinical features suggest that damage to multiple radicular arteries with compromise of both ASA and PSA distributions is an important etiologic factor. Sudden onset of paraplegia and sensory loss are usually accompanied by sharp chest or abdominal pain, which often radiates into the lower extremities. Loss of peripheral pulses is a frequent feature. Surgical repair of the aorta has also been associated with ischemia and infarction of the spinal cord, with the highest incidence of cord complications resulting from repair of aortic aneurysms. Similar to the situation with aortic dissections, the incidence of cord ischemia is related to the extent of the aneurysm. In one large series, repair of thoracoabdominal aneurysms resulted in a 21% incidence of paraplegia, whereas repair of aneurysms confined to the abdominal aorta resulted in only a 1% incidence of this complication (101). Repair of aortic coarctation has also resulted in spinal cord ischemia, with reported rates of the complication varying from 0.4% to nearly 3% (102,103). Procedures using endovascular stent grafts have also resulted in cord ischemia. Spinal ischemia may also result from procedures in which ligation of radicular arteries was performed such as scoliosis correction and pneumonectomy. Angiographic examination of thoracic or abdominal branches of the aorta may rarely result in ischemic spinal cord complications. The spinal cord damage probably arises from inadvertent catheterization of branches giving rise to radiculomedullary arteries with resultant arterial spasm or accidental introduction of atheromatous emboli, blood clot, or air. Although a feared complication of spinal angiography, ischemic cord damage is uncommon with current angiographic techniques. Two recent studies evaluated the incidence of complications associated with spinal angiography in 151 patients. They found that spinal angiography carries a risk of neurologic complications in the range of 2.2% to 3.6% (34,104). All complications identified in the studies were transient. Although the small numbers of patients evaluated preclude definite conclusions regarding incidence of complications, data suggest that when performed by experienced personnel, risks of spinal angiography are similar in 1791

incidence to those associated with cerebral angiography (105). Atherosclerotic involvement of the aorta with occlusion of radicular arteries is extremely common; nonetheless, ischemic myelopathy rarely results. The infrequency of cord ischemia may reflect the slow progression of the arterial occlusion in atherosclerosis, which permits adequate collateralization via intersegmental collaterals from adjacent levels. Similarly, thromboembolic occlusion of vessels leading to cord ischemia also appears to be a rare phenomenon. An autopsy study of 1,000 cases found only one instance of atheromatous emboli to the ASA in a patient with symptoms of cord ischemia (106). Decompression sickness has been associated with ischemic myelopathy in a number of reports (107,108). In such cases, blockage of epidural veins by nitrogen bubbles appears to result in impairment of spinal cord venous return with a consequent hemorrhagic myelopathy. Cases of spinal cord ischemia have also been associated with polyarteritis, giant cell arteritis, syphilis, sickle cell anemia, antiphospholipid antibody syndrome, prothrombin variants, and protein S deficiency (109–111). MRI findings in spinal cord ischemia are similar regardless of the etiology of the infarction (105,112,113). In the early acute phase of spinal cord ischemia, diffusion-weighted imaging (DWI) sequences in the axial plane of section are the most sensitive and reliable MR technique to detect or exclude acute cord ischemia. Acute cord ischemia exhibits high signal intensity due to restricted diffusion caused by the intracellular, vasogenic edema in the involved ischemic territory (Fig. 23.28). In a recent study, 14 out of 14 patients with clinically suspected acute spinal cord ischemia demonstrated abnormal high signal intensity on DWI images in a location and with a distribution compatible with the clinical symptoms (114). From day 2 on following symptom onset, T2-weighted images show abnormal high signal intensity of the involved ischemic territory of the cord. T1-weighted images are often normal or demonstrate only subtle cord enlargement in the acute stage. In the subacute phase of spinal cord ischemia, areas of intrinsic cord signal abnormality are best seen on proton density–weighted and T2-weighted images (Fig. 23.27). Both axial and sagittal images are useful in demonstrating the areas of abnormal signal. Signal abnormality may involve only the gray matter structures, but in more severely affected patients it extends throughout the entire cross section of the cord to affect both gray and white matter, suggesting involvement of both ASA and PSA vascular distributions. T1-weighted images are often normal or demonstrate only subtle cord enlargement in the acute stage. Small studies also suggest that DWI has the potential to be a useful and feasible technique for the detection of spinal infarction (Fig. 23.29) (115).

FIGURE 23.28 A 70-year-old man became paraplegic following surgery of a thoracoabdominal aortic aneurysm. A: Sagittal T2-weighted images show central increased signal intensity (arrows) of thoracic spinal cord extending down into the conus. B: Central hyperintensity with classic configuration conforming to spinal cord gray matter, indicating infarction. Also note the diseased aorta along the left side.

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FIGURE 23.29 Spinal cord infarction, diffusion MR (courtesy L. Tannenbaum, Newark). A: Sagittal T1, postcontrast; B: sagittal T2; C: sagittal DWI. Note abnormal distal spinal cord and conus on conventional images (A,B) with slight enhancement. Diffusion-weighted images (C) show marked hyperintensity indicating restricted diffusion in acute infarction.

After administration of gadolinium, cord enhancement may occur, especially involving the gray matter. Enhancement has been noted within several days of infarction and may last as long as several months. In the chronic stages, cord atrophy may be present. MR signal abnormalities representing areas of infarction within adjacent vertebral bodies or evidence of aortic dissection may suggest the ischemic etiology of the cord signal abnormalities. The MRI findings of cord ischemia and infarction are often nonspecific; however, and highlight the usefulness of clinical information in suggesting the diagnosis. MRI findings in patients with SDAVF may be similar and reflect venous hypertension, possibly with venous infarction of the cord. Similar MRI findings may also result from transverse myelitis, demyelinating disease, intrinsic cord tumor, or inflammatory etiologies (116–118), although the predilection for the central gray matter and the abrupt clinical syndrome make the diagnosis of arterial spinal cord infarction obvious in most cases. Spinal Hemorrhage SCAVM is a common cause of nontraumatic spinal hemorrhage, and a finding of hematomyelia or spinal subarachnoid hemorrhage should prompt serious consideration of the diagnosis. CMs of the spinal cord, similar to those in the brain, may hemorrhage with resultant hematomyelia or spinal subarachnoid hemorrhage (89,119). Recent reports have also implicated vascular malformations, particularly small epidural AV shunts, in the etiology of spinal epidural hemorrhages (27,120,121). Anticoagulant therapy represents an important predisposition to hematomyelia and should also be considered in any patient presenting with nontraumatic intramedullary spinal hemorrhage (122). Hemorrhage into cord tumor, syrinx, or hemorrhagic areas associated with inflammatory myelitis may also be clinically significant (123). Extramedullary intraspinal hemorrhage also may occur spontaneously. The appearance of intramedullary hemorrhage on the various MRI pulse sequences is time dependent and its detection and analysis follow the same rules as hemorrhage in the brain parenchyma.

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24 Spinal Infection and Inflammatory Disorders Renato Adam Mendonça

INTRODUCTION This chapter discusses the role of magnetic resonance imaging (MRI) in the diagnosis of infectious and other inflammatory conditions that affect the spine and its contents. The most common of these conditions will be discussed according to their location, using an external to internal anatomic approach. Subsequently, many of the infectious pathogenic agents are discussed individually.

INFECTIOUS SPONDYLODISCITIS Infectious spondylitis is a condition that may affect one or more of the components of the spinal column and can be described etiologically as pyogenic, granulomatous (tuberculous, brucellar, fungal), and parasitic. Although rare, it is the main manifestation of hematogenous osteomyelitis in patients aged over 50 years (1) and represents 3% to 5% of all cases of osteomyelitis (1). The incidence of pyogenic spondylodiscitis is around 1:250,000 (1). Hematogenous spread, resulting in lodgment of organisms in the vertebral marrow, is the accepted mechanism of spondylodiscitis in adults. Although the venous plexus of Batson and arterial systems have both been implicated in carrying the pathogens, the latter is now recognized as the more important path to infection. In order to distinguish the different patterns of disease in adults and children, it is important to have some understanding of the vascular anatomy of the spine and its developmental modifications. In children, intraosseous arteries display extensive anastomoses that prevent a septic embolus to produce a substantial osseous infarct. On the other hand, as terminal arterioles penetrate the disc, infection affects initially and is usually limited to this structure. In adults, the disc is avascular, the intraosseous anastomoses involute, and the intraosseous metaphyseal arteries become end vessels, for this reason susceptible to infarcts. A septic embolus can then cause a septic infarct of a large wedge-shaped subdiscal area of bone when it occludes one of them. Due to the relatively slow flow of the intraosseous metaphyseal artery, the thrombus will eventually extend retrogradely and circumferentially, obtruding the origins of other intraosseous metaphyseal arteries, disseminating the process to the whole plateau. Further progression of the infection is also dependent on the vascular anatomy. As the adult superficial net of arteries become extensive, the infection can extend straight to the opposite vertebral endplate of the same vertebral body, without affecting its central part, through primary periosteal arteries. It can also reach the adjacent vertebral body endplate, across an intact disc, through intermetaphyseal arteries. Pyogenic spondylitis is most frequently caused by hematogenous spread from distant infectious foci, but it can occur also by direct inoculation, most commonly iatrogenic following spinal surgery, lumbar puncture or epidural procedures, or by contiguous spread from neighboring infected organs like the oropharynx, pleural cavity, and thoracoabdominal wall. Rarely, it may follow stab or gunshot wounds to the spine. The most common sources of septic emboli are, in decreasing order of frequency, infections from genitourinary tract, skin, and upper respiratory tract. Staphylococcus aureus is the most common organism identified (up to 60%), 2% to 16% of which are reported to be methicillin-resistant S. aureus (MRSA) (1) followed by Enterobacteriaceae (up to 30%). Other organisms commonly isolated include Staphylococcus epidermidis, Haemophilus influenzae, and different groups of Streptococcus. Salmonella infection is known to be more common in patients with sickle-cell disease. 1798

Elderly diabetic patients, 60 to 70 years old, are more frequently affected, men almost twice than women. Hematogenous pyogenic spondylodiscitis affects preferentially the lumbar spine, followed by the thoracic and cervical spine in decreasing frequency (58%, 30%, and 11% respectively) (2), possibly reflecting the relative proportions of blood flow. Other risk factors include advanced age, injecting drug use, immunosuppression, malignancy, renal failure, rheumatologic disease, liver cirrhosis, and previous spinal surgery (Table 24.1). Spondylodiscitis is characterized clinically by back pain, localized tenderness, muscular spasm, and stiffness with or without neurologic compromise. The presence of fever is variable, and if absent should not sway anyone away from the diagnosis. The time interval between onset of suggestive clinical symptoms and presentation to medical services is between 2 weeks and 6 months, most often between 2 and 6 weeks. The erythrocyte sedimentation rate (ESR) is almost always elevated and constitutes a good laboratory index. C-reactive protein (CRP) is similarly raised in the large majority of cases with spondylodiscitis and some authors suggest that it is the preferred marker for monitoring response to treatment (3). The leucocyte count is the least useful among the inflammatory markers; it is high in only a third to half of affected patients. TABLE 24.1 Predisposing Factors for Spinal Infections (2)

Although the final diagnosis relies on culture of causative organisms from a biopsy sample, blood culture, pus culture, or even urine culture, it is not infrequent to treat patients without identification of the agent. Cultures of specimens may be falsely negative in up to 39% of cases of osteomyelitis (3). The accuracy of histopathology in the diagnosis of osteomyelitis is high, but its clinical utility is limited since the antimicrobial treatment must be guided by the identification of the causative organism. Besides that, MRI can detect and diagnose the infection noninvasively. The primary treatment of the neurologically intact patient involves the use of immobilization and antibiotics (3). In most cases this is effective, and surgical intervention is not required. However, in a small proportion of cases, open or endoscopic surgery is warranted. Radiographic and MR findings may be very slow or inconsistent in resolution of infection-related abnormalities. For this reason the efficacy of conservative treatment may be estimated in individual cases by diminution of pain, resolution of fever and leukocytosis, as well as by a declining ESR and CRP. A falling ESR during the first month of nonsurgical treatment is a good prognostic sign; however, success of conservative treatment is seen in 40% of cases with persistently elevated or rising ESR. Plain radiographies have a sensitivity of 82%, specificity of 57%, and accuracy of 73%, and they are frequently employed as a screening test. They may reveal early changes such as subchondral radiolucency, loss of definition of the endplate, and loss of disc height. Later changes include destruction of the opposite endplate, loss of vertebral height and paravertebral soft tissue mass. The radiologic changes, however, tend to appear only 2 to 8 weeks after onset of symptoms and false positive results can occur due to degenerative changes. Several tracers have been used in the radionuclide imaging of spondylodiscitis.Technetium-99 mmethylene diphosphonate bone scintigraphy has a reported sensitivity of 90%, but a poorer specificity of 78%, degenerative changes resulting in false-positive results. Gallium-67 scintigraphy is a valuable adjunct to bone scan and when combined they have a sensitivity of 90%, a specificity of 100%, and accuracy of 94% (Table 24.2). Fluorine-18 fluorodeoxyglucose positron emission tomography (FDGPET) can effectively distinguish infection from degenerative changes even when MRI is inconclusive, 1799

although it cannot differentiate infection from neoplasm. TABLE 24.2 Diagnostic Studies in Spinal Osteomyelitis

Computed tomography (CT) is the best modality at delineating bony abnormalities, including early endplate destruction before they become visible on x-ray, later sequestra or involucra formation, or pathologic calcification suggestive of tuberculosis (TB). It is inferior to MRI in imaging neural tissue and abscesses. Disc changes appear as hypodense areas. CT is currently mostly used for the radiologic guidance of spinal biopsy. MRI is unquestionably considered the modality of choice for the radiologic diagnosis of spondylodiscitis. It has a reported sensitivity of 96%, specificity of 93%, and accuracy of 94%, with the advantage of providing anatomical information related to the paravertebral muscles, the epidural space, and the spinal cord. In spite of MRI being the most sensitive technique for diagnosing spondylodiscitis, its findings may still lag behind the clinical symptoms, which may even include severe back pain. When the diagnosis is uncertain, a follow-up MR in 1 week may be helpful to show the evolution of the early changes. The MR findings of spondylodiscitis include the following: 1. Areas of low signal intensity on T1-weighted images (T1WI) and high signal intensity on T2-weighted images (T2WI) (Figs. 24.1 and 24.2), the latter better depicted on fat-saturated, fast spin-echo (FSE) or short-TI inversion recovery (STIR) images). They are usually homogeneously distributed throughout the whole vertebra but mostly at one of the vertebral body metaphyses. These signal alterations often precede the destructive changes and are predominantly a consequence of edema.

FIGURE 24.1 Magnetic resonance imaging of a 1-year-old boy presenting with irritability, lumbar paravertebral musculature spasm, and crural paraparesis. Discitis at the L1–L2 level. A: Sagittal T1WI showing hypointensity of L1 and L2 vertebral bodies, and in distinction of the vertebral endplates. B: Sagittal T2WI showing hyperintensity of adjacent portions of L1 and L2 vertebral bodies and of the intervertebral disc. Note the absence of the internuclear cleft in the normal intervertebral discs at this age. C: Sagittal Gd-T1WI showing marked enhancement of L1–L2 intervertebral disc, L1 and L2 vertebral bodies, and prevertebral soft tissue mass.

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FIGURE 24.2 Spondylodiscitis in a 13-year-old boy complaining of worsening lumbar pain that began around 65 days before the magnetic resonance examination. Fever (40°C [104°F]). A: Sagittal T1WI showing hypointensity of adjacent portions of L2 and L3 to the intervertebral space L2–L3 and in distinction between the disc and intervertebral bodies. B: Sagittal T2WI depicts hypointensity of the periphery of the intervertebral disc, absence of the internuclear cleft, and hyperintensity of the central portion of the disc that bulges into adjacent endplates. Reduction of the height of the disc. Hyperintensity of adjacent portions of vertebral bodies. C: Sagittal Gd-T1WI showing enhancement of adjacent intervertebral bodies and around the central part of the disc, suggesting abscess.

2. The intervertebral disc presents variable intensity on T2WI, typically hyperintensity, and one cannot identify the internuclear cleft. The height of the intervertebral disc may be reduced (Figs. 24.2 and 24.3). Sometimes disc material can herniate into the softened neighboring endplates (Fig. 24.2) or into the spinal canal. 3. There is discontinuity of the margin between the disc and the intervertebral body, better depicted on T2WI (Figs. 24.1B and 24-2B). 4. Diffuse and homogeneous enhancement is seen in the affected marrow and most of the infected discs (Figs. 24.1C and 24-2C) (4). 5. Extension of the process into the paraspinal region is variable, being insignificant in most cases of pyogenic spondylitis. Some granulation tissue, however, may be produced and distributed evenly and circumferentially around the vertebral body (24-4C). Intravenous administration of paramagnetic agents has been shown to be very important to establish with confidence the presence of epidural extension and associated meningeal inflammation. When there is a true abscess, the enhancement is peripheral, helping characterization and delimitation. 6. Intraosseous or extra-axial abscesses show restricted diffusion (bright) on diffusion-weighted imaging (DWI) and dark appearance on diffusion-weighted maps. DWI sequence may help to distinguish acute from chronic stage of the disease. These findings are summarized in Table 24.3. In the same way in which the MR findings lag behind the early signs of disc space infection, they also lag behind in the healing phase of vertebral osteomyelitis. Once adequate antibiotic treatment has been instituted, the clinical symptoms improve dramatically, whereas the MR findings evolve much more slowly. The findings of healing osteomyelitis include persistent disc space narrowing, decreased signal intensity of the disc on T2WI consistent with disc degeneration, fusion of the adjacent vertebral bodies, and resolution of the high signal intensity in the adjacent endplates corresponding to resolution of the edema (Fig. 24.3). If there was an epidural or paraspinal abscess, these compartments also return to normal. In the early stages of treatment, laboratory findings such as sedimentation rate, CRP, and white cell count are more helpful in monitoring the response to treatment than the MR findings. Follow-up in patients with spondylodiscitis after the first 2 months can easily be done with MR. The finding of high signal intensity on T1WI from a previously infected vertebra reflects replacement of cellular marrow by fat, indicating healing. Involvement of posterior elements of the spine with infection can be isolated to the facet joint and pedicle or lamina or can be contiguous with anterior vertebral body infection, which occurs more commonly with tuberculosis than with pyogenic spondylytis. Childhood discitis is an infectious process of the intervertebral disc that differs from that of the adult because of patterns of arterial spine circulation. In children there are terminal arteries to the disk and 1801

consequently it is affected primarily by the germ, while in teenagers and in adults the disc involvement follows that of the endplate. It has a bimodal distribution occurring between 6 months and 4 years of age, with a second peak from 10 to 14 years of age. It most commonly involves the lumbar region at the L2–L3 and L3–L4 levels. Clinical presentation is variable and there is frequently a delay in the diagnosis due to the uncharacteristic symptoms and signs as well as to the difficult communication with child of 1 to 3 years of age. Symptoms include fever, irritability, refusal to walk, back pain, inability to flex the lower back, and a loss of lumbar lordosis. Mild leukocytosis and an elevated ESR and CRP levels are usually present; results of blood cultures can often be negative. In one-third to one-half of patients, however, results of blood cultures or biopsy materials are positive and the infectious agent is almost always S. aureus. Radiographs of the spine are usually normal in the early stages of disease, findings of bone scintigraphy can be positive as soon as 1 to 2 days after the onset of symptoms, demonstrating increased uptake in the intervertebral bodies on each side of the disk involved. However, bone scintigraphy is not specific and cannot differentiate discitis from other causes of back pain. Radiographs become very specific after the second and third weeks of disease. In a series of 33 children with discitis, 76% had abnormalities detected on spine radiographs and the most frequent finding was decreased height of the discs and erosion of adjacent vertebral endplates. MRI is the study of choice because it can detect discitis early on, reduces the diagnostic delay, and may help to avoid the requirement for a biopsy. MRI findings include loss of the normal hyperintense signal intensity of the disk on T2WI, narrowing or complete absence of the disc, and abnormal increased T2WI in the adjacent vertebral bodies, consistent with marrow edema. There may be contrast enhancement of the disk and adjacent vertebral body, disc herniation, extradural flegmon, and abscess. The evaluation for suspected discitis must exclude spinal cord compression (5). Treatment includes bed rest, spinal immobilization, and most children receive systemic antibiotics, what is usually successful. Some argue that the natural history of this condition is benign and that antibiotics are only indicated when symptomatic treatment, such as immobilization, has failed. Follow-up radiographs will show persistent narrowing of the intervertebral disk space and sclerosis at adjacent vertebral bodies weeks or months after the initial diagnosis. Most patients will be asymptomatic within 3 weeks following antibiotic treatment. Disc space height can sometimes be restored. Patients must be followed up at least for 2 years, when most spines are mobile and the patients free from pain. Radiologic fusion occurs in approximately a fifth of the cases. MRI shows variable appearances: changes in the vertebral body usually resolve at 24 months and recovery of disc is seen after 34 months (5).

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FIGURE 24.3 Discitis: evolution after therapy. A 55-year-old woman with no infectious risk factors presenting with severe low back pain. A,B: Sagittal proton density–weighted image and T2WI demonstrate typical findings of L5–S1 discitis and a large epidural mass suggesting epidural abscess (arrow). C: Gd-T1WI demonstrates no area of low intensity in the epidural mass to suggest the presence of pus. This appearance is more suggestive of granulation tissue. D,E: Sagittal proton density—weighted image and T2WI. F: Sagittal Gd-T1WI after antibiotic treatment demonstrates almost complete resolution of the disc infection and epidural granulation (arrow). Note the complete loss of disc height with fusion of the L5 and S1 vertebral bodies. The patient was asymptomatic.

Discitis should be considered as diagnosis in children with refusal to walk or gait disturbances especially in combination with elevated ESR. MRI is the tool of choice to set the diagnosis early. With an adequate and early therapy with bracing and antibiotics, a result without spine instability or deformity can be achieved. Postoperative spondylodiscitis is an infrequent complication of lumbar disc surgery, being the reported incidence 1%-3, 4% (6). The most probable cause is intraoperative contamination rather than hematogenous spread, although both may happen in a surgically traumatized and poorly vascularized area (locus minoris resistentiae). The most common clinical features are recurrent pain after initial postoperative relief, muscle spasm, elevated temperature, and positive straight leg-raising test. ESR is not a good test because it is usually increased postoperatively in the absence of infection. CRP is a more reliable screening test for infections after lumbar disc surgery, especially if it was known to be negative before surgery. The roentgenographic findings appear several weeks after the initial symptoms. MR may be helpful earlier, but only infrequently it is possible to reliably diagnose infection before 3 weeks. Distinguishing early MR findings of postoperative discitis from normal postoperative disc space changes may be a challenge. Depending on the surgical technique, the operated disc and the adjacent endplates may show more or less extensive changes, besides those existing previously to the surgery. These changes are due to the intervention itself and to the degree of supervening aseptic inflammatory response. A minimally invasive surgery of the intervertebral disc is completely different from extensive disc instrumentation for placement of a cage, for example, making sometimes impossible the differential diagnosis with infection. 1803

FIGURE 24.4 Discitis in a 7-year-old boy complaining of back pain. A: Sagittal T2WI showing hyperintensity of the posterior part of the L3–L4 intervertebral disc that is bulging at the inferior posterior endplate of L3. There is also slight hyperintensity of the adjacent vertebral bodies. B: Sagittal Gd-T1WI showing enhancement underneath the posterior longitudinal ligament and slight enhancement of the adjacent portions of vertebral bodies related to the L3– L4 intervertebral disc. C: Axial Gd-T1WI. Note the granulation tissue distributed evenly and circumferentially around the vertebral body and the enhancement of the posterior part of the intervertebral disc.

Gadolinium enhancement of the vertebral bone marrow, disc space, and posterior annulus fibrosus is not specific for bacterial infection, being seen also in asymptomatic patients what makes MRI more effective for exclusion than for confirmation of postoperative spondylodiscitis. Suspicion of septic postoperative discitis should be confirmed by MRI, serum CRP, and disc puncture. MRI is not reliable as the sole method for distinguishing septic from aseptic discitis in the early postoperative stage (6). Some general guidelines, however, may be followed: 1. The absence of vertebral endplate changes with low signal on T1WI and high signal on T2WI makes septic spondylodiscitis highly unlikely. 2. The absence of contrast enhancement of the intervertebral space makes spondylodiscitis improbable. TABLE 24.3 Magnetic Resonance Imaging of Spondylodiscitis

3. An enhancing rim of soft tissue around the affected intervertebral space is suggestive of spondylodiscitis. 4. The presence of two parallel thin bands of enhancement in the disc space suggests postdiscectomy, while more amorphous enhancement is generally seen with infection. Conservative management based on bed rest, immobilization, and antibiotics is the initial treatment of choice for postoperative spondyldiscitis. However, surgical treatment is indicated much more frequently than in cases of spontaneous septic spondylodiscitis. The differential diagnosis of septic spondylodiscitis includes degenerative changes, granulomatos spondylitis, dialysis-related arthropathy (Fig. 24.5), pseudoarthrosis, neuropathic arthropathy, and Richter syndrome (Table 24.4).

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Hematogenous Pyogenic Facet Joint Infection This is a rare but underdiagnosed condition that occurs primarily in the lumbar spine (Fig. 24.6) but also in the cervical spine and rarely in the thoracic spine (Fig. 24.7). The exact incidence of this entity is unknown because it is believed that some of the patients may heal spontaneously without any treatment. Although pyogenic facet joint infections may occur after facet joint injections or complicating an epidural abscess, most cases are primarily hematogenous. As part of the spine pyogenic infection spectrum, the predisposing factors, the infectious agents, and probably the same physiopathology are the same as those previously mentioned for pyogenic spondylitis. TABLE 24.4 Differential Diagnosis of Infectious Spondylodiscitis

FIGURE 24.5 Chronic dialysis arthropathy in a 48-year-old man undergoing long-term dialysis treatment. Sagittal T1WI (A) and T2WI (B). Notice the substitution of the C4–C5 disc by material with intermediate signal on T1WI and T2WI, the extradural accumulation of the same material, and the compression of the spinal cord.

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FIGURE 24.6 Infectious arthritis at left L3–L4 interapophyseal joint consequent to intra-articular injection of corticosteroid in a 45-year-old man. Parasagittal T1WI (A) and T2WI (B). There is loss of cortical bone, effacement of soft tissues, and signal heterogeneity of the involved facets. Axial T2WI (C) showing destruction of cortical bone and slight hyperintensity of L3 left inferior and L4 left superior facets. Axial Gd-FS-T1WI (D) showing intense enhancement of the joint of ligament flavum and of bilateral paravertebral muscles.

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FIGURE 24.7 Septic arthritis and extradural empyema at T5–T6 in a 35-year-old man. Sagittal T2WIs (A,B) and axial Gd-FS-T1WI (C). There is hyperintensity of the left pedicles and facets of T5 and T6 and a small extradural fluid collection posterior to T5 and T6. The same bone-affected areas enhance vividly by the paramagnetic agent, as do the margins of the collection. (Courtesy of Dr. Marcelo Rossi, Campinas SP, Brazil.)

It represents around 4% of all hematogenous spinal osteomyelitis and ESR and CRP are elevated in all cases. Positive tissue and/or blood cultures are easily obtained. Formation of epidural abscess complicates 25% of the cases; of these, 38% develop severe neurologic deficit. The usual presentation of lumbar facet joint infection is severe back pain that may radiate to the flank or buttocks and does not improve with bed rest. Hematogenous cervical facet joint infection shares many characteristics with the more common lumbar entity. However, the very few cases reported have been complicated by epidural abscess or granulation tissue formation that has led to neurologic deficit, suggesting a less benign course than in the lumbar spine. When it occurs in the cervical spine there may be stiffness of the neck besides neck and trapezius muscle pain. Patients may be febrile, present chills, and report radicular symptoms. The time between initial symptoms and diagnosis is a little shorter than for spondylodiscitis, around 4 weeks. In addition, the symptoms associated with facet arthritis tend to be unilateral and present more acutely and severely in the earlier stages. Imaging studies are essential for diagnosis. Plain radiographs, including oblique views, may show changes consistent with erosive arthritis of the interapophyseal joints after 6 to 12 weeks. These changes consist in narrowing or enlargement of the articular space and the presence of irregular lytic lesions and erosions on the facets themselves. CT can show alterations earlier than that, although they may take as long as 9 weeks to appear: loss of subchondral bone adjacent to the facet joint, variable expansion of the joint with fluid density, loss of density of ligamentum flavum, presence of mixed lytic and sclerotic changes, and presence of contiguous posterior paraspinal phlegmon inflammation or abscess. Although nonspecific, technetium-99 bone scintigraphy and gallium-67 scintigraphy are both sensitive 1807

in the early detection of septic facet join arthritis but may be falsely negative in the first week. MRI is sensitive and specific in diagnosing pyogenic facet joint infection as early as 2 days after the beginning of symptoms. Besides being more sensitive, MR shows signal intensity changes and enhancement of the affected bone structures and soft issue component of the lesion (Figs. 24.6 and 24.7; Table 24.5). The differential diagnosis includes neoplastic processes, erosive arthritidis such as rheumatoid arthritis (RA), multicentric reticulohistiocytosis, and scleroderma. TABLE 24.5 Magnetic Resonance Imaging of Septic Arthritis of Apophyseal Joints

Rheumatoid Arthritis The cervical spine involvement in RA is frequent and early in the course of the disease. The positive radiographic signs of its involvement are in the range of 43% to 86% depending on the duration of the affection. After the metacarpophalangeal joints the cervical spine is the most common site affected in RA. Acute and chronic manifestations of synovitis in patients with RA were characterized with MRI including contrast-enhanced images obtained immediately and 5 minutes after the injection, and histologically correlated, as follows: Joint effusion: hypointense on T1WI, hyperintense on T2WI, enhancement initially on the periphery, homogeneous enhancement on late images Hypervascular pannus: hypointense on T1WI, hyperintense on T2WI-weighted, intense, and early enhancement that remain constant on late images Hypovascular pannus: hypointense signal on T1WI, intermediate signal on T2WI, moderate enhancement that persists o late images Fibrous pannus: hypointense on T1WI and on T2WI, slight if any enhancement The usual findings at the discovertebral junction of patients with RA are intervertebral disc space narrowing, subchondral osseous irregularities, and erosions with adjacent eburnation. Osteophytes are not included, which constitutes an important element in the differential diagnosis with degenerative changes. In the interapophyseal joints, narrowing and erosions are common. In approximately 10% of patients with RA, erosions or even destruction of one or more spinous processes can be detected. Evolving RA can eventually lead, sometimes in only 2 years after its first clinical manifestation, to three different patterns of instability in decrescent frequency: atlantoaxial subluxation, subaxial subluxation, and atlantoaxial impaction. Subaxial subluxations can be observed at one or more levels of the cervical spine caudad to C2, particularly at the C3–C4 and C4–C5 levels (Fig. 24.8). The prevalence of atlantoaxial subluxation is between 12% and 33% (4,7), most of them anterior atlas axis subluxation (AAAS). Although it is more frequently asymptomatic, it can evolve initially to compression of the occipital nerve roots, and sequentially to compression of the spinal cord, resulting in myelopathy with long tract symptoms, tetraparesis and, without proper treatment, to death. Atlantoaxial instability is a consequence of transverse ligament laxity that follows synovial inflammation between the dens and the atlas. It can be further accentuated by erosion of the odontoid process, detected in 14% to 35% of RA patients (Figs. 24.9 and 24.10). AAAS is diagnosed when the distance between the posteroinferior aspect of the anterior arch of C1 and the most anterior aspect of the dens (ADI) is ≥3 mm. Dislocations can occur also in vertical and lateral directions. Vertical subluxation, atlantoaxial impaction, and cranial settling are names given to the upward migration of the odontoid process caused by loss of the supporting ligamentous structure. It is a relatively uncommon and life-threatening 1808

complication that affects 5% to 8% of patients with longstanding RA. In lateral subluxation of the atlantoaxial joints, the atlas shifts and tilts laterally due to bone erosion, disruption of the articular capsules, or collapse of the lateral masses of the axis. Evaluation of the craniocervical junction is clinically difficult, which is why the examination is frequently supplemented with imaging diagnostic methods. The radiographic study can include the careful dynamic assessment with films obtained with the patient flexing and extending the neck to determine the existence of instability. Besides the dynamic evaluation, plain films can detect only advanced stages of the disease, and multichannel spiral CT is the preferred method for evaluating the effect on bone structures at the higher cervical spine. Evaluation of the soft tissues is still better achieved with MRI. Dynamic MRI studies of the cervical spine can also be obtained with the acquisition of sagittal images, respectively, with flexion and extension of the neck (Fig. 24.11). Some authors suggest that this procedure be realized in patients with RA in whom cervical subluxation is suspected and routine MRI findings were equivocal. However, when dynamic studies are performed, patient monitoring is advised, and rapid sequences are desirable because the position is risky and uncomfortable. The procedure is unnecessary and even contraindicated in patients in whom medullary or spinal cord compression is discovered on studies made in the neutral position. It was recently shown that MR is more sensitive than standard dynamic studies of the cervical spine to diagnose AAAS. It provides important biomechanical clues, other than ADI, that improve accuracy in diagnosing atlantoaxial instability. These signs are the presence of significant amount of pannus, dental erosion, tilting of anterior atlantoaxial joint, peridental effusion, lateral facet arthropathy, abnormal spinolaminar line, and focal myelopathy. The combination of peridental effusion, lateral facet arthropathy, abnormal intramedullary signals, and abnormal spinolaminar line showed a sensitivity of 100% and a specificity of 90% in diagnosing AAA subluxation (8). The imaging evaluation of cranial settling deserves special consideration because of the erosion of the odontoid process. In this case, the Redlund–Johnel line is used, which measures the distance from the base of C2 to the plane of Chamberlain’s line. Cranial settling is considered present when the distance between the cortical margin of the base of the axis and the Chamberlain’s line is less than 29 mm in women or 34 mm in men. Approximately 6% of the cases of atlantoaxial impaction or cranial settling in rheumatoid patients would be missed even with elaborate plain radiographic studies. For this reason, CT or MRI should be performed on an RA patient whenever plain radiographs leave any doubt about the diagnosis of vertical subluxation. In addition, it is mandatory to use MRI of the cervical spine whenever there is suggestion of spinal cord compression.

FIGURE 24.8 Juvenile rheumatoid arthritis, C3–C4 and C7–T1 subluxations. Sagittal T1WI (A) and T2WI (B) subluxations at C3–C4 and to a lesser extent at C7–T1. Partial fusion of C4–C6 bodies. Note the compression of the spinal cord at C3–C4 and the intrinsic spinal cord lesion characterized by the hyperintense region on the T2WI.

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FIGURE 24.9 Rheumatoid arthritis in a 63-year-old woman presenting with tetraparesis and tetraparesthesis. Compression of the cervical spinal cord by hypovascular inflammatory pannus. A: Sagittal T1WI, (B) sagittal T2WI, and (C) sagittal Gd-T1WI showing the dens completely involved by inflammatory pannus that presents intermediate signal on T1WI and T2WI and enhances moderately after gadolinium chelate injection. Axial computed tomography (CT) slices (D) and sagittal (E) and coronal (F) CT reformations demonstrate that the dens is linked to the body of C2 by only a narrow strip of bone.

FIGURE 24.10 Rheumatoid arthritis. C1–C2 anterior subluxation and spinal cord compression. Sagittal T1WI (A) and T2WI (B). Partial destruction of the dens that is posteriorly dislocated. Segmental atrophy of proximal cervical spinal cord. Axial T2WI (C1,C2) show narrowing of the spinal canal, segmental cord atrophy, and intrinsic lesion of the cord.

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FIGURE 24.11 Atlantoaxial instability in a 45-year-old woman with rheumatoid arthritis and neurologic signs of cervical spine compression. Sagittal T2WI in extension (A) and in flexion (B) showing anterior dislocation of the atlas over the axis after transverse laxity secondary to synovial inflammation. Note the accumulation of fluid in the predental space and the hyperintense lesion at the cord at the level of the atlas.

Seronegative Spondyloarthritis Seronegative spondyloarthritis is a chronic inflammatory rheumatic disease, seronegative for rheumatoid factor, and often associated with the presence of HLA-B27 (9). These diseases affect preferentially the axial skeleton, causing pain and stiffness by the preferential involvement of enthesis, but also of discs and synovial joints. In this group are included ankylosing spondylitis, by far the most common, reactive arthritis (former Reiter’s syndrome), psoriatic arthritis, arthritis associated with Crohn’s disease and ulcerative colitis, and undifferentiated spondyloarthritis. CT and MRI are more sensitive and specific than conventional radiographs for assessing involvement of the spine and sacroiliac joint in these conditions (9), helping to optimize the treatment of patients. The most characteristic spinal involvement in spondyloarthritis is enthesitis, an inflammatory process affecting the insertions of the vertebral ligaments. MRI is best suited to depict the acute inflammatory enthesis damage and also the following fatty degeneration (9). CT shows better the more chronic sclerotic changes, and bone formation. One must remember, nevertheless, that all these alterations can occur simultaneously in the same patient, and that the chronic changes can also be shown by MRI, although less conspicuously. Initial inflammatory phase histopathologic examinations show erosive lesions with infiltrating macrophages and lymphocytes at the insertion of ligaments. The adjacent marrow spaces depict edema, infiltration of plasma cells, and paucity of hematopoietic tissue (10). Four different manifestations can be identified: Romanus spondylitis at vertebral corners, Andersson aseptic spondylodiscitis, and arthritis of the facet and costal joints, all very similar to their pyogenic counterparts, as well as true ligamentous inflammatory involvement (9,10). Romanus spondylitis describes the inflammatory changes involving the anterior and posterior edges of the vertebral endplates, secondary to enthesitis of, respectively, the anterior and posterior longitudinal ligaments. MRI can show the edematous corners hyperintense on T2WI, hypointense on T1WI, and enhancing after intravenous (i.v.) administration of gadolinium chelate. Andersson aseptic spondylodiscitis encompasses the inflammatory changes involving the disc and adjacent vertebral endplates, which imaging aspect is similar to that described for pyogenic spondylitis. The disc and the endplates appear hyperintense on T2WI, hypointense on T1WI, all which may enhance after gadolinium administration. Bone erosions of the vertebral endplates may be observed later on CT. Arthritis of the facet joint, costotransverse and costocostal joints acutely encompass bone marrow edema, effusion, erosions, and contrast enhancement, all best depicted by MRI. At the end stage, there are reactive subchondral bone formation, osseous fusion (Fig. 24.12), capsular ossification, and the articulations may undergo ankylosis, all better shown by CT or even in radiographs (9). At the atlantoaxial joints, inflammatory changes of the synovial and adjacent ligamentous structures can lead to erosion and resorption of the dens, similar to, but less frequent than, what is observed in RA. In spite of the fact that ligamentous lesions are most commonly centered at the bone insertions, other parts of the ligament can be affected, corresponding to true ligamentous inflammation (9). Fat-saturated T1WI with administration of gadolinium is more sensitive than fat-suppressed T2WI sequences in the 1812

detection of this type of involvement. All vertebral ligaments may be affected, most often the interspinal and the supraspinal ligaments. Obviously, inflammation of the bone marrow adjacent to their insertions may also be seen (9). Later in the course of the disease, inflammatory zones may be replaced by fatty bone marrow. MRI may show fatty infiltration at either edge of the vertebral endplates representing postinflammatory changes after Romanus spondylitis or at the vertebral margins associated with Andersson spondylodiscitis, the last mimicking Modic Type II degenerative changes. The final stage consists of sclerotic changes and formation of syndesmophytes through continuing enchondral ossification in most previously inflamed tissues, what eventually leads to ankylosis of the spine and of the sacroiliac joints. When syndesmophytes bridge several adjacent vertebral bodies, or even the whole spine, the imaging of this structure resembles bamboo; hence the name “bamboo spine.”

FIGURE 24.12 Ankylosing spondylitis in a 36-year-old man. Sagittal T1WI (A) and T2WI (B), and axial T1WI of the sacroiliac joints (C). Axial T1WI at the level of the L3–L4 interapophyseal articulations (D). There is almost complete osseous fusion of the sacroiliac joints and of the interapophyseal articulations. Magnetic resonance imaging can also consistently show articular and osseous alterations in spite of the advantage of multislice computed tomography in this regard.

Calcification and ossification of the posterior longitudinal ligament, as well as of the interspinous and supraspinous ligaments, may be prominent in ankylosing spondylitis. Ossification of the posterior longitudinal ligament can cause compression of the spinal cord. Insufficiency hyperextension vertebral fractures, known as Andersson fractures, may occur as a consequence of the ankylosis and osteoporotic changes (9). Because of the osteopenic changes, the fracture may pass through the vertebral body (transvertebral), but it may also pass through the disc space (transdiscal) or even through both. Several findings must be looked for in MRI of the spine to avoid missing this threatening condition (Table 24.6) (11). Sacroiliac joints, predominantly made of fibrocartilage and containing very little synovial fluid, for these reasons considered enthesis, may be involved either unilaterally or bilaterally. The different stages of inflammatory sacroiliac involvement on CT and MRI follow the pattern previously described to the spine. The earliest sign of sacroiliitis, inflammatory subchondral bone edema, is hyperintense on fatsaturated T2WI or STIR sequences and may enhance after administration of gadolinium chelates. Enhancement of the fibrous connective of the joints may also be present. CT may initially depict subchondral demineralization followed by bone erosions. Early diagnosis of either sacroiliac or spinal inflammatory involvement helps in initiating early treatment what may prevent ankylosis (9). TABLE 24.6 Imaging Findings in Ankylosing Spondylitis Patients with Spinal Fractures or Pseudoarthrosis

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Later in the course of the disease, inflammation usually decreases and subchondral edema is progressively replaced by fatty bone marrow, which appears hyperintense on T1WI. The final stage of sacroiliac involvement consists of subchondral sclerosis and fusion of the joint with ankylosis. At this stage, MRI may show sclerotic changes, hypointense on T1 and T2WI, and fusion of the articulation (9). However, in cases in which radiographs and MRI are equivocal, CT is the best imaging technique for depicting subchondral density and sacroiliac ankylosis (9). The cauda equina syndrome (CES) is a late, rare, and poorly understood but well-recognized complication of longstanding ankylosing spondylitis. Symptoms of CES, which include cutaneous sensory impairment of lower limbs and perineum and sphincter disturbance, usually appear when ankylosing spondylitis is quiescent and laboratory tests are normal. Although the exact pathogenesis of CES is not known, the mechanisms of nerve root injury include arachnoiditis and compression from expanding thecal diverticula. There are cases in which the authors described the MR findings of florid multilocular dural ectasia, marked irregularity and thickening of nerves, and adherence to the diverticular in patients with ankylosing spondylitis and neurologic symptoms of CES. These cases provide evidence for the role of arachnoiditis in the pathogenesis of the CES of ankylosing spondylitis. Gout Gout is a common rheumatologic disease but is infrequently diagnosed in the axial skeleton, with fewer than 30 cases reported in the literature (12), what is probably underestimated because patients who may have asymptomatic tophi are not routinely imaged, and such lesions, even if diagnosed, are not pathognomonic. Most patients presenting spinal involvement by gout have chronic polyarticular tophaceous gout and hyperuricemia, with a mean duration of disease of 14 years. The clinical symptoms vary from none to acute quadriparesis. All segments of the spine are affected in approximately equal distribution. The frequency of neural compromise is high, leading frequently to an acute neurologic deficit that may require emergency surgical decompression. A tophus is the pathognomonic lesion of gout, and patients usually have had gout for 10 to 12 years before these lesions become visible radiographically or on physical examination. It is a mass constituted by urates, either crystalline or amorphous, surrounded by tissue showing increased vascularity and an intense inflammatory reaction composed of macrophages, lymphocytes, fibroblasts, and foreign-body giant cells. MRI data obtained from 13 patients showed all lesions to have T1 isointensity or hypointensity and variable signal intensity on T2WI that was related to the amount of calcium in the tofi (13). There is strong enhancement by gadolinium chelates (Fig. 24.13).

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FIGURE 24.13 Surgically proven tophaceous gout of the lower thoracic spine in a 51-year-old man suffering from gout for 7 years before the examination and presenting with lower limb paresis and paresthesias and lumbar pain for 2 years before that. The physical examination showed many tophi affecting several joints of the hands, elbows, knees, and feet. A: Myelography showing compression of the extradural type of the thecal sac at the level of T9– T10. B: Myelography computed tomography. Extradural hyperdense mass situated posterior and to the right of the thecal sac (T9–T10 interspace). C: Axial T1WI at the level of the T9–T10 interspace. The mass is hypointense and compresses the cord, causing it to deviate anteriorly and to the left. D: Axial Gd-T1WI. There is slight heterogeneous enhancement of the lesion, predominantly at its periphery. (Courtesy of Dr. Artur da Rocha Corrêa Fernandes and Dr. Henrique Carrete Jr., São Paulo, Brazil.)

Descriptions of the involvement of the spine by gout consist of extensive lytic lesions associated with a soft tissue mass, with the above-described characteristics, affecting more commonly the posterior vertebral structures. These lesions are sharply delineated, without surrounding infiltrative changes; normal disc tissue persists immediately adjacent to destroyed discal areas; and no significant bone marrow edema is seen in the trabecular bone adjacent to the lesion (12). It was recently shown a tophaceous gout hypermetabolism by FDG-PET (12), making the differential diagnosis with malignant tumors more difficult. It must be considered, however, that this diagnostic must be suspected on clinical grounds. Spinal Epidural Abscess Despite the progress in imaging, early diagnosis of spinal epidural abscess (SEA) remains difficult, and treatment is often delayed. The morbidity of SEA is high, and its mortality ranges from 18% to 31% in modern series (14). The predisposing factors and the etiologic agents of SEA are the same above described for pyogenic spondylodiscitis and pyogenic facet joints arthritis. S. aureus is the causative agent in 62% to 67% of cases, and in 15% of infections these organisms are methicillin resistant (14).The occurrence of SEA in children represents less than 1.5% of cases. Prompt diagnosis and treatment are critical because SEA patients can rapidly progress to paraplegia, quadriplegia, and death if untreated or if treatment is delayed. The features suggesting the diagnosis are back pain, progressive neurologic deficit, low-grade fever, and obtundation; however, there may be no 1815

fever in the subacute and chronic cases. Peripheral leukocyte count is elevated in approximately 60% of patients, and ESR rate is elevated in most patients. The most frequent source of functional compromise of the spinal cord is mechanical compression (Fig. 24.14), but deterioration can be seen also related to ischemic compromise (Fig. 24.15). It may be encountered in all segments of the spinal canal. SEA occurs most commonly in the lower thoracic and lumbar spine, followed by the cervical and upper thoracic spine. SEA can be classified as diffuse (Fig. 24.16) when it involves six or more vertebral segments and as focal when it involves five or fewer vertebral segments (Fig. 24.17). The most common concomitant infections are spondylodiscitis, facet infection, posterior paraspinal abscess, and retroperitoneal abscess. Most cases are anterior to dural sac or involve it circumferentially and are associated with spondylodiscitis. When abscess involves the ventral epidural space, it tends to conform to a pattern anatomically dictated by the posterior longitudinal ligament/central septum complex and lateral membranes. MR is the most effective diagnostic technique for SEA, its sensitivity varying between 91% and 100% (Table 24.7).

FIGURE 24.14 Epidural abscess situated anterior to the spinal cord, extending from C2 through C7. Spondylodiscitis at C6–C7. Swelling of prevertebral tissues and presumably prevertebral abscess anterior to C6–C7. The patient is an 81-year-old man that became tetraparetic 2 days before the exam. A: Sagittal T1WI showing hypointensity of C6 and C7 vertebral bodies and of discs C5–C6 and C6–C7. The cervical cord is posteriorly compressed by an anteriorly situated, slight hypointense collection compared with the spinal cord. There is slight swelling of the prevertebral tissues. B: Sagittal T2WI. The epidural collection is slightly hypointense relative to cerebrospinal fluid and hyperintense relative to the cord. There are small hyperintense images at the discs C4–C5 and C5–C6 and at the C6 and C7 vertebral bodies. The disc C6–C7 is diffusely and heterogeneously hyperintense. C: Sagittal Gd-FS-T1WI. Peripheral enhancement of the epidural collection (white arrowheads) and heterogeneous enhancement of the prevertebral tissues. There is also enhancement of C6 and C7 vertebral bodies and of the C6–C7 disc and small areas of enhancement at the discs C5–C5, C5–C6, and C7–T1. D,E: Axial T2WIs show the anteriorly situated crescentic epidural abscess and compression of the spinal cord. In some slices there are some small hyperintense lesions of the cord that can be associated with edema, ischemia, or even malacia. (Courtesy of Dr. Maria Lúcia Mourão, São Paulo, Brazil.)

SEA can be hypointense, isointense, or slightly hyperintense compared with the spinal cord on T1WI, depending on its fluidity. When there is associated spondylodiscitis, the related vertebral bodies and intervertebral discs are hypointense on T1WI. 1816

On T2WI, SEA is mostly hyperintense, being difficult to differentiate from cerebrospinal fluid (CSF) 3D FSE and 3D CISS, can help to overcome this difficulty, better showing the SEA in relation to CSF and to the spinal cord. Postcontrast sequences can help to differentiate granulation tissue from frank pus, although this may not be clinically relevant because both conditions can result in neurologic compromise and require surgical decompression. TABLE 24.7 Concomitant Infectionsa in Patients with Spinal Epidural Abscess

FIGURE 24.15 Spondylitis at T2 vertebral body, prevertebral and epidural granulation tissue, and ischemic lesion of the cervical spinal cord in an immunocompromised 2-year-old girl. A: Sagittal T2WI. There is a small area of hyperintensity anterior and superior located at T2, just under the intervertebral disc. There is a slight enlargement of prevertebral tissues that presents with intermediate signal intensity. There is an intrinsic lesion of the spinal cord from C5–C6 through T1–T2, characterized by central cord symmetric hyperintense lesions, probably of ischemic nature. There is a small epidural hyperintense collection anterior to the spinal cord from C5–C6 through T1–T2. B: Sagittal Gd-T1WI showing enhancement of prevertebral tissues, of the lesion on the superior part of the body of T2, and of the epidural granulation tissue. C: Axial T2WI showing two small, rounded, and hyperintense lesions in the gray matter of the cervical spine, characteristic of ischemia.

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FIGURE 24.16 Epidural abscess, the consequence of intra-articular injection of corticosteroid, in an 80-year-old diabetic woman. Sagittal T2WIs of thoracic (A) and lumbar (B) spine. There is extensive epidural collection, mostly anterior to the spinal cord, that presents with intensity slightly lower than that of cerebrospinal fluid. Sagittal Gd-FST1WI (C) of the thoracic spine shows an epidural collection hypointense relative to the spinal cord. Axial Gd-T1WIs of lumbar (D) and thoracic (E) spine show the crescentic shape and the slight hypointensity of the collection relative to cerebrospinal fluid. Axial Gd-FS-T1WI of lower lumbar spine (F) showing left interapophyseal L5–S1 pyoarthritis, left paravertebral abscess, and bilateral intrapelvic abscesses, posterior to the psoas muscles, around emerging L5 roots. Sagittal T2WIs of thoracic (G) and lumbar (H) spine and sagittal Gd-FS-T1WI (I) of the thoracic and lumbar spine obtained 1 month after clinical treatment show complete recovery, without any evidence of epidural collection. (Courtesy of Dr. Adelson Martins, Presidente Prudente, SP, Brazil.)

There are two main patterns of enhancement in SEA. The most common one is diffuse enhancement at the site of the solid component of the SEA, in either a homogeneous or heterogeneous fashion (Fig. 24.15). The second most common pattern of enhancement is a thin or thick rim around a collection of low signal intensity, representing, respectively, granulation tissue and pus (Figs. 24.16 and 24.17). Linear enhancement along the compressed dura mater may be observed in most patients with diffuse SEA on sagittal images (Fig. 24.16), which is not usually observed in patients with focal SEA. Sagittal 1819

views are the most useful projections for assessment of cephalic and caudal extensions of SEA (Figs. 24.16A–C and 24.17A,B). Axial views are needed to define the exact site of granulation tissue and collections of pus relative to the dural sac and to the bony structures (Figs. 24.16D–F) as well as for demonstrating concomitant paraspinal abscess.

FIGURE 24.17 Spondylodiscitis and epidural abscess in a 72-year-old diabetic woman tetraparetic since 4 days before magnetic resonance exam. A: Sagittal T2WI. Slight heterogeneous hyperintensity of C2–C4. There is a small area of hyperintensity at the central portion of the intervertebral C3–C4 disc. There is a hyperintense epidural collection extending from C2 through C5. There is hyperintensity within the cord from C1 through C5 that may be related to edema, ischemia, or malacia. B: Sagittal Gd-T1WI showing heterogeneous enhancement of C2, C3, and C4 vertebral bodies of the peripheral part of the abscess, that is multiloculated and of the prevertebral soft tissues.

To prevent serious morbidity and mortality, early diagnosis is essential for proper management of SEA. Patients at risk for developing such abscesses who present with local back pain and/or have an increased ESR and/or neurologic deficit should have an immediately MR scan, including postgadolinium sequences. Surgical drainage and prolonged antibiotic use are the cornerstones of treatment, although selected patients may be treated conservatively. Spinal DWI can better characterize epidural collections, as restricted diffusion, and should be part of the routine MRI of the spine (Fig. 24.18).

FIGURE 24.18 Postsurgical extradural abscess in a 23-year-old woman with an ependymoma of the cauda equina.

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Sagittal T1- (A), T2- (B), FS-T2, Gd-FS-T1- (D), DWIs (E) and ADC (F). The images show postsurgical changes with L2 spinal process resection and a residual filum terminale ependymoma. The images in panels B and C show an ovoid hyperintense fluid collection at the level of L2. The sagittal Gd-FS-T1WI (D) shows enhancement of the ependymoma and avid pericollection enhancement. There is restriction of the diffusion in panel E, confirmed by the map in panel F. (Courtesy of Dr. Heraldo Mello Neto, Curitiba-Paraná, Brazil.)

FIGURE 24.19 Pachymeningitis, arachnoiditis, and spinal cord intrinsic lesions in a 6-month-old girl. These conditions were a complication of long-term parenteral nutrition. Lumbar puncture motivated by meningismus revealed the same components present in parenteral nutrition fluid. Plain films of the thorax (not shown) demonstrated the tip of the subclavian catheter into the spinal channel. A: Axial T2WI at high thoracic and lower cervical levels confirms lesions at the three compartments: hyperintense epidural collection, intermediate-signal subdural fluid, and hyperintense spinal cord intrinsic lesion. B: Coronal Gd-FS-T1WI of the craniocervical transition showing diffuse enhancement of the meninges and a subarachnoid ring-enhancing lesion at the cerebellopontine angle. C: Proton brain examination–point-resolved spectroscopy spectrum obtained with an echo time of 35 ms at the ring-enhancing lesion demonstrates a significant lactate-lipid region peak and lowering of the peaks of all other metabolites, compatible with inflammatory origin of the lesion (abscess).

When an epidural abscess is primary, differential considerations include malignancy, particularly metastasis. Compared with neoplasms, more acute processes such as epidural abscess and hematoma more commonly violate the midline septum of the ventral epidural space (15). Epidural hematoma, extruded or migrated disc fragment, and epidural lipomatosis are included in the differential diagnosis too. Spinal Hypertrophic Pachymeningitis Hypertrophic pachymeningitis is a rare chronic inflammation of the cranial and/or spinal dura mater. The usual location of the hypertrophy is the cervical or thoracic spine, but the whole spine may be affected (16). Most cases of idiopathic pachymeningitis are characterized by a nonnecrotizing chronic inflammatory infiltrate of lymphocytes, plasma cells, and occasional histiocytes, giant cells, polymorphonuclear cells, or eosinophils. Granulomas, necrosis, and vasculitis are less frequently identified. The etiology of hypertrophic pachymeningitis is unknown, but many causal factors or cofactors have been implicated, including Wegener’s granulomatosis, SLE, sarcoidosis, multifocal fibrosclerosis, orbital idiopathic inflammatory syndrome, RA, carcinomatosis, metabolic diseases, trauma, toxins, 1821

thrombophlebitis, syphilis, tuberculosis, fungi, HIV, HTLV-1, meningococcal meningitis, intrathecal steroid deposition, and vasculitis (16,17). For this reason, extensive workup is required to exclude all these causes in order to diagnose idiopathic hypertrophic pachymeningitis (Fig. 24.19). In the majority of cases, the final diagnosis is clear only after surgery (18,19). Early surgical intervention can successfully improve neurologic symptoms. Laminectomy or laminoplasty followed by durotomy and duroplasty is the recommended surgical treatment for the disease (18,20,21). However, corticosteroids may achieve symptomatic control and reduction in dural thickness, which can be virtually complete. It has been proposed that hypertrophic spinal pachymeningitis should be considered in the differential diagnosis for patients with spinal cord compression and radicular pain in more than three spinal levels (16). The clinical course of idiopathic hypertrophic spinal pachymeningitis (IHSP) may follow one of three patterns; sustained remission, relapse with corticosteroid resistance, or relapse with corticosteroid dependence (17). There are few studies regarding the frequency or cause of recurrence (19). An extended extramedullary mass of low T2 signal intensity with peripheral enhancement, linear or nodular, represents a specific MRI finding that is highly suggestive of IHSP. The linear enhancement pattern appears to show better therapeutic response than the nodular form, possibly related to less fibrosis and more vascularity. It is difficult on MRI alone, however, to distinguish these findings from diffuse leptomeningeal carcinomatosis. Subdural Abscesses Spinal subdural abscess (SSA) is very rare and its exact incidence is unknown; only less than 70 cases of patients with this condition have been reported (22). S. aureus is the most frequent causative agent, the thoracolumbar region is the most frequent localization, and the group of risk is the same of spondylodiscitis, septic spondiloarthritis, and SEA. However, SSA is much less common than SEA and it is only infrequently related to spondylodiscitis. Most patient’s age are between 60 and 70 years (22,23). The development of SSA can be secondary to hematogenous spread of infection from other region, infected CSF and direct spread into the subdural space, hematogenous inoculation during the course of meningitis, secondary inoculation due to lumbar puncture, direct contact with intraspinal space (osteomyelitis), and secondary infection after spinal surgery (22). There are only two cases of SSA in the literature that are unrelated to such conditions and without well-documented etiology (24). Back pain at the level of the affected spine, fever, and neurologic deficits such as para/tetraparesis, bladder dysfunction, disturbances of consciousness, and inflammatory signs are some typical symptoms of SSA (25). Contrast-enhanced MRI is the imaging method of choice in this instance because it is less invasive and due to its superiority and sensitivity in detecting the exact location and extension of the abscess, which is essential for planning surgery (25). MRI is also the modality of choice for diagnosing compressive myelopathy. Leukocyte count, ESR, and CRP are usually elevated. MRI depicts an intradural extramedullar collection, better defined on axial images, with intermediate signal on T1WI and most frequently hyperintense on T2WI. Postcontrast images show heterogeneous, diffuse subdural enhancement or a clear rim-enhancing fluid collection in the subdural situation. There may be cord impingement, edema, or malacia (22). Surgical drainage together with systemic antibiotics is the treatment of choice (23,25). Without intervention, patients who are already with spinal compression signs would almost certainly not reverse the neurologic deficits. Because the rate of progression of neurologic impairment is difficult to predict and some patients became paralyzed within hours after the onset of neurologic deficit, laminectomy, evacuation of the puslike material, and debridement of infected tissues should be done as soon as possible (25,26). Arachnoiditis Arachnoiditis is an inflammatory condition of the spinal leptomeninges, manifested more commonly as subarachnoid adhesions involving the spinal roots, that may produce varying degrees of CSF blockage, subarachnoid cysts, syringomyelia, and, rarely, hydrocephalus. The most common form is lumbar spine adhesive arachnoiditis. Among its causes, most of them are iatrogenic; are agents injected into the subarachnoid space, like contrast media, anesthetic agents, and intradural steroids; infection, trauma, intradural, or extradural surgery; and intrathecal hemorrhage (Table 24.8). All contrast media used before the introduction of metrizamide and the later water-soluble nonionic myelographic agents are known to cause arachnoiditis, manifesting as intradural adhesions on subsequent myelography or MR in 1822

up to 60% to 70% of patients. Arachnoiditis has been cited as a cause of “failed back surgery” syndrome in up to 16% of patients. Patients with persisting symptoms after lumbar disc surgery often have a complex history of investigations and therapeutic procedures, many of which could be responsible for arachnoiditis. Therefore, multiple causative factors have been implicated, among them myelographic contrast media being used during the preoperative assessment, perioperative infection, therapeutic or inadvertent intraspinal injections of anti-inflammatory agents, and intrathecal hemorrhage or other forms of operative trauma. The inflammatory reaction of arachnoiditis involves initially the influx of white blood cells in response to an insult to the subarachnoid space, foreign substance, or infectious agent. This is followed by infiltration of macrophages and mesenchymal cells, with the latter evolving into fibroblasts and producing collagen. In the more advanced phases, there is predominance of fibrinous exudates, and the cellular response is minimal. Usually the fibrinolytic process, which breaks down excessive scar tissue, limits this process. In arachnoiditis, it seems that there is a defect in the fibrinolytic pathway, and the fibrin-coated nerve roots and arachnoid membrane adhere to one another. These adhesions are subsequently reinforced by proliferating fibroblasts. TABLE 24.8 Causes of Arachnoiditis

When the arachnoiditis is local, the symptoms may be very specific and related to a particular lumbosacral root, and, most of the time, it is very difficult to determine whether they are related exclusively to arachnoiditis or to another associated condition like compression by a residual disc or osteophyte, or even the coexistence of epidural fibrosis. The most common clinical signs of lumbar adhesive arachnoiditis are pain in the lower back and weakness and sensory loss in the lower limbs. Some patients refer to bladder and sexual dysfunction. An important observation, however, is that the clinical symptomatology of arachnoiditis may be complicated by multifactorial factors that include psychosomatic, legal, and employment-related aspects. In a series of patients with benign lumbar arachnoiditis caused by previous myelography and/or surgery, acquired MR both before and after intravenous injection of gadopentetate dimeglumine correlated well with myelographic and postmyelographic CT, supporting the findings of other authors that arachnoiditis can be diagnosed with unenhanced MRI. Sagittal and mostly axial T2WI best demonstrate centrally clumped or peripheral adherent roots (Figs. 24.20 and 24.21), although these changes can also be seen on T1WI. In mild and severe cases of arachnoiditis, the diagnosis may be established if there are segmentally clumped roots centrally located or roots adherent to the wall in the lower lumbar thecal sac. Gadolinium chelate enhancement of the nerve roots is infrequent, inconspicuous, often uncertain, and not helpful in the diagnosis of arachnoiditis. In selected cases, however, the use of contrast media is indispensable (Fig. 24.22). State-of-art MRI has replaced myelography as the reference examination to detect arachnoiditis. Highresolution FSE imaging permits reliable identification of the anterior and posterior roots for each spinal root within the thecal sac and multiple rootlets within each root sheet, further signs of arachnoiditis can be seen that should permit recognition of mild and even minimal cases (Table 24.9). Syringomyelia and subarachnoid cysts are recognized complications of arachnoiditis, more commonly those associated to inflammation or infestation and tend to be more common in the thoracic region. The main MR findings of syringomyelia associated to arachnoiditis are loss of the sharp cord–CSF interface resulting from obliteration of the subarachnoid space by arachnoid adhesions and septation of the syrinx on axial T1WI, probably representing parallel areas of cavitation rather than within the same 1823

cavity. Arachnoid cysts, most of them located at the upper aspect of the syrinx, suggests a role in the development of cord cavitation (Fig. 24.23–24.25). Hydrocephalus may also rarely complicate arachnoiditis (Fig. 24.22).

FIGURE 24.20 Arachnoiditis in a 58-year-old woman. Patient has undergone surgery 5 years before the magnetic resonance examination. Persistent lumbar pain irradiating to the inferior limbs, mainly to the right side. Sagittal T2WI (A) and axial T2WIs (B,C) show the featureless or empty thecal sac. Note the adherence of the roots to the dural tube.

A rare manifestation of arachnoiditis is ossification of the leptomeninges, or arachnoiditis ossificans of the spine, that may result in severe neurologic decline. One has to consider that calcifications of the meninges are common. These calcifications are most often asymptomatic due to their relatively small size in relation to the spinal canal. This process of asymptomatic calcification is distinct from the pathologic one, which is due to chronic inflammation. Plain radiographs in only the most severe cases may identify it and CT and MRI are necessary complementary studies.

FIGURE 24.21 Arachnoiditis in a 47-year-old man complaining of lumbar pain irradiating to the left inferior limb down to the foot. Lessened left Achilles reflex was observed at physical examination. Axial T2WIs at L4–L5 (A), L4 (B), bottom L3 (C), and upper L3 (D) show clumping of the roots and pseudocord sign.

Acute Transverse Myelopathy The term acute transverse myelopathy (ATM) refers to a monophasic focal inflammatory disorder of the spinal cord of unknown etiology that involves both halves of the spinal cord, producing paraplegia, a sensory impairment level, and sphincter dysfunction. Both terms ATM and acute transverse myelitis have often been used interchangeably in the literature, creating considerable confusion. ATM has 1824

inflammatory and noninflammatory causes such as demyelinating diseases, viral infections, postviral and postvaccinal processes, collagen vascular disorders, vascular disorders, paraneoplastic syndromes, and also may be idiopathic. There was a time when the term acute transverse myelitis was reserved for idiopathic cases, but currently the term ATM is also used to encompass the general clinical syndrome, whether or not the cause is known (27). In fact, a recent series showed that cases of ATM secondary to an identifiable cause are much more common than those still considered idiopathic (28). In addition, considering the fact that the clinical syndrome of ATM may have noninflammatory causes, such as vascular, traumatic, and compressive, the diagnosis of acute transverse myelitis is only possible after the exclusion of these conditions. The Transverse Myelitis Consortium Working Group proposed the diagnostic criteria for idiopathic acute transverse myelitis (Table 24.10). The diagnosis of idiopathic ATM requires that all of the inclusion criteria and none of the exclusion criteria are fulfilled. The diagnosis of disease-associated ATM requires that all the inclusion criteria are met and that the patient is identified as having an underlying condition listed among the disease-specific exclusions. Patients meeting all diagnostic criteria are considered to have definite idiopathic ATM, whereas those who do not meet the MRI or CSF criteria for inflammation have possible idiopathic ATM. TABLE 24.9 Magnetic Resonance Imaging Diagnosis of Arachnoiditis

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FIGURE 24.22 Chemical arachnoiditis. Female, 2-year-old. Twenty days prior was operated of a probable dermal sinus and developed a chemical meningitis by methylene blue; complicated by arachnoiditis and hydrocephalus. She was submitted to an external ventricular shunt and posteriorly to a ventriculoperitoneal shunt. Axial T1WI (A)—there is a subtle blurring of the subcutaneous and extradural fat tissues and a thin fistulous tract. Axial T2WI (B)—the roots are attached to the dural sac, characterizing the “empty sac” sign. Sagittal T2WI (C) and Gd-FS-T1WI (D). Arachnoiditis with disruption of the normal anatomy of the cauda equina roots, tethering of the cord, and pial enhancement. Sagittal T2WI (E) and axial GRE T2*WI (F)—derived extraventricular obstructive hydrocephalus.

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FIGURE 24.23 Syringomyelia secondary to arachnoid adhesions in a middle-aged woman with a history of bacterial meningitis. A: Sagittal T1WI shows a large syrinx with an ill-defined cord–cerebrospinal fluid interface. B: Axial T1WI in the thoracic spine shows the septated aspect of the syrinx, most likely representing two parallel areas of cavitation. C: Axial T1WI in the cervical region shows that the cord has a triangular shape because of compression by arachnoid loculations (arrows).

FIGURE 24.24 Syringomyelia secondary to arachnoid adhesions and intramedullary Pantopaque. A: Sagittal T1WI demonstrates a thoracic syrinx (arrowhead) and intramedullary high signal (arrow) consistent with fat or hemorrhage. B: Axial T1WI demonstrates a chemical shift artifact, confirming that the intramedullary high signal represents Pantopaque and not subacute hematoma. Extramedullary Pantopaque is also present ventrally and to the right.

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FIGURE 24.25 Chemical myeloradiculitis in a 26-year-old woman submitted to spinal anesthesia with subarachnoid injection of drugs. Sagittal T2WI (A) and axial T2WI (B) show bilateral hyperintense lesions at the frontal horns (arrows), and axial Gd-T1WI (C) shows enhancement of the anterior roots (arrows).

TABLE 24.10 Criteria for the Diagnosis of Idiopathic Acute Transverse Myelitis

ATM is characterized clinically by acute or subacute development of symptoms and signs of bilateral dysfunction in motor, sensitive, and autonomic nerves and nerve tracts of the spinal cord, frequently with a sensorial rostral level, which progresses to a nadir over 4 to 21 days from onset. It usually affects middle-aged adults, and the thoracic spine is most commonly involved, followed by the cervical spine. 1828

MRI may directly demonstrate a centrally located increased signal intensity on T2WI, usually occupying more than two-thirds of the cross-sectional area of the cord and extending more than three to four vertebral segments in length (Fig. 24.26). The spinal cord may be of normal caliber or slightly expanded, which in the latter case may even suggest a neoplasm. Cord expansion may be found in up to 47% of cases. After gadolinium administration, the abnormal areas may (Figs. 24.27 and 24.28) or may not show enhancement, and both patchy and diffuse patterns were described. It is important to note that MRI findings became one of the diagnostic criteria of ATM. The Transverse Myelitis Consortium Working Group proposed that at least one of the three following criteria is required for the diagnosis of ATM (1): MRI demonstration of abnormal gadolinium enhancement of the spinal cord, (2) CSF pleocytosis, or elevated CSF immunoglobulin G (IgG) index (3). They also proposed that if none of the inflammatory criteria are met at symptom onset, one should repeat MRI and lumbar puncture evaluation between 2 and 7 days, to determine whether these criteria are met. One drawback of these criteria is that cord enhancement is reported in only up to 38% to 53% of the cases (28). There are two important considerations. First, in the emergency setting, a complete workup is not always done, and there is no certainty that all diagnosable conditions are excluded. Second, it remains to be determined how to distinguish, at disease onset, idiopathic ATM patients who do not have evidence of disseminated CNS disease from those with multiple sclerosis (MS) or neuromyelitis optica (NMO) (Table 24.11) (28). The evolution of idiopathic transverse myelitis is extremely variable, resulting in severe disabilities in about one-third of the patients (28). Follow-up MRI reflects this variability, showing resolution of the abnormal signal and return of the cord to a normal caliber when the evolution is favorable or to spinal cord atrophy in disabled patients (Figs. 24.29 and 24.30). TABLE 24.11 Conditions that May Present with a Transverse Myelopathy (28)

Systemic Lupus Erythematosus–Related Myelitis Transverse myelitis is an uncommon but well-recognized complication of systemic lupus erythematosus (SLE). It affects females to males by a ratio of 8:1. It is characterized by back pain, paraparesis or tetraparesis, and sensory loss caudad to the lesion and tends to be recurrent, hence the term recurrent transverse myelitis associated with SLE. CNS involvement in SLE is most often seen in the setting of antiphospholipid antibody syndrome (APS), mainly associated with IgG type of anticardiolipin antibodies, that includes premature cerebrovascular diseases, migraine, epilepsy, chorea, dementia, depression, deep brain reversible encephalopathy, and myelitis (29). A strong association between transverse myelitis in SLE and the presence of these antibodies has been suggested, although their precise role in neurologic conditions has not been established.

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FIGURE 24.26 Transverse myelitis in a 7-year-old boy who presented with abrupt onset of tetraplegia and sensitive level at the nipples. Nonspecific changes on blood and cerebrospinal fluid tests. There was no history of recent viral illness. A: Sagittal T1WI shows swelling of the cervical spinal cord without significant change of signal intensity. B: Sagittal T2WI shows hyperintensity of the central portion of the cervical spinal cord. C: Sagittal Gd-FS-T1WI shows no evidence of disruption of the blood–brain barrier. (Courtesy of Dr. Arnaldo Lobo, Belem, PA, Brazil.)

FIGURE 24.27 Acute transverse myelitis in a 30-year-old man. A: Sagittal T1WI demonstrates an area of low intensity in the conus (arrow) and midthoracic region, where the low-intensity cord blends with the low-intensity cerebrospinal fluid. B: Sagittal T2WI demonstrates multiple areas of high signal intensity in the conus and midthoracic cord (arrows) with skip areas of normal cord. This appearance is against the diagnosis of a neoplasm. C: Sagittal Gd-T1WI demonstrates multiple small nodular areas of enhancement (arrows). D: Cytologic smear from a thin-needle biopsy of a similar patient shows cord edema, a round cell infiltrate consistent with lymphocytes, and no evidence of a neoplasm. No evidence of vasculitis is seen.

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FIGURE 24.28 Acute transverse myelitis in an 11-year-old child. A: Sagittal T2WI demonstrates several foci of high signal intensity in the upper thoracic cord (arrows). The cord is of normal caliber. B: Sagittal Gd-T1WI demonstrates several areas of enhancement (arrows) separated by a nonenhancing area. C: Axial Gd-T1WI demonstrates patchy enhancement of both sides of the cord (arrows).

FIGURE 24.29 Postvaricella spinal cord atrophy in a 30-year-old man with a history of transverse myelopathy beginning less than 1 month after varicella infection 15 years before. Sagittal (A) and axial T2WIs (B) show marked atrophy of the thoracic segment of the cord.

The MRI pattern of spinal cord involvement is a centrally located increased signal intensity on T2WI, generally occupying more than two-thirds of the cross-sectional area of the cord, and extending more than three to four vertebral bodies (Fig. 24.31). Spinal cord involvement in SLE tends to be severe, resembling more NMO and NMO spectrum disorders (NMOSD) than MS. A positive test for aquaporin-4 (AQP-4) autoantibodies enables the diagnosis of NMO coexisting with either humoral autoimmune diseases, including SLE, or nonorganspecific autoantibodies (30). Multiple Sclerosis MS of the spinal cord may present as an acute or subacute myelopathy, more often resulting in a subacute monosymptomatic motor and/or sensory syndrome mainly affecting lower extremities. The Lhermitte sign is often referred. A large proportion of patients diagnosed with ATM are subsequently confirmed as having MS, being ATM considered as a clinical phenomenon, in this setting termed 1831

clinically isolated syndrome (CIS).

FIGURE 24.30 Segmental atrophy of the thoracic cord, sequelae of transverse myelitis. Sagittal T1WI of the thoracic spine (A), sagittal T2WI of the lumbar spine (B), and axial T2WI of the distal thoracic cord of the lumbar spine (C) show segmental atrophy of the thoracic spinal cord due to transverse myelopathy of unknown origin.

FIGURE 24.31 Systemic lupus erythematosus myelopathy. Sagittal T2WIs of cervical (A) and thoracic (B) segments of the spinal cord show diffuse heterogeneous hyperintensity affecting mainly the central portion of the cord. Axial T2WI of the thoracic spine (C) shows the involvement of the central portion of the cord (gray matter), which suggests edema or ischemia. Sagittal lumbar cord (D) and axial spinal cervical cord (E) Gd-FS-T1WIs show peripheral enhancement (pial) and tiny heterogeneous parenchymal enhancement.

Spinal cord lesions are very commonly seen, mainly in the cervical segment, even in the earliest stage of MS (31). Certain characteristics are considered typical of MS, although none of these are specific: hyperintensity on T2WI, more than 3 mm of diameter, craniocaudal extension less than two vertebral 1832

bodies, no significant spinal cord swelling, and partial involvement of the transverse cord area. Spinal cord MS plaques tend to be elongated in the direction of the long axis of the cord and do not involve its entire cross-sectional area. They present as peripherally located (i.e., in the white matter), sharp and well-circumscribed areas, that generally do not respect boundaries between white and gray matter (Figs. 24.32 and 24.33). Hypointense lesions on T1WI are commonly seen in advanced stages in the brain (“black holes”), but not in the spinal cord. Gadolinium enhancement is commonly observed (56%) when patients are studied during clinical exacerbations, presenting with spinal cord symptoms. This enhancement appears as an early and consistent event in MS lesions, and may adopt different forms (nodular, complete ring, incomplete ring). Incomplete ring enhancement is a very specific sign of demyelinating lesions. All these patterns are considered as active inflammation, directly dependent on gadolinium extravasation. The concurrent administration of corticosteroids can interfere in the detection of gadolinium enhancement. Diffuse abnormalities such as a mild intramedullary hyperintensity that may extend longitudinally more than two or three vertebral bodies, are more common in progressive forms of MS, and are better shown on proton density–weighted images (32). A recent study associated upper cervical cord lesion load with physical disability (Expanded Disability Status Scale Score) using high in-plane resolution axial 3-T MRI, and the correlation was higher in progressive forms of MS than in relapsing–remitting MS. Clinical disability has been associated with atrophy of the spinal cord in a proposed MRI method to monitor disease progression. Incidental imaging findings suggesting inflammatory demyelination in the absence of clinical signs or symptoms attributable to CNS demyelination have been largely reported. This is currently named as radiologically isolated syndrome (RIS) and there are evidences that these lesions, particularly in the spinal cord or associated with gadolinium enhancement, may predict disease progression and eventual diagnosis of MS (33). Currently, RIS is not be considered an MS phenotype, but typical imaging findings compatible with focal spinal cord demyelination should support accurate clinical and paraclinical prospective evaluations (34).

FIGURE 24.32 Multiple sclerosis (MS) in a 28-year-old woman. A 3-T magnet was used. Sagittal T2WI (A), axial multiple-echo recombined gradient-echo imaging (B), and axial T2WI (C) of the cervical spine show the typical MS lesions of the spinal cord at the C2 and C2–C3 levels. Sagittal (D) and axial T2WIs (E) of the thoracic spine show a

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third lesion at the level of T10. Note that the lesions are cylindrical or fusiform, longitudinally do not exceed the length of two vertebral bodies, and are restricted to less than one fourth of the transverse surface of the cord.

FIGURE 24.33 Multiple sclerosis plaques in the cervical spine of a 32-year-old woman. A 3-T magnet was used. Sagittal T2WI (A) and axial multiple-echo recombined gradient-echo imaging (B) at the C3–C4 and at C6–C7 levels show fusiform hyperintense lesions peripherally situated. At C3–C4 there are lesions on both lateral compartments. At the C6–C7 level the anterior compartment is affected.

On gross pathologic examination of the spinal cord in MS patients, most show evidence of disease, variable according to its stage. Lesions within the cord are relatively more common in the dorsal horns. They are usually firm and brittle in texture. Histologically, early lesions are characterized by fragmentation of myelin, relative axonal preservation, and microglial proliferation. In the following weeks, the loss of myelin and oligodendrocytes becomes total, neutral fat can be demonstrated free and within macrophages, and there is marked proliferation of astrocytes with perivascular inflammation. If the plaques involve the gray matter, there is a striking preservation of the neuronal cell bodies. Several months later, fibrillary gliosis is established. In very old plaques, there is evidence of Wallerian degeneration, especially in the long tracts of the spinal cord (32). As focal spinal cord lesions have been included in the latest MS MRI criteria, imaging became very important in patients presenting with signs and symptoms of MS. Demonstrating spinal cord lesions is useful to confirm dissemination in space (DIS) and/or dissemination in time (DIT), helping establish the diagnosis of MS in patients with nonspinal CIS who do not fulfill brain MRI criteria (31,35). As spinal cord lesions are rare in healthy aging and cerebrovascular patients, their demonstration also increases the specificity of the MS diagnosis in patients with white matter brain abnormalities (35).

FIGURE 24.34 The better conspicuity of STIR images to depict MS lesions can be observed on the sagittal FSE (A) and STIR (B) sequences obtained in the same exam. Both sequences are softened obtained routinely in the evaluation of the spinal cord for MS patients.

Acute MS symptoms are more often caused by spinal cord lesions than by brain lesions. In most instances when a spinal cord lesion suggests focal demyelination, even without clinical manifestations, brain MRI is recommended not only to potentially define the diagnosis (CIS vs. MS), but also to exclude other possibilities. 1834

Conventional T2WI and PDI have shown to be more sensitive in detecting focal lesions in the sagittal plane, and have been proposed to be included in MS imaging protocols with good results on clinical grounds (32). However, excessively long acquisition times preclude the clinical use of this sequence. Both magnetic transfer gradient-echo and fast short-TI inversion recovery (fast-STIR) sequences depict more cervical cord MS lesions than the FSE sequence (Fig. 24.34), with fast-STIR having the best sensitivity. The better performance of the fast-STIR sequence may be attributable to the synergistic effect of prolonged T1 and T2 relaxation times; this is particularly advantageous in lesions with only slightly increased T2, as might be the case for chronic MS lesions. The use of STIR sequences is an option for sagittal plane of the spinal cord, particularly in the cervical segment. Gradient-echo sequences with short echo times have been used for axial plane studies of cervical segment, although the use of T2-weighted fast sequences is also common, particularly with long echo times (32). The double inversion recovery (DIR) sequences have improved the detection of lesions in the brain, especially in the cortex. A recent report using a 3-T magnet demonstrated better detection of cervical spinal cord lesions on 3D DIR in comparison with conventional T2WI, especially in patients with suspected or established MS (36). The pathology of MS is characterized by macroscopic lesions in the white matter and by microscopic changes occurring in the so-called normal-appearing white matter (NAWM). Pathologically, these latter changes include diffuse astrocytic hyperplasia, patchy edema, perivascular infiltration, abnormally thin myelin, and axonal loss. MR is the ideal imaging modality for showing this subtract in vivo. Magnetization transfer– and diffusion tensor–derived measures are emerging modalities in research studies, particularly for evaluating NAWM by conventional sequences. In a report comparing magnetization transfer ratio (MTR) histograms, MS patients had significantly lower average cervical cord MTR and peak height than control subjects. Patients with locomotor disability had significantly lower average cord MTR and peak location than those without it. Cervical cord MTR histogram analysis might be useful in the assessment of patients with MS because it encompasses both the macro- and microscopic aspects of MS pathology, and reduced MTR values are correlated strictly with severe axonal loss and demyelination. Fractional anisotropy (FA) values have proved to be significantly lower in MS patients than in control subjects, in the cervical spine. Another study showed significantly lower FA values in lateral, dorsal, and central parts of the NAWM at C2–C3 levels of the cervical spine in patients with MS. Although these data make clear that there are significant changes in the diffusion tensor imaging (DTI) metrics in the cervical spine of MS patients, the range of values of DWI of the healthy and diseased spinal cord has not yet been established (37). Neuromyelitis Optica NMO or Devic syndrome is classically referred as the association of recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis (LETM), with multifocal CNS demyelinating illness in severe inflammatory attacks. NMO was long considered as a severe variant of MS because both can cause attacks of optic neuritis and myelitis. NMO and NMOSD have distinctive clinical, radiologic, and pathologic characteristics, and, in most cases, a highly specific biomarker (NMO-IgG) that target AQP-4, an astrocyte water channel that is widely distributed within the CNS (38). NMO has a worldwide distribution with a quite variable relative frequency regarding human groups, being higher in Asian, Hispanic, and African populations and much lower among Caucasians (39,40). NMO begins at an older age, presenting a worse outcome than MS, with frequent and early relapses. It is assumed that within the first 5 years of onset, 50% of patients are blind in both eyes and cannot walk unassisted; furthermore, 20% die of respiratory failure due to upper cervical affection (41). An expanded spectrum of NMO has been demonstrated. One is the presentation with inner specific signs of encephalopathy, in the absence of typical optic nerves or spinal involvement, but with brain MRI lesions typical of NMO-AQP-4 autoimmunity, in periventricular, in the brainstem, and/or in the hypothalamus. Other is the clinical picture of optic neuritis or LETM with typical brain MRI findings in the absence of NMO-IgG (39). Pathologic basis has underlined the primary assault of astrocytes in NMO lesions, but also indicate that different mechanisms of tissue injury operate in parallel in the same patient and even within the same lesion (42). More recently, an additional biomarker was reported in patients with NMOSD who have myelin oligodendrocyte glycoprotein (MOG) antibodies with evidences of distinct clinical features, fewer attacks, and better recovery than patients with AQP-4 antibodies or patients seronegative (43,44). The 1835

observation that anti-AQP-4+ and anti-MOG+ NMO may be separate disorders remains not concluded. However, some phenotypic differences between monophasic (selectively anti-MOG+) and relapsing forms of NMOSD (typically anti-AQP-4+) are noticeable (43,44). Anti-MOG+ may be associated with a broad spectrum of acquired human CNS demyelinating diseases (high-titer MOG antibodies), particularly in children, including ADEM, MS, AQP-4-seronegative NMO/NMOSD (45). Despite the fact that patients with anti-MOG+ can fulfill the diagnostic criteria for NMO, several distinct features have been reported, including a higher proportion of males, younger age, more favorable outcomes, and greater likelihood of involvement of the conus and deep gray matter structures on imaging. It is assumed that patients with seronegative NMO/NMSD (AQP-4) should be tested for anti-MOG (44,46). MRI typically shows longitudinally confluent lesions, hyperintense on T2WI, extending across ≥3 vertebral segments (LETM), usually affecting spinal central gray matter, associated with hypointense signal intensity on T1WI (Fig. 24.35). There may be swelling and gadolinium enhancement in approximately 25% of the cases (Fig. 24.36) (Table 24.12). Spinal atrophy may be observed in chronic stages (40,47). Despite this confluent pattern of spinal cord lesions, secondary progressive course is considered rare in NMO. Despite these classical MR features, short transverse myelitis does not exclude consideration of AQP-4 testing or NMOSD diagnosis. Short transverse myelitis was recently reported as not uncommon in this setting, as it was found in 14% of initial myelitis episodes among patients with NMOSD, in association with optic neuritis (52%) or preceded by a nausea and vomiting episode (8%). To prevent delayed diagnosis and treatment of NMOSD when short transverse myelitis is demonstrated, some clinical and imaging features have been listed, including nonwhite group ethnicity, tonic spasms; coexisting autoimmunity, central spinal cord lesions, focal hypointensity on T1WI, and focal brain abnormalities inconsistent with MS, as well as the absence of oligoclonal bands in the CSF analysis (48). “Bright spotty lesions” have been described as a discriminative finding of NMO defined as very hyperintense spotty lesions on axial T2WI, visually more hyperintense than the signal intensity of surrounding CSF without flow void effects (Fig. 24.37) (49). This finding seems to be relevant for specific diagnosis of the NMO spectrum of lesions, particularly in the spinal cord, presumably reflecting the large amount of liquid in this autoimmune channelopathy (water channel), which forms the microcystic lesions reported on pathologic studies. Abnormal DTI-derived metrics, especially FA, in the cervical spinal cord and MTR acquisition have been used with preliminary results in NMO patients. Conventional and nonconventional neuroimaging investigations in NMOSD have accelerated the understanding of the pathobiology of this disease during the last decade (47). Asymptomatic brain lesions are common in NMO, and symptomatic brain lesions do not exclude the diagnosis of NMO. Several different anatomic sites involvement has been reported, mainly periventricular brain regions, reflecting the distribution of AQP-4, not restricted to optic nerve and spinal cord (40,47). Upper cervical spinal cord is commonly involved, including the area postrema at the floor of the rhomboid fossa that seems to be a selective target in NMO, compatible with clinical reports that highlight intractable nausea/vomiting/hiccups preceding episodes of optic neuritis and transverse myelitis or being the heralding symptoms of NMO.

FIGURE 24.35 Neuromyelitis optica in a 32-year-old woman with sudden loss of vision in the left eye and clinical

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signs of cervical myelopathy. Sagittal T2WI (A) and Gd-T1WI (B) show an extensive hyperintense lesion of the cervical cord, swelling, and little enhancement after injection of the paramagnetic agent (myelitis). Axial T2WI (C) and coronal Gd-FS-T1WIs (D) show left optic nerve inflammation with swelling and hyperintensity of the nerve on T2WI and intense enhancement of this structure.

FIGURE 24.36 Neuromyelitis optica. A 17-year-old female. There was a reduction of visual acuity in the left eye since six months prior. Acute transverse myelitis presentation and uncontrollable vomiting. Sagittal and axial T2WIs (A,B) and sagittal and axial Gd-FS-T1WIs (C,D). Observe extensive involvement of the cervical cord and of the medulla reaching the level of the area postrema. The lesion is hyperintense on T2WI, partially hypointense on T1WI, and there is tenuous enhancement by the gadolinium chelate.

There is a vast list of differential diagnosis in a patient with focal/multifocal hyperintense T2weighted lesions in the spine, with or without gadolinium enhancement, which includes, among others, MS; NMOSD; arteriovenous malformation, especially dural fistula; collagen vascular disease such as SLE and Sjögren syndrome; Behçet’s disease; acute disseminated encephalomyelitis (ADEM); sarcoidosis; infectious myelopathies; and rarely neoplastic, metabolic, and degenerative diseases (47). Nevertheless, MRI lesion distribution and serologic abnormalities have great relevance to narrow the list of possibilities. Acute Disseminated Encephalomyelitis ADEM is an immune-mediated inflammatory demyelinating disease characterized by widespread demyelination that predominantly affects the white matter of the brain and spinal cord. It is characterized by an acute or subacute encephalopathy with polyfocal neurologic deficits. In the absence of specific biologic markers, its diagnosis is currently still based upon a combination of clinical and neuroimaging features and exclusion of mimic disorders. ADEM can occur at any age, but it is more common in children and young adults (50). Symptoms usually develop within 3 weeks after the onset of viral infection or immunization, although it is not always possible to prove such a relationship. In a cohort of 84 pediatric patients, 70% reported a clinically evident antecedent infection or vaccination during the prior few weeks. However, in a study of ADEM in adults, there was such an antecedent in less than 35% of the cases. It is believed that the apparent absence of clinical antecedent is related to preceding subclinical infection. TABLE 24.12 Differences between Neuromyelitis Optica and Multiple Sclerosis

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FIGURE 24.37 Neuromyelitis optica. A 28-year-old male. Right eye amaurosis with sudden onset a year before the MRI examination. Progressive tetraparesis and sphincter control loss that began two weeks before. Sagittal T2WI (A), sagittal STIR (B), and axial T2WIs (C,D) of the cervical spine. Cervical myelitis extending to the area postrema. Note the “bright spot lesions” in the axial images.

Although ADEM usually has a monophasic course, recurrent or multiphasic forms have been reported. Although infrequent in children, up to 35% of ADEM cases in adult patients develop definite MS on follow-up. In general, a prodromal phase with variable nonspecific symptoms, including fever, malaise, headache, nausea, and vomiting, is followed rapidly by meningeal signs and drowsiness. The clinical course is rapidly progressive and the nadir is reached within days with clear evidence of encephalopathy associated with a combination of multiple neurologic deficits (50). An autoimmune response to myelin basic protein is thought to play a role in the pathogenesis of ADEM, resembling the histologic and clinical pattern found in experimental autoimmune encephalomyelitis. When severe hemorrhagic necrosis is identified as a major component, the disease is referred to as acute hemorrhagic leukoencephalopathy or acute hemorrhagic encephalomyelitis (Weston–Hurst disease) (Fig. 24.38). It is usually triggered by upper respiratory tract infections, and a rapid progression to a fatal outcome is usual. Spinal cord involvement in ADEM has been described in 11% to 28% of patients, although it is probably underdiagnosed. The main reasons are that not all cases of ADEM have clinically detectable spinal involvement, the information received on brain imaging is usually enough to make the proper therapeutic decisions, and most patients are not sufficiently cooperative during the acute phase to submit to MRI. The typical spinal cord lesion is large and swollen, showing variable enhancement, and predominantly affecting the thoracic region (Fig. 24.39). It is assumed that a cardinal finding is characterized by lesions in the same stage, without gadolinium enhancement. Different patterns of enhancement have 1838

been described: complete or incomplete ring-shaped, nodular, gyral, or diffuse-patchy, particularly when brain lesions are evaluated (50). Most frequently, ADEM is clinically differentiated from MS by its clinically monophasic course (51,52). Myelopathy in MS is frequently partial, but in ADEM it is often complete and associated with areflexia. Most ADEM patients recover completely, without further neurologic deficit; however, the outcome of the disease in the acute phase may be fatal (Table 24.13) (51). MRI serial studies usually show complete or partial lesions resolution, playing a key role in supporting the diagnosis of ADEM. Complete resolution on imaging follow-up is frequently documented (37% to 75%) (50). However, partial resolution with spinal cord or brain sequelae, even in long-term follow-up, is common (25% to 53%) (50) and it does not favor the diagnosis of MS in the absence of encephalopathy and documented DIT/DIS (52).

FIGURE 24.38 Presumed acute disseminated encephalomyelitis with hemorrhage. Sagittal T1WI (A) shows an enlarged high-intensity cervical cord, consistent with hemorrhagic lesion. Note the extensive high intensity on the proton density images (B) extending throughout the entire cervical cord and up into the brainstem. (Courtesy of Dr. Clark Carrol, Houston, TX.)

FIGURE 24.39 A 13-year-old male. Acute encephalitic presentation with mental confusion and asymmetric paraparesis of the lower limbs. A: Sagittal T2WI of the cervical spine. B: Sagittal Gd-FS-T1WI of the cervical spine. C: Axial T2WI of the cervical spine. D: Sagittal FLAIR of the head. There are multiple moderate and large demyelinating lesions in the subcortical and deep white matter of the brain, as well as extensive lesion of the lower spinal cord—acute disseminated encephalomyelitis.

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A study using magnetization transfer and DTI in patients with ADEM, patients with MS, and normal controls showed that, in contrast to what happens in MS, the normal-appearing brain and cervical tissues in ADEM are spared in the pathologic process. The association of an acute encephalopathy and demyelination of the CNS is not pathognomonic of ADEM and a vast list of inflammatory and noninflammatory disorders may have a similar clinical and radiologic presentation and should be considered in the diagnostic evaluation (50,51). Infectious diseases should be promptly ruled out in order to start corticotherapy, but some demyelinating diseases should also be included in differential diagnoses, mainly NMOSD and Marburg disease in acute phase and MS in the follow-up. Radiation Myelopathy Radiation myelopathy is an uncommon complication of radiation therapy. The incidence of radiation myelopathy correlates positively with the total radiation dose, dose per fraction, and length of the spinal cord irradiated. The incidence of radiation myelopathy after radiotherapy for nasopharyngeal carcinoma is estimated to be between 1% and 10%. A 50% incidence of radiation myelopathy may be expected when the cord receives between 68 and 73 Gy and only 5% when the cord receives between 57 and 61 Gy. The latent period of radiation myelopathy has two distinctive peaks—one at 12 to 14 months and the other 24 to 28 months—and the latent periods decrease with an increasing dose. TABLE 24.13 São Paulo Reported Causes of Acute Disseminated Encephalomyelitis

The histopathology of radiation myelopathy can be classified as primarily white matter parenchymal lesions (type 1), primarily vascular lesions (type 2), or a combination of vascular and white matter lesions (type 3). The white matter lesions and the combination of vascular and white matter lesions have a shorter latent period, corresponding to the earliest peak at 12 to 14 months, whereas the vascular lesions are associated with a longer latent period, corresponding to the second peak, at 24 to 28 months. When there is frank coagulative necrosis, which may affect the entire transverse section of the cord at the site of maximum damage, there may be considerable expansion, simulating intramedullary tumor. In the later stages, the necrotic segment may be reduced to a narrow ribbon. As in the brain, the lesions 1840

tend to progress, even though these areas not originally exposed to the radiation, as a consequence of swelling and loss of myelin sheets that may result in Wallerian degeneration in the ascending and descending tracts. A spectrum of MR findings has been described in patients with radiation myelopathy (Fig. 24.40). There is no correlation between the MR findings and the latency of radiation myelopathy; however, there appears to be correlation between the time of MRI after the onset of symptoms and the MR findings, including low signal intensity on T1WI and high signal intensity on T2WI in a long segment of the cervical cord in the early stages. Swelling of the cord and/or focal enhancement after contrast administration may also be seen. Imaging longer than 3 years after the onset of symptoms usually reveals atrophy of the cord. The diagnosis of radiation myelopathy remains a diagnosis of exclusion, mainly confident after exclusion of spinal cord tumor or infectious diseases. Diffuse increased signal intensity on T1WI within the vertebral bodies due to fatty replacement is useful to demarcate the radiation therapy field and it also reminds us that previous radiation therapy might be involved in the current disorder. Sarcoidosis Sarcoidosis is a multisystem disease of unknown etiology characterized by the presence of noncaseating granulomas. Primary involvement of the spinal cord is very rare. Young adults, in the third or fourth decades, are most frequently affected, usually presenting with pulmonary symptoms. The prevalence is higher in women, particularly among African Americans and northern Europeans (53). The diagnostic workup of neurosarcoidosis should include an evaluation for potential extra-neural involvement and histologic confirmation of sarcoidosis. Definite neurosarcoidosis is diagnosed when there is confirmation by biopsy results showing noncaseating granuloma. Biopsy, however, is not always possible or desirable. If there is no appropriate extra-neurologic organ for biopsy, neural tissue needs to be considered for this purpose. Biopsy of the dura and leptomeninges is less invasive than biopsy of the brain or spinal cord parenchyma. Gadolinium-enhanced MRI of the brain and spinal cord is the most sensitive test for neurosarcoidosis, while for the others, including CSF analysis, serologic tests and nuclear medicine are all considered limited.

FIGURE 24.40 Breast cancer 7 years ago treated with mastectomy, chemotherapy, and radiotherapy. Sagittal T2WI (A), axial T2WI (B), and sagittal Gd-T1WI (C) images. Three weeks before the exam, the patient presented progressive tetraparesis and sphincter incompetence. Observe extensive myelopathy affecting the cervical and upper thoracic spinal cord. There is swelling of the spinal cord, high signal on T2WI, low signal on T1WI, and heterogeneous enhancement of the necrosis foci. The high signal of the fat bone marrow is coincident with the extension of the myelitis.

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FIGURE 24.41 Presumed vertebral sarcoidosis in a 42-year-old man with known mediastinal and pulmonary sarcoidosis complaining of lumbar pain. Sagittal T1WI (A) and T2WI (B) of the lumbar spine show small hypointense osseous lesions on the T1WI and some hypointense and some isointense on the T2WI, presumed to correspond to sclerotic lesions of sarcoidosis.

Spinal sarcoidosis includes vertebral, disc space, intramedullary, intradural extramedullary, and extradural lesions. Sarcoidosis of the vertebral bodies is rare, and there is a predilection for involvement of the thoracolumbar spine. An associated paraspinal mass may be present, and disc space involvement is rare. These findings usually suggest tuberculosis or a neoplasm. When the disc is involved, because pyogenic discitis is the most common diagnosis, biopsy is necessary for a definitive diagnosis. Only a few cases of MR of vertebral sarcoidosis have been described. In all of them, multiple lesions were seen that were hypointense on T1WI (Fig. 24.41) and variably hyperintense on T2WI, with heterogeneous enhancement after gadolinium administration. Involvement of the CNS is characterized by arachnoid infiltration by lymphocytes and granulomatous noncaseating nodules, consisting of epithelioid and giant cells, lymphocytes, and other mononuclear cells, and sometimes associated with a fibrous tissue reaction. The parenchyma is involved through extension of the nodules along the perivascular spaces in the brain, as well as in the spine. In the CNS, the most characteristic imaging finding of sarcoidosis is thickening and enhancement of the leptomeninges, but it may involve the dura mater, nerve roots, leptomeninges, and parenchyma, individually or in combination. Extramedullary intradural lesions are represented most frequently by leptomeningeal infiltration that is probably the precursor of intraspinal involvement. Extramedullary sarcoid granulomatous masses are rare, have a dural base like their counterpart inside the skull, and apparently, in spite of the paucity of reports, involve indistinctly the cervical, thoracic, and lumbar spine. The lesions are hypointense or isointense on T1WI, hyperintense on T2WI, and are enhanced vividly by the paramagnetic agent. There may be a dural tail. The imaging differential diagnosis includes meningioma, nerve sheath tumors, lymphoma, carcinomatous metastasis, chloroma, hemangiopericytoma, and other granulomatous conditions. Sarcoid myelopathy may mimic MS, tumor, vacuolar myelopathy, tuberculosis, and fungal infections. MR findings of spinal cord sarcoidosis include fusiform enlargements of the cord in the cervical or upper thoracic region, with increased signal intensity in T2WI, low signal intensity in T1WI, and patchy intramedullary enhancement, pial enhancement after contrast administration (Fig. 24.42) (53). Although unusual, a calcification may show as an area of low intensity on T2WI at the core of the lesion. Junger et al. proposed an MR classification of intraspinal sarcoidosis in four stages, correlating with possible histologic stages of the disease (54a). They hypothesized that phase 1 corresponds to early inflammation, with gadolinium demonstrating “linear” leptomeningeal enhancement along the surface of the spinal cord. In phase 2, parenchymal involvement could be secondary to spreading of the leptomeningeal inflammatory process to the Virchow–Robin spaces, with or without enhancement on MR; this suggests centripetal spread of the disease, which may result in a diffusely enhancing lesion. In phase 3, inflammation decreases, and the enlarged spinal cord tends to return to normal size with focal or multifocal intramedullary lesions. In phase 4, the chronic phase, spinal cord atrophy may occur. Phases 2 and 3 are most frequent at clinical presentation. 1842

Necrotizing Myelopathy One very well-defined, but rare, entity characterized by cord necrosis is necrotizing myelopathy secondary to venous stasis and venous hypertension caused by a dural arteriovenous fistula, known as Foix–Alajouanine syndrome. It is an uncommon neurologic disorder characterized pathologically by abnormal intraparenchymal vessels with thickened hyalinized walls, central coagulative necrosis, demyelination, lipid-laden macrophages, and gliosis. It is clinically manifested by progressive motor and sensory deterioration, followed by abrupt worsening. Due to the advent of MRI, vascular malformations of the spine are diagnosed earlier, which allows earlier endovascular or surgical treatment, and the stage of frank necrosis has tended to become even less frequent. In the medical literature, however, the term necrotizing myelopathy encompasses different entities, some of which have been more recently better classified as part of the spectrum of disease-related transverse myelitis, including inflammatory and demyelinating conditions such as MS, ADEM, SLE, and infectious diseases due to varicella-zoster, herpes simplex, mumps, rubella, mononucleosis, pulmonary tuberculosis, as well as clioquinol intoxication. Necrotizing myelopathies may also occur as epiphenomena of a neoplasm, as a paraneoplastic syndrome. The clinical presentation is of rapidly ascending paraplegia followed by rapid deterioration and death not associated with radiation therapy, cord compression, or tumor infiltration. This condition is associated with a variety of neoplasms, such as lung and breast carcinoma, lymphoma, and leukemia. It is characterized pathologically by massive or patchy multifocal areas of coagulative necrosis in both the gray and the white matter, with a paucity of inflammatory cells. The pathogenesis is unknown, but two such cases have been associated with the presence of herpesvirus type II. Other factors predisposing the development of necrotic myelopathy include hypercoagulability, migratory thrombophlebitis, and polycythemia. There are also idiopathic cases. Katz and Ropper reported clinical, laboratory, and radiologic findings on nine patients who had progressive idiopathic myelopathy with evidence of spinal cord necrosis (54b). The most distinctive feature of these cases was a saltatory progression of symptoms punctuated by acute and subacute worsening approximately every 2 to 9 months, culminating in paraplegia or tetraplegia. The CSF analysis showed elevation of proteins, between 500 and 100 g/L, without oligoclonal bands, accompanied infrequently by pleocytosis. MRI showed features that, according to the authors, were suggestive of cord necrosis, swelling, signal hyperintensity on T2WI, and gadolinium enhancement over several spinal cord segments, succeeded months later by atrophy. Necrosis of the cord was found in biopsy material from one patient and in the necropsy material of another patient, but inflammation and blood vessel abnormalities were absent.

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FIGURE 24.42 Intramedullary sarcoidosis. A 40-year-old woman with acute paraplegia and sensory loss below C3. A: Sagittal T1WI demonstrates marked enlargement of the cord in the entire cervical and upper thoracic region. B: Sagittal T2WI demonstrates increased intramedullary signal in the entire cervical and upper thoracic regions. C: Sagittal Gd-T1WI demonstrates marked enhancement in the posterior aspect of the cord in the entire cervical and upper thoracic region (arrows). D: Axial Gd-T1WI through the midthoracic spine demonstrates enhancement in the posterior aspect of the cord (small arrow). Note the mediastinal adenopathy consistent with sarcoidosis (large arrow).

Behçet’s Disease Behçet’s disease (BD) is a multisystem relapsing in ammatory disorder of unknown cause, which is characterized by recurrent ulcerations of the mouth and genitalia accompanied by uveitis or iridocyclitis. The term neuro-BD (NBD) has been used to describe CNS involvement that include either the development of an immune-mediated meningoencephalitis, which predominantly involves the brainstem, but can also involve the basal ganglia, thalamus, cortex and white matter, spinal cord, or cranial nerves; or it can result in intracranial venous thrombosis. The reported frequency of NBD is variable, predominating in males, particularly in the Middle East, the Mediterranean basin, and the Far East regions, being considered rare in Europe and North America. Most commonly, the neurologic component of the disease is a brainstem syndrome, a meningomyelitis, or an organic confusional syndrome, although nearly any part of the neuraxis may be involved. Isolated transverse myelitis is an uncommon presentation of NBD, whereas involvement of the spinal cord as part of the diffuse type of parenchymal NBD pattern is not, particularly affecting the cervical and/or dorsal segments of the spinal cord. There are evidences that spinal cord involvement carries a bad prognostic factor in parenchymal NBD. If the major nonneurologic features of BD (oral and genital ulceration, uveitis, and/or iridocyclitis) are absent or inapparent, the diagnosis of NBD is particularly difficult. In such circumstances, it may be confused with other multifocal, inflammatory, or demyelinating CNS disorders, including MS, sarcoidosis, and SLE, all of which can present as a relapsing–remitting disorder. Pathologic studies in NBD reveal perivascular cuffing with predominating lymphocytes or neutrophils, demyelination with vasculitis, multifocal necrosis, and/or glial proliferation. The most common sites of 1844

pathologic changes are the brainstem and basal ganglia, but they are demonstrated in the meninges, small blood vessels, and spinal cord.

FIGURE 24.43 Behçet’s syndrome. Cervical spine sagittal T1WI (A) not showing abnormalities, sagittal T2WI (B) demonstrating irregular small hyperintense intrinsic lesions of the cervical spinal cord, and sagittal Gd-T1WI (C) showing several irregular punctate areas of enhancement. Sagittal T1WI (D), T2WI (E), and Gd-T1WI (F) of the thoracic spinal cord showing the aspects already described for the cervical spine. (Courtesy of Dr. Antônio Rocha, São Paulo, Brazil.)

The MR findings of NBD are more commonly reported in the mesodiencephalic junction, followed by the pontobulbar region. The hypothalamothalamic region, basal ganglia, cerebral hemispheres, cerebellum, and the spinal cord are also involved, but less commonly. Brain and spinal cord lesions are hyperintense on T2WI, but not usually detected on T1WI and may occasionally enhance after gadolinium administration. MR can also demonstrate atrophy of the brainstem and cerebellum; and hyperintense optic nerve lesions on T2WI in patients with optic neuropathy. If there is myelopathy, MR scanning of the spinal cord may show atrophy and/or scattered lesions or a diffuse area of altered signal on T2WI. These may or may not enhance (Fig. 24.43). Guillain–Barré Syndrome Guillain–Barré syndrome (GBS) is characterized by peripheral polyneuropathy affecting all four limbs, with or without cranial nerve involvement, which causes acute neuromuscular failure, clinically characterized by symmetric weakness or paralysis, associated with loss of tendon reflexes, with little or no sensory loss, as well as elevated levels of proteins in the CSF without pleocytosis. It is the most frequent worldwide cause of acute flaccid paralysis (54). Although the pathogenesis of GBS remains unclear, there are increasing indications that it is an autoimmune disease, often triggered by a preceding gastrointestinal tract or pulmonary infection. There are predominant forms of the syndrome, which are defined on clinical, electrophysiologic, and pathologic basis. GBS and Miller Fisher syndrome (MFS) have been considered to represent a continuum rather than distinct entities, due to the overlap in their clinical features (39,54). While GBS is initially characterized by progressive and ascending weakness of the extremities and areflexia, MFS is considered 1845

the cranial nerve variant of GBS, and the diagnosis is based on the triad of ophthalmoplegia, ataxia, and areflexia. Because the diagnosis of GBS is determined mainly on the basis of clinical findings and CSF analysis, most imaging studies are realized to exclude other conditions (54). In GBS, neuroimaging demonstrates involvement of the cauda equina roots; however, in MFS, MRI findings are usually more extensive. GBSMFS has been considered part of a broader autoimmune neuropathy, demonstrated by involvement of the cauda equina roots associated with enhancement of cranial nerves (54). MR findings in GBS have shown variable patterns of abnormalities, more commonly gadolinium enhancement of the thickened nerve roots, including ventral roots predominance in some patients, slightly high signal intensity on precontrast T1WI with no signal abnormalities detected on T2WI, in addition to gadolinium enhancement and thickening of the spinal nerve roots that decreased at followup MR, corresponding to minimal clinical and electrophysiologic findings. In patients with suspected GBS-MFS, particularly in children, the routine cranial and spinal cord imaging could be integrated into the workup. Selective or predominant gadolinium enhancement of the anterior nerve roots favors this diagnosis, particularly associated with cranial nerves involvement (Fig. 24.44). Nevertheless, the contrast enhancement of the spinal roots is a nonspecific finding that can be seen in neoplastic or other inflammatory processes (Table 24.14). TABLE 24.14 Differential Diagnosis of Nerve Root Enhancement

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FIGURE 24.44 Guillain–Barré syndrome. Sagittal T1WI (A) and Gd-T1WI (B) show pial and radicular enhancement by contrast. Axial Gd-T1WI (C). The ventral roots are selectively enhanced by the paramagnetic agent. (Courtesy of Dr. Antônio Rocha, São Paulo, Brazil.)

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Chronic inflammatory demyelinative polyneuropathy (CIDP) is an acquired neuropathy, presumably of immunologic origin. Its clinical presentation and course are extremely variable and it is one of the few peripheral neuropathies amenable to treatment. Although it can occur at any age and in both genders, CIDP is more common in young adults, and it is more common in males than in females. Typical cases associate progressive or relapsing–remitting motor and sensory deficit with increased CSF protein content and electrophysiologic features of demyelination. Axon loss associated with demyelination is the most important factor of disability and resistance to treatment. CIDP is closely related to GBS and it is considered the chronic counterpart of that acute disease. MRI depicts enlargement and T2 hyperintensity of nerve roots, plexi, or peripheral nerves. There may be slight, moderate, or accentuated contrast enhancement (Fig. 24.45). Intradural and extraforaminal spinal cervical, thoracic, and lumbar nerve roots may be affected, as well as the cranial nerves and the brachial and lumbar plexuses. The diagnosis is clinical and the MRI findings do not correlate with the activity or severity of the disease. Treatment consists of immunomodulation and immunosuppression.

SPINAL CORD INFECTIONS Agents implicated in spinal cord infections include bacterial (pyogenic, granulomatous), fungal, parasitic, and viral organisms. The hematogenous route is the most frequent, but extension from brain and meningeal infection and from vertebral osteomyelitis has been observed. In the acute form, back pain is severe and is followed immediately by paresthesia with a rising level of sensory impairment until complete transverse myelitis develops. Disturbance of sphincteral function is an early finding. Subacute or chronic intramedullary infections tend to mimic the clinical presentation of neoplasms with regard to the fluctuation of symptoms. 1847

The diagnostic challenge posed by the diversity of pathologic processes associated with the different infectious diseases that can cause spinal cord infections. Constant migration or population shifts and international travel carry infected individuals to the remotest areas of the world. For the diagnosis in most of the spinal cord infections, one should consider epidemiologic data, exposure risks, job, travels, and also hobbies, which can contribute to the specific suspicion. Systemic symptoms and remote organ abnormalities may present important clues to suggest etiologic agents. MRI is the method of choice for diagnosing spinal cord infections, mainly during their early phase. Clinicoradiologic suspicions are important to indicate specific serologic and CSF tests, and finally to support proper treatment for each of the diseases preventing disabilities or neurologic complications. Infectious Diseases and Infectious Agents Brucellosis Brucellosis is a zoonosis of worldwide distribution, endemic in Saudi Arabia and Mediterranean countries as well as in the midwestern United States, that is caused by a gram-negative bacilli of the genus Brucella. Of the four species implicated in human infection, Brucella melitensis is the most common, the most invasive, and the most frequently associated with spondylitis (55).

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FIGURE 24.45 Chronic inflammatory demyelinating polyradiculoneuritis. Sagittal and axial Gd-FS-T1WIs of, respectively, the cervical (A,C) and the lumbar spine (B,D). There is enlargement and enhancement of the cervical and lumbar roots.

The infection most commonly follows the ingestion of contaminated milk or milk products but can occur also as consequence of occupational exposure among animal handlers, slaughterhouse workers, and veterinarians. The diagnosis is established by detecting high titers of antibodies to Brucella antigens in the standard tube agglutination test, positive results from blood cultures, and the presence of characteristic imaging features (55). The most commonly affections are arthritis, sacroiliitis, and spondylodiscitis. Vertebral involvement is striking in all, with the lumbar region predominating (40%), followed by the lumbar– sacral (32%), thoracic (16%), and cervical (8%) regions (56). Changes may occur slowly, sometimes resembling a degenerative disease. The radiographic findings of brucellar spondylitis include areas of bone erosion at the discovertebral junction; reactive bone sclerosis; areas of gas (peripheral vacuum phenomenon) entrapped between vertebral endplate and disc; and anterior osteophytes, disc destruction, paravertebral abscess formation, and extension of granulation tissue into the epidural space. MRI has high sensitivity for detecting the disease in early stages and provides excellent definition of paravertebral and epidural extension. It also allows the detection of otherwise-unsuspected additional noncontiguous spinal foci. In acute forms, MRI shows low-to-intermediate signal intensity on T1WI of the intervertebral disc and low signal intensity in the adjacent vertebral bodies. The signal in these areas is hyperintense on T2WI, with either a homogeneous or heterogeneous pattern. Gadolinium enhancement allows better definition of the spinal inflammatory lesion and offers a confident assessment of soft tissue involvement and epidural affection (55). Spinal tuberculosis is the major differential diagnosis for brucellosis. Unlike spondylodiscitis by brucellosis, tuberculous spondylitis is commonly seen in younger patients. The diagnosis is confirmed by serologic results and/or positive blood culture (56). Although both diseases induce a granulomatous inflammatory reaction in the spine, certain distinguishing MR features can be helpful. While brucellosis has a predilection for the lower lumbar spine (Fig. 24.46), tuberculosis tends to favor the lower thoracic spine. In brucellosis, the height of the vertebral bodies is usually preserved even though signal abnormalities consistent with osteomyelitis are noted. Conversely, in tuberculosis the vertebral bodies are severely damaged, with marked gibbous deformity and osteophytes are uncommon. Brucellosis tends to spare the posterior elements that may be affected by tuberculosis. The disc tends to be 1849

preserved in brucellosis as well as in tuberculosis, although it may also be affected in both conditions. Brucellosis rarely extends into the epidural space, whereas tuberculosis often presents with epidural abscesses and involve the meninges. The paraspinous soft tissues are also affected by brucellosis, but lesser common and more undefined than by tuberculosis, which causes cold abscesses (55,57). Actinomycosis Actinomycosis is a chronic bacterial infection that induces both a suppurative and a granulomatous inflammatory response. Actinomyces israeli is the species most often recovered from human cases of actinomycosis. Actinomyces are gram-positive anaerobic bacteria found normally in the mouth and fecal flora and within the female reproductive tract. Infection of the cervicofacial tissues comprises 50% to 60% of reported cases. The second most common localization is thoracic and represents 15% to 30% of the cases, usually after aspiration of infectious material from the oropharynx.

FIGURE 24.46 Brucellosis in a 30-year-old man. A: Coronal STIR image demonstrates a focus of high intensity in the L4 vertebral body (small arrow) and a paraspinous high-intensity lesion consistent with granulation (large arrow). Axial T1WI (B), Gd-T1WI (C) and T2WI (D) confirm the paraspinous granulation (arrow). Follow-up magnetic resonance imaging 8 weeks later demonstrates considerable extension of the disease. E: Coronal STIR image demonstrates enlargement of the paraspinous granulation area and increased signal in the L3, L4, and L5 vertebral bodies consistent with osteomyelitis (asterisks). Sagittal T2WI (F) and Gd-T1WI (G) show the associated epidural granulation (arrows) and disc space enhancement and disc herniation at L3–L4.

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The vertebral involvement of actinomycosis is usually secondary to an infection of contiguous tissue rather than hematogenous spread. Sixty percent of the cases are caused by A. israelii, the average age of the patients is 42.2 years, most in males, and 66.7% of the cases are associated with thoracic involvement or other pulmonary symptoms (58). Affection of several vertebrae may demonstrate lytic defects with surrounding sclerosis. The intervertebral discs are usually spared. Paravertebral abscesses are usually smaller than in tuberculosis and do not calcify (Fig. 24.47). At the thoracic spine the association with rib lesions and the presence of cutaneous sinus tracts are common. Secondary involvement of the spinal cord may occur as a consequence of epidural extension of the process.

FIGURE 24.47 Syphilitic polyradiculopathy. A 23-year-old human immunodeficiency virus—positive Ethiopian woman with sudden onset of profound bilateral polyradiculopathy. A: Sagittal Gd-T1WI demonstrates multiple foci of pial enhancement on the dorsal aspect of the lower cervical and upper thoracic cord (arrows). B: Axial Gd-T1WI demonstrates enhancement of the cervical roots (arrows). Cerebrospinal fluid studies confirmed the diagnosis of syphilis. A follow-up study after antibiotic therapy demonstrated resolution of the enhancement, and the patient’s condition improved. (Courtesy of Dr. P. Blake, Washington, DC.)

Syphilis Syphilis is a chronic infectious disease caused by the bacterium (spirochete) Treponema pallidum, usually acquired by sexual contact. There has been a sharp increase in the number of cases of syphilis in the era of AIDS, with a corresponding increase in the incidence of neurologic disease. It progresses, when not treated, through primary, secondary, and tertiary stages. In about 30% of untreated patients, late disease of the heart, CNS, or other organs develops. Neurosyphilis in a nonimmunocompromised host is a relatively rare condition since the introduction of routine use of laboratorial tests and of penicillin. Neurosyphilis can be asymptomatic or cause different disorders such as tabes dorsalis, general paresis, and meningovascular syphilis. The spinal cord can be affected in different forms by the disease: tabes dorsalis, meningomyelitis, polyradiculitis, pachimeningitis, or meningovascular syphilis (56). Syphilitic meningomyelitis and polyradiculitis are rare manifestations of secondary syphilis. The most common presentation of syphilis in the spine involves the presence of syphilitic gummas, which result from an intense leptomeningeal inflammatory reaction (Fig. 24.48) and may show the classic “candle guttering appearance” on contrast studies, as well as the “flip-flop sign” characterized by a low signal intensity on T2WI and avid enhancement. Another classic but currently rare presentation is tabes dorsalis (the tertiary form), which involves the posterior column of the spinal cord and can be demonstrated by nonspecific atrophy associated with hyperintensity on T2WI. In immunosuppressed patients there may occur an ATM presentation (Fig. 24.49). The lesions may or may not resolve on follow-up imaging after adequate therapy with penicillin (56). Neuroborreliosis (Lyme Disease) Lyme disease is an infectious disease with multisystem inflammatory manifestations caused by a spirochete, Borrelia burgdorferi sensu lato complex, transmitted by ticks of the Ixodes ricinus group (59). It is the most commonly reported vector-transmitted disease in the United States. Although cases of the illness are concentrated in certain endemic areas, foci of neuroborreliosis are widely distributed around the world (59). The disease typically manifests in the acute phase by a characteristic migratory erythema that may 1851

emerge associated with some influenza-like symptoms. The secondary stage appears days or months after the initial contagion and is characterized by articular, neurologic (10% to 15%), and cardiac complications (59). Involvement of the CNS includes encephalitis, myelitis, and demyelinating lesions or combinations of these indications. Various spinal syndromes such as diffuse back pain syndromes, myelitis, or radiculitis, as well as different combinations of these may occur. Determination of specific antibody titers, performed by enzyme-linked immunosorbent assay (ELISA), is the most helpful additional diagnostic test for Lyme disease. However, the interpretation of serologic evidence of exposure to B. burgdorferi in individuals who live in endemic areas of this disease may be limited. On MR, spinal involvement in neuroborreliosis shows diffuse or multifocal hyperintense signal changes of the spinal cord on T2WI and additional leptomeningeal and spinal nerve roots enhancement (Fig. 24.50), due to lymphocytic meningoradiculitis, predominantly in lower spinal regions, on postgadolinium T1WI. In severe myelitis, multifocal contrast-enhancing lesions of the spinal cord may occur (56,60). Additional intracranial findings, such as multifocal hyperintense lesions on T2WI with or without contrast enhancement on T1WI simulating demyelinating lesions and different types of cranial nerve enhancement on postcontrast T1WI, especially on facial nerve, may aid the diagnosis (56,60).

FIGURE 24.48 Actinomycosis. Biopsy-proven actinomycosis in a 28-year-old man complaining of lumbar pain and presenting with fever. Human immunodeficiency virus negative. A: Sagittal T1WI shows hypointensity of T12 and L1 vertebral bodies. Mild reduction of height and posterior bulging of T12 body. B: Sagittal T2WI shows hyperintensity of the T12 body. Note the integrity of the internuclear cleft of neighboring discs. C: Sagittal Gd-T1WI shows enhancement of the T12 body and granulation tissue behind T11, T11–T12, T12, and T12–L1. D: Coronal T1WI shows low intensity of the T12 and L1 bodies and of the left part of the T11 vertebral body. E: Coronal Gd-T1WI shows enhancement of the T12 body and granulation tissue formation on the left side of T11, T11–T12, and T12 and on the right side of T12–L1.

Baggio–Yoshinari syndrome was described in Brazil, transmitted by ticks of the genera Amblyomma and/or Rhipicephalus, caused by spirochetes, which determines systemic and relapsing complications, including immunologic disorders, throughout the prolonged clinical evolution. This disease is characterized by the triad of lymphomonocitary meningitis, cranial neuritis, and peripheral radiculopathy, and less commonly encephalomyelitis (Fig. 24.51), with a distinctive high frequency of relapses, especially when the patients are not diagnosed and treated early in the acute phase and neurologic involvement (59,61). Listeriosis Listeriosis, an infectious disease caused by the gram-positive bacillus Listeria monocytogenes, is distributed widely throughout the world. Asymptomatic human intestinal carriage of the bacillus is present in 1% to 5% of healthy adults. Sporadic disease manifests as meningitis, encephalitis, or spontaneous abortion. However, most affected patients are immunocompromised and present with 1852

meningitis, rhomboencephalitis, and, less frequently, spinal abscess. However, L. monocytogenes can also affect healthy adults, often in the setting of contaminated delicatessen meats or dairy products (62). L. monocytogenes is the cause of 1% of the cases of acute bacterial meningitis. However, among patients with cancer, it is responsible for more than 20% of the cases. Among patients with Listeria meningitis, 25% have a malignancy, 25% are transplant recipients, and 20% have another underlying disorder (e.g., diabetes mellitus, cirrhosis) or are receiving corticotherapy. The diagnosis is often difficult, and the organism is rarely identified from CSF cultures but, more commonly, from blood cultures.

FIGURE 24.49 A 30-year-old, HIV-positive. Transverse myelopathy presentation with sensitive level in T10. Reactive CSF VDRL test result. Sagittal STIR (A) and axial T2WI (B) images of the thoracic spine. Lower spinal cord myelitis characterized by nonspecific centrally located hyperintensity on T2WI.

FIGURE 24.50 Lyme meningitis. A: Sagittal Gd-T1WI demonstrates pial enhancement (arrow). B: Axial Gd-T1WI demonstrates enhancement of the roots (arrows).

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FIGURE 24.51 Lyme disease. Sagittal T1WI (A), T2 WI (B) and Gd-T1WI (C), and axial T2WI (D) and Gd-T1WI (E). Several small, irregular hyperintense lesions can be seen on the T2WI widespread through the spinal cord; only some can be identified on the T1WI as small and not well-defined hypointense images. After gadolinium– diethylenetriamine penta-acetic acid venous injection there is widespread irregular enhancement with pial and parenchymatous components. (Courtesy of Dr. Antonio Rocha, São Paulo, Brazil.)

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FIGURE 24.52 Transverse myelitis in a 42-year-old woman due to Listeria monocytogenes. Two months before the exam there was an abrupt onset of tetraparesis and a sensitive level at T8. CSF showed 676 cells, 83% of neutrophils, proteins 120, lactate 39, and glucose 24. Blood culture identified L. monocytogenes. Using a 3-T magnet. Sagittal T1WI (A) and T2WI (B) of the thoracic spine, sagittal T2WI of the cervicothoracic spine (C), and parasagittal Gd-FS-T1WI of the thoracic spine (D). There is hyperintensity on T2-weighted imaging and swelling of the cord restricted to the segment between C7 and T3. The enhancement is focal, intense, and restricted to the affected area, most probably representing a focal zone of myelitis.

MR of intramedullary Listeria abscesses has been reported as patchy hyperintensities on T2WI in a variable extension in the spinal cord and the presence of enhancing lesions after gadolinium chelate administration that depend on the specific phase of abscess formation (Fig. 24.52). In early stages, it appears as a solid lesion, later becoming peripheral and ringlike in its appearance. There may be also meningeal enhancement. The MR findings by themselves do not allow the differentiation from meningitis and intraspinal cord abscess of other etiology. There is also a description of a case of chronic spinal arachnoiditis caused by L. monocytogenes, which aspect was also nonspecific. Tuberculosis Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. There has been in increase in global prevalence of tuberculosis predominantly in men, particularly immunocompromised (27). Tuberculous Spondylodiscitis It is believed that skeletal involvement in tuberculosis occurs mainly by hematologic dissemination, whether by arterial or venous route is still under debate, from a primary infection of the lung, particularly in children, or, later, from a quiescent primary site or an extraosseous focus. Tuberculosis onset is insidious, with symptoms ranging from months to 2 to 3 years. Pyogenic infections tend to have symptoms from days to months. Spinal tuberculosis usually starts in the anteroinferior portion of the vertebral body. Spread of infection can occur beneath the anterior longitudinal ligament involving the adjacent vertebral bodies. Disc space narrowing occurs secondarily and is usually limited to the degree of bone destruction that allows herniation of the disc material into the affected vertebral body. A lack of proteolytic enzymes in Mycobacterium as compared with pyogenic infection has been proposed as the cause of relative 1855

preservation of the intervertebral disc. If uninvolved, the disc will not show increased signal on T2WI, one of the main imaging findings of pyogenic infections (Fig. 24.53) (63). The thoracolumbar junction is affected most commonly, and the disease is relatively infrequent in the cervical and sacral segments of the spine. The cortical definition of affected vertebrae is invariably lost, in contrast to pyogenic spondylitis (Table 24.15). Although the vertebral body is involved more commonly than the posterior elements, these latter structures may be affected initially or predominantly in some persons. When there are posterior element abnormalities, with or without involvement of the vertebral body, differentiation of infection from tumor may become difficult, particularly when there is also a relative preservation of the disc space, one of the criteria for the imaging diagnosis of neoplasm rather than infection. Extension of tuberculous spondylodiscitis to the adjacent ligaments and soft tissues is frequent, varying in the literature from 55% to 96%. This extension usually occurs anterolaterally; it is rarely observed posteriorly in the peridural space. The paravertebral masses are characterized by a thick, irregular enhancement on CT and MR (63). In a significant series, the paraspinal masses had no distinguishing features on the sequences used, and most of them were hypointense on T1WI and hyperintense on T2WI. Enhanced MR studies are especially useful for characterizing tuberculous spondylitis. Rim enhancement around intraosseous and paraspinal soft tissue abscess is more common than in other spinal infections (Fig. 24.54). The use of gadolinium–DTPA has also been shown to be useful in delineating communications between the vertebral and paravertebral components of tuberculous spondylitis (27). The size of the paraspinal masses has been noted to be generally larger in tuberculosis than in pyogenic infections (Fig. 24.55) and the rim enhancement around intraosseous and paraspinal soft tissue abscess is more common than in other spinal infections (27,63).

FIGURE 24.53 Tuberculous spondylodiscitis. Sagittal T1WI (A), T2WI (B), and Gd-T1WI (C). Collapse of the T5 vertebral body is seen together with slight hypointensity of T4, T5, and T6 on T1WI corresponding to hyperintensity signal on T2WI. There is an extradural component posterior to C6 that significantly compresses the spinal cord. After intravenous injection of gadolinium–diethylenetriamine penta-acetic acid there is heterogeneous enhancement of collapsed T5, of the posterior part of the intervertebral disc T5–T6, and of the periphery of the T6 body, delimiting an inner abscess. There is associated enhancement of the peridural component. Note that the discs T3–T4, T4–T5, and T6–T7 are preserved. The disc T5–T6 is still relatively preserved, considering the vertebral body destruction. Note the anterior-situated prevertebral granulomatous reaction (white arrow).

Collapse of partially destroyed vertebral bodies can lead to severe deformities, typically kyphosis or gibbous deformity and less frequently scoliosis. The degree of angulation varies with the site and extent of vertebral disease, but despite the sometimes striking deformity, the diameter of the spinal canal may not be altered significantly. There may be destroyed and, rarely, extruded vertebral bodies in the area of angulation. Neurologic abnormalities may be encountered as a result of spinal cord compression from abscess, granulation tissue or bone fragments, arachnoiditis, ischemia of the cord resulting from endarteritis, or intramedullary granulomas. Intramedullary involvement of the spinal cord is rare and affects typically young adults, although children and elderly patients may also be affected. Lesions are more frequently solitary, although additional lesions may be encountered in the spinal cord or brain or both (27). Signal characteristics of these tubercular lesions on T1- and T2-weighted MRI are variable. This diversity of MRI signal characteristics is related to the histologic stage of tuberculoma. The majority of lesions 1856

appear to be iso- or hypointense on T1WI, while the liquefactive necrosis present as hyperintense lesions on T2WI, and caseous necrotic lesions typically appear as markedly hypointense foci on T2WI. A majority of the lesions variably enhance with gadolinium showing diffuse, nodular, ringlike, and also tumorlike patterns (56,64). Tubercular Spinal Arachnoiditis Tuberculosis is an important potentially treatable cause of spinal arachnoiditis. It is frequently associated with radiculomyelitis, which helps to distinguish it from other causes of arachnoiditis. The meninges show variable degrees of congestion, and the spinal cord and nerve roots are surrounded by gelatinous exudates and may be edematous. A tuberculoma may be located anywhere within the thecal sac. It usually closely adheres to the inner aspect of the dura and may even dig a crater in the cord, making it difficult to determine whether it is extramedullary or intramedullary. In the chronic stages, fibrin-covered roots stick to each other and to the thecal sac, forming dense collagen adhesions by proliferating fibrocytes. TABLE 24.15 Differential Diagnosis between Tuberculous Spondylitis and Pyogenic Spondylitis

FIGURE 24.54 Tuberculous spondylodiscitis. Parasagittal (A,B) and axial Gd-FS-T1WIs (C). There is involvement of the posterior aspects of L2, L3, and L4. Note also the involvement of right posterior arch of L3. The peripheral enhancement delimiting areas of abscess is characteristic of tuberculosis. Note once more the relative preservation of intervertebral discs.

Although the disease may occur as a primary event, more than 50% of the cases are associated with meningitis or spondylitis. The diagnosis is usually based on clinical features, CSF analysis, evidence of tuberculosis elsewhere in the body, especially meningitis, and characteristic imaging findings. CSF analysis usually reveals an elevated protein level, a reduced glucose level, and an increase in the number of cells, mainly lymphocytes, which in endemic areas or in suspected patients should always raise the suspicion of tuberculosis. Acid-fast bacilli are rarely identified. A negative India ink study is recommended to rule out cryptococcal infection (56). A large published series showed the results of the retrospective analysis of MR findings in tubercular spinal arachnoiditis. Eighty-six percent of the patients had involvement of more than one spinal region, with the dorsal region most commonly involved (Fig. 24.56). CSF showed increased signal intensity on T1WI in 77% of the patients, leading to complete loss of cord–CSF interface in some of the cases and shaggy cord outline in others. There were areas of increased signal intensity on T2WI in the spinal cord in 82% of the patients. In 10% of the patients there was evidence of cord cavitation (Fig. 24.57). Other findings on unenhanced images were CSF loculations, nodules in subarachnoid space, and clumping of 1857

cauda equina nerve roots (Fig. 24.58). Meningeal enhancement was seen in 80% of patients and nerve root enhancement in 30% of them. Cord enhancement was seen in 20% of patients, along the surface of the cord in half of the cases and central in the other half. Associated findings were tubercular spondylitis, basal meningitis, and intracranial granulomas.

FIGURE 24.55 Tuberculous spondylodiscitis. Coronal (A) and axial (B,C) Gd-FS-T1WIs showing the collapse of T3 and T4 vertebral bodies. Also shown are ring enhancement of intra- and extraosseous abscesses, voluminous paravertebral masses, and epidural component.

FIGURE 24.56 Surgically confirmed tuberculous arachnoiditis in a 15-year-old girl. Sagittal T1WI (A) and T2WI (B) of the cervicothoracic spine show an anteriorly situated arachnoid cyst extending from C6 through T3, the contents of which behave like cerebrospinal fluid and compress the spinal cord. Sagittal T2WI (C) and T1WI (D) of the thoracic

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cord show an extensive syrinx caudad to the arachnoid cyst, extending through T9–T10. Axial T2WI (E) of the distal cervical channel shows the severe cord compression.

FIGURE 24.57 Syringomyelia secondary to tuberculous meningitis. Parasagittal Gd-T1WIs of the cervical cord (A) and the thoracic cord (B), axial Gd-T1WIs of the cervical cord (C) and the conus and cauda equina (D) show a whole-cord syrinx, obliteration of the subarachnoid space, and strong enhancement of the cauda equina.

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FIGURE 24.58 Tuberculous meningitis in a 40-year-old, HIV-positive man presenting with nausea, malaise, and vomiting. There was also involvement of the lungs and of the bowels by the disease. Axial high-resolution lung computed tomography (A) shows diffuse pulmonary infiltration characterized by micronodularity due to miliary tuberculosis. Sagittal T1- (B) and Gd-T1WI (C) of the thoracic spine show intense pial enhancement around the spinal cord and the roots of the cauda equina. Parasagittal Gd-T1WIs of the lumbar spine (D) show pial-arachnoid enhancement due to tuberculosis.

FIGURE 24.59 Mycobacterium avium–intracellulare epidural abscess in an immunosuppressed patient. A: Sagittal T1WI demonstrates abnormal signal intensity and destruction in the C2 vertebral body (asterisk) and an anterior epidural abscess. B,C: Respective sagittal and axial Gd-T1WIs demonstrate the abscess to better advantage. (Courtesy of Dr. N. Petronas and Dr. M. Koby, Bethesda, MD.)

Mycobacterium Avium-intracellulare M. avium and M. intracellulare are closely related and are commonly grouped as M. avium-intracellulare complex. They are distributed worldwide and rank first among nontuberculous mycobacteria isolated in the United States. M. avium-intracellulare complex causes about 80% of nontuberculous mycobacteria lymphadenitis cases. M. avium complex is the most common opportunistic bacterial infection in AIDS patients. Extrapulmonary or disseminated disease, infrequently seen in immunocompetent patients, occurs in 1860

up to 40% of individuals with AIDS, usually in patients with advanced disease. Prior to HAART, the disease had been reported in up to 30% of living patients and 50% of patients dying of AIDS. In addition to massive infiltration of the lymph nodes, the bone marrow may be diffusely infiltrated with M. aviumintracellulare complex, resulting in diffuse decreased intensity on T1WI. This appearance, however, is nonspecific and may be seen with any diffuse inflammatory or neoplastic process involving the marrow. The infection’s course is usually more insidious than tuberculosis and epidural extension of the M. avium–intracellulare infection, indistinguishable from other infections, may be seen (Fig. 24.59) (64,65). Fungal Infections Fungal infections of the spine and spinal cord can be caused by pathogens and by saprophyte fungi, the latter in immunocompromised patients. Candida and Aspergillus are the most common causes of human opportunistic mycotic infections. In the spine these include osteomyelitis, discitis, meningitis, formation of abscesses and granulomas, and, when invasion of the vessel walls occurs, thrombosis that may eventually lead to cord infarction. As with pyogenic agents, infection can occur by direct implantation, invasion, or hematogenous spread from elsewhere in the body. Some fungi are distributed worldwide, whereas others are encountered only in certain geographic regions. The diagnosis is achieved by the isolation of the fungus or by the presence of characteristic histopathologic changes. North American Blastomycosis North American blastomycosis is caused by the pathogen fungus Blastomyces dermatitidis. The disease is found in southern Africa, Central and South America, and in the north, south, central, and mid-Atlantic states in the United States. The disease may be acquired by contamination of the skin after cutaneous injuries or by inhalation of spores. Blastomycosis is generally a chronic indolent systemic disease with predominantly cutaneous involvement. However, multiple organ involvement is common and the bones may be involved in as many as 50% of patients with disseminated disease. In immunocompromised patients, reactivation of an indolent focus may occur. In the nervous system, the disease can present as meningitis or as single or multiple abscesses (blastomycomas). The meninges may be involved in the form of an extradural lesion or pachymeningitis, and may compress the underlying cord and cause obstructive hydrocephalus. Intramedullary involvement is extremely rare. MRI and CT are valuable in determining the presence and extent of involvement by the granulomatous disease. In the spine, blastomycosis resembles tuberculosis, with a thoracolumbar predilection. Findings considered unusual in tuberculosis are involvement of the overlying skin with necrotic ulcers and concurrent involvement of other bones, as well as neighboring ribs erosion (Fig. 24.60). The prognosis is exceedingly poor and no clinical syndromes or imaging modalities are characteristic. Final diagnosis can be made only by visualization of the yeast in pus, sputum, and secretions, and on the basis of the histologic examination. Therefore, a diagnostic biopsy should be done in patients with mass lesions. Coccidioidomycosis Coccidioidomycosis is a systemic infection caused by Coccidioides immitis and is endemic in the southwestern United States, as well as in parts of Central and South America. Virtually all coccidioidal infections are the result of inhaling arthroconidia, the sporulated form of the fungus.

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FIGURE 24.60 Spinal blastomycosis in a young man with progressive thoracic myelopathy. A: Sagittal T2WI demonstrates collapse of a midthoracic vertebra with an anterior epidural mass (black arrow) compressing the cord and an anterior prevertebral mass (white arrow). B: Axial T1WI confirms these findings. Note also the anterior prevertebral mass (asterisk) and the rib destruction (black arrow). (Courtesy of Dr. Azmi Hamzaoglu, Istanbul, Turkey.)

Approximately two-thirds of infections are asymptomatic and detected only through a dermal test to coccidioidal antigens. Most symptomatic patients usually present with a mild pulmonary syndrome. Disseminated disease occurs in only a small percentage of patients. This more aggressive form of infection is more commonly seen in young, elderly, and immunocompromised patients. Osseous manifestation occurs in 10% to 50% of patients with disseminated disease, specially involving the spine, ribs, and pelvis. Circumscribed radiolucent lesions characterize spinal changes. Vertebral involvement has a variety of appearances, ranging from diffuse and patchy to focal and contiguous. Paraspinal masses and sparing of the intervertebral discs are also common, simulating other granulomatous diseases. However, vertebral collapse and fistulous tracts are uncommon and late manifestations. Involvement of multiple vertebral bodies, with skull and rib contiguous lesions are common features, unlike in patients with tuberculosis (66). Rarely, marked sclerosis of the vertebra may mimic prostate carcinoma metastases. The MR findings are nonspecific, characterizing a unifocal or multifocal disease, involving the intervertebral disk, vertebral body marrow, and adjacent epidural and soft tissue (Figs. 24.61 and 24.62). Meningitis is not unusual in patients with disseminated coccidioidomycosis.

FIGURE 24.61 Coccidioidomycosis. A: A 22-year-old man with a 3-month history of neck pain, fever, and left C8 radiculopathy. Axial T2WI demonstrates a left anterior epidural mass originating in the vertebral body. B,C: Coccidioidomycosis of the lumbar spine in another patient. Sagittal T1WI (B) and T2WI (C) demonstrate severe destruction of the L4 and L5 vertebral bodies and intervertebral disc and a prevertebral and anterior epidural mass. The radiographic appearance is not specific. (Courtesy of Dr. M. Koby, Bethesda, MD.)

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FIGURE 24.62 Coccidioidomycosis polyradiculopathy. A 30-year-old, HIV-positive man with a 3-month history of back pain and lower extremity weakness. Cerebrospinal fluid analysis confirmed the diagnosis of coccidioidomycosis. Sagittal T1WI (A) and Gd-T1WI (B) demonstrate enhancement of the pia over the conus and of the roots of the cauda equina (arrows). (Courtesy of Dr. C. Lindan, San Francisco, CA.)

The diagnosis is made by biopsy in a patient from an endemic area. Diffuse skeletal disease with characteristic well-circumscribed radiolucent lesions combined with abnormalities of the spine, including disk space, bone marrow, and soft-tissue involvement, should heighten one’s index of suspicion for wide-spread coccidioidomycosis (66). Paracoccidioidomycosis Paracoccidioidomycosis is a systemic disease caused by the dimorphic fungus Paracoccidioides brasiliensis, predominating in South America and, therefore, it was previously known as “South American blastomycosis” (67), and it is considered the most important systemic profound mycosis in Latin America, especially in Brazil. Rare cases have been reported in patients who have lived in or visited endemic areas (56,67). This disease occurs by inhalation of the fungus, with hematogenous or secondary lymphatic dissemination to the kidneys, spleen, adrenal glands, and bone, as well as CNS. This disease has also been recognized as an AIDS-related opportunistic infection in endemic areas. Diagnostic confirmation is based on biopsy, usually outside the CNS. When paracoccidioidomycosis is suspected, a lung study, usually a CT, is recommended for identifying the appropriate lesions for biopsy in the lung tissue (56,67). CNS lesions may manifest as granulomas, meningitis, or as a mixed form. Localization in the spinal cord is considered rare, constituting only 0.6% of systemic infection cases and 4% when the CNS is involved (67). CNS granulomas are lesions with an expanding aspect commonly associated with the involvement of other organs, most notably the lungs (56,67). These lesions may also be associated with diffuse leptomeningeal enhancement, characterizing the meningeal form (Fig. 24.63). Cryptococcosis Cryptococcosis is a systemic mycosis that most often involves the lungs and CNS and, less frequently, the skin, skeletal system, and prostate gland. It is the most common systemic and CNS fungal infection in immunocompromised populations and is due to Cryptococcus neoformans, also known as Torula histolytica or to C. gattii. It has a worldwide distribution and immunocompromising related to altered Tcell function is the most common predisposing factor. About 20% to 30% of patients with the disease have no apparent condition or predisposing factor, except for unexplained CD4 cytopenia in some (68). Cryptococcal spondylitis is a rare condition usually seen in immunocompromised patients and occasionally reported in immunocompetent patients. MR features of a cryptococcal spondylitis were indistinguishable from those of tuberculous spondylitis, with involvement of the vertebral body and extensive involvement of the posterior elements and paraspinous and perivertebral soft tissues with relative preservation of the disc (Fig. 24.64). There is occasionally meningeal enhancement around the spinal cord, although this does not happen very frequently because there is very little inflammatory reaction at this level (68). Brain lesions are more common and consist of meningitis involving the skull base, dilated Virchow– 1863

Robin spaces, and intraparenchymatous cryptococcomas. These intracranial findings are relevant for imaging suspicion. However CSF studies, including the detection of cryptococcal capsular polysaccharide antigen, is highly sensitive and specific for cryptococcosis. India ink stains of the CSF are also very helpful. Aspergillosis Aspergillosis is the name given to infection by any of the species of the genus Aspergillus. Aspergilli are ubiquitous, with more than 350 known species, although the most common pathogen is Aspergillus fumigatus. Aspergillosis generally results from air-borne conidia and is not contagious. The lungs are more commonly affected, and there are several resultant clinical syndromes. The invasive form of the disease is generally a problem of immunocompromised hosts. Targets of disseminated disease include the CNS. It is estimated that 60% to 70% of patients with disseminated aspergillosis have neurologic lesions. The disease may produce a granulomatous reaction but commonly results in abscess formation. Histologically, the most striking feature is the intensity of the vascular invasion with thrombosis (69). There are no pathognomonic radiologic or clinical indicators for spinal involvement in aspergillosis and a high index of suspicion is necessary for early diagnosis. MRI is the most important modality for lesion detection and staging of disease (70). A combination of individual risk factors, suspect radiologic findings, and mycologic findings is highly suggestive (69,71). The spinal cord involvement is rare and usually present in immunocompromised patients. It may shows a tumorlike lesion, aspergiloma, or an abscess, characterized as a nonspecific ring-enhancing medullary mass (72). A. osteomyelitis has also been described most in recipients of organ transplants, but also in patients with other immunocompromising. MR features may be distinct from pyogenic osteomyelitis, including absence of disc hyperintensity and preservation of the intranuclear cleft on T2WI (69,71). Infarctlike lesions and abscess have been reported on MRI in immunocompromised patients (70,73). Although minimal paraspinal inflammation was present in most cases, epidural abscesses with cord compression secondary to aspergillosis have also been reported (74). Candidiasis Candida species, most commonly Candida albicans, can cause a variety of clinical syndromes that are usually categorized by the site of involvement. In most patients, candidiasis is an opportunistic disease, although it can occasionally occur in previously healthy individuals. The CNS is only occasionally involved by hematogenous dissemination, with primary focus in the respiratory and/or gastrointestinal tracts. The early brain lesions resemble hemorrhagic infarcts, with abscesses and granulomas without central foci of necrosis that occur later (75). CNS candidiasis rarely involves the spinal canal and most often arises due to contiguous spread from a paravertebral abscess. In the spine, the disease has been reported in different forms: spondylodiscitis, intramedullary abscess, and arachnoiditis. Candida osteomyelitis presents imaging findings similar to those of other relatively indolent infectious agents, tending to preserve or only later affect the discs (Fig. 24.65). Multiple-level disease may be present. An intramedullary abscess caused by Candida species cannot be differentiated by imaging alone, but must be considered in the immunocompromised patient. Arachnoiditis (Fig. 24.66) is a potential hazard of meningitis and can cause syringomyelia as a complication.

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FIGURE 24.63 Paracoccidioidomycosis. Cervical spinal cord paracoccidioidomycosis in a 62-year-old man complaining of left cervicobrachialgia since 15 months before the magnetic resonance exam and presenting with progressive paresis of the left superior and inferior limbs. A: Sagittal T1WI shows fusiform enlargement of the cervical spinal cord. B: Sagittal T2WI shows an intraspinal ellipsoid lesion heterogeneously hypointense at C4–C5 levels. There is an extensive area of hyperintensity from C1 through C6 that most probably represents edema. C: Sagittal Gd-T1WI shows ring enhancement of the intraspinal lesion. D: Surgical resection of the lesion. E: Surgical resection and surgical specimen. F: Microscopy with hematoxylin–eosin shows cord tissue with recent hemorrhage and reactive astrocytes (black arrowheads). G: Microscopy with silver stain shows characteristic spores of Paracoccidioidis brasiliensis. H: Axial high-resolution computed tomography of the lungs shows interstitial infiltrate and different-sized nodules. (Courtesy of Ney Vilamil Azambuja, MD, and Claudio Pitta Pinheiro, MD, Porto Alegre, RS, Brazil.)

Histoplasmosis Histoplasmosis is caused by Histoplasma capsulatum and is worldwide in distribution, with greatest prevalence in tropical and temperate zones. Histoplasmosis is endemic in the south, north central, and selected areas of the eastern United States, being considered the most common endemic systemic mycosis in this country (76). The primary route of acquisition is inhalation of spores. It is associated with a variety of clinical syndromes, the most frequent of which is an asymptomatic or self-limited influenza-like respiratory infection in immunocompetent. Less frequently, the disease can evolve as chronic cavitary pulmonary disease, a progressive disseminated disease involving multiple organs, or an immune-mediated disease of the mediastinum or eye. The majority of HIV-positive individuals diagnosed with histoplasmosis, on the other hand, will present with disseminated disease. Involvement of the CNS is uncommon, occurring in 10% to 20% of patients with disseminated histoplasmosis (68,76). In addition, histoplasmosis may be the cause of chronic meningitis in patients with no other evidence for dissemination (68). Less commonly, intracranial mass lesions, cerebral embolism secondary to endocarditis, encephalitis, and an isolated myelopathy can occur. The mass lesions most often present as 1866

miliary granulomas but can also, in rare instances, present as the larger-sized histoplasmomas. The MRI characteristics of these mass lesions typically involve a ring-enhancing or nodular-enhancing mass, which is usually a noncaseating granuloma (68,77).

FIGURE 24.64 Cryptococcosis of the spine. A 3-year-old, HIV-positive child with back pain. Sagittal T1WI (A) and T2WI (B) demonstrate abnormal signal in the L4 and L5 vertebral bodies, loss of disc height, and a small epidural mass at the disc level (arrow), a nonspecific finding consistent with discitis of any cause. Biopsy revealed Cryptococcus. (Courtesy of Dr. J. Ahmadi and Dr. M. Koby, Los Angeles, CA.)

A positive fungal culture of the CSF is the gold standard but is insensitive. One should maintain a high index of suspicion in patients who are from any area endemic for histoplasmosis (68). Parasitic Infections Spinal Cysticercosis Cysticercosis is the most common parasitic infection of the CNS. It is a worldwide disease that affects 50 million people, with a prevalence of 3% to 6% of the population in endemic areas such as Central and South America, Eastern Europe, Africa, and some regions of Asia. With the growing number of immigrants from these countries, the disease has increased in frequency in the United States. A population study in a Hispanic community in California found the prevalence of Taenia solium cysticercosis to be 2.8% in adults, similar to the prevalence data from some endemic regions in Latin America (78). The organism responsible for the disease is the larval stage of T. solium, a tapeworm (Table 24.16). The most common larval form is Cysticercus cellulosae, which characteristically has a scolex and causes brain intraparenchymal lesions or, rarely, spinal intramedullary lesions. C. racemosae, which lacks a scolex, usually grows in grapelike clusters of thin-walled cysts and shows a tendency to predominate in the subarachnoid space (27). These organisms are both forms of the same parasite, commonly coexisting in a single patient. The proposed diagnostic criteria include epidemiologic factors and the results of physical examination, fundoscopy, serologic tests, and imaging. Additionally, imaging plays a main role in confirming and fully characterizing the different forms of neurocysticercosis (NCC) (56).

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FIGURE 24.65 Candida discitis. A 70-year-old diabetic man with back pain and paraplegia. A: Sagittal T1WI demonstrates destruction of the disc, vertebral body (asterisk), and adjacent endplates (V) and a prevertebral (arrowhead) and an epidural mass compressing the cord (arrow). Sagittal (B) and axial (C) Gd-T1WIs demonstrate the epidural mass to better advantage. (Courtesy of Dr. P. Baum, Sacramento, CA.)

FIGURE 24.66 Candida meningoradiculitis. Brain axial fluid-attenuated inversion recovery images pre- (A) and postgadolinium-diethylenetriamine penta-acetic acid intravenous injection (B). There is slight enlargement of the ventricular system and leptomeningeal enhancement. Sagittal Gd-T1WI of the cervical spine (C) shows linear enhancement around the brainstem and the spinal cord, indicating pial arachnoid involvement. Parasagittal Gd-

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T1WIs of the lumbosacral spine (D) and (E) showing pial enhancement around the conus and at the roots of cauda equina.

Spinal cord involvement is extremely uncommon and is reported in 1.2% to 5.8% of patients with neurocysticercosis. The leptomeningeal form is six to eight times more frequent than the intramedullary form. The extradural form is even rarer, and only a few cases have been reported (79). The pathogenesis of the leptomeningeal form of spinal cysticercosis is probably due to the downward migration of larvae from the cerebral to the spinal subarachnoid space, following the path of CSF flow (Figs. 24.67 and 24.68). In the spinal subarachnoid space, the larvae usually lodge in the cervical region because of the arachnoid trabeculae that are found there. The cysts are usually located in the posterior subarachnoid space, where they appear to grow more favorably, without bringing about a marked meningeal reaction. TABLE 24.16 Classification of Spinal Cysticercosis

Pathophysiologically, there are three possible mechanisms by which neurologic symptoms and signs might appear in cases of spinal cysticercosis: an inflammatory reaction caused by the metabolites of the parasite or the degenerated larval remains, mass effect of intramedullary or extramedullary cysts (Figs. 24.69 and 24.70), and cord degeneration due to meningitis or vascular insufficiency. The topographic distribution of intramedullary cysticerci is statistically proportional to the blood flow to each of the regions, being the thoracic spine most involved in this presentation, suggesting a hematogenous route of infestation (79). MRI is the most useful modality to evaluate spinal neurocysticercosis, as this approach can reveal the intensity of the viable cystic fluid, which (whether in the spinal cord or the subarachnoid space) is usually similar to that of the CSF on both T1WI and T2WI. Degenerated cysts may have increased signal intensity, probably resulting from increased protein content. MR further demonstrates mass effects, variable vesicular enhancement, and adjacent edema as a result of dead larvae. The absence of a CSF flow void is commonly observed adjacent to extramedullary cysts. High-resolution highly T2-weighted sequences, such as the use of constructive interference in steady-state (3D-CISS, FIESTA, BALANCE) techniques, allow for better delineation of the cyst and its scolex, when it is present (Fig. 24.67). Cisternal MRI, as in myelography, enables detection of the cyst, which appears as a hypointense cystic wall surrounded by contrast material (80).

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FIGURE 24.67 Subarachnoid neurocysticercosis. Sagittal T2WI (A) and sagittal T2WI fast imaging employing steadystate acquisition (FIESTA)/three-dimensional constructive interference in steady-state (3D CISS) imaging (B) of the lumbar spine show subarachnoid cysticercotic cysts.

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FIGURE 24.68 Intradural extramedullary cysticercosis in a 51-year-old man with radiating low back pain and symptoms referable to the conus. Sagittal T1WI (A) and T2WI (B) of the thoracic spine show irregular intradural extramedullary loculations with associated hyperintensity in parenchyma (A). Axial T2WI (C) demonstrates loculated intradural collections in the lower thoracic region that mimic epidural disease in their configuration. After gadolinium (D), extra-axial enhancement is seen. Surgery confirmed racemose cysticercosis.

FIGURE 24.69 Intramedullary cysticercosis in a 46-year-old woman with 9 months of lower-extremity weakness and paresthesias. Sagittal T1WI (A) and T2WI (B) of the cervical spine show a heterogeneous, loculated, multicystic intramedullary lesion with marked expansion of the cervical spinal cord. After gadolinium (C), intramedullary disease with heterogeneous enhancement is noted. Intraoperative photographs (D) show the multicystic loculated nature of the lesion, proven to be cysticercosis.

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FIGURE 24.70 Neurocysticercosis. A,B: Respective sagittal T1- and T2WIs of the cervical spine. There is an intraspinal cystic lesion extending from C4 through T3. Its content behaves similarly to cerebrospinal fluid. Presumed edema rostrally to the cyst can also be seen in panel B. C: Axial computed tomography at the upper part of the cyst shows a calcified portion of the wall of the cyst. D,E: Surgical specimens. F: Surgical specimen of the cysticercus vesicle and the scolex. (Courtesy of Dr. Flavio Kei Miura, São Paulo, Brazil.)

However, the MRI features of intramedullary neurocysticercosis are not specific in the absence of the scolex, and the differential diagnosis includes neoplastic, inflammatory, demyelinating, vascular, and granulomatous lesions. Epidemiology and marked eosinophilia may be useful for differentiation from a spinal arachnoid cyst (79). Intramedullary neurocysticercosis may also occur in conjunction with cysticercal meningitis and intracranial lesions, which should be recognized, even in asymptomatic patients. Spinal Cord Schistosomiasis Spinal cord schistosomiasis, the best known form of neuroschistosomiasis, is a severe, under-recognized form of this disease that occurs at any time during the parasitic infestation (81). Schistosomiasis is an infection caused by platyhelminth of the genus Schistosoma. Humans and other mammals are definitive 1873

hosts, and aquatic and amphibious snails are intermediate hosts of these blood flukes. Five species of Schistosoma can affect humans: Schistosoma mansoni, located in South America, Africa, the Caribbean Islands, and the Middle West; S. haematobium, located in Africa (Middle East); S. japonicum, located in Japan, China, and the Philippines; S. intercalatum, located in Africa (west central); and S. mekongi, located in southeast Asia. It is one of the most widespread parasitic diseases worldwide and is an important public health problem, particularly in tropical areas. Approximately 200 million people worldwide are afflicted with schistosomiasis, and approximately 20 million develop severe disease, including CNS forms. Neuroschistosomiasis has been increasingly reported not only in endemic areas but also in Western countries, owing to immigration and international travel (56,82). Almost all reported cases of neuroschistosomiasis are caused by infection with S. mansoni, whereas S. haematobium primarily affects the urinary tract and S. japonicum has an increased likelihood of extending to the brain parenchyma (56). Neurologic symptoms may result from the deposition of eggs surrounded by granulomatous reactions in circumscribed areas of the brain or spinal cord, although the simultaneous occurrence of cerebral and spinal schistosomiasis is extremely rare (83). In endemic areas, spinal schistosomiasis is more common in children, adolescents, and young adults; the disease usually presents acutely or subacutely as conus medullary syndrome and is often associated with the involvement of cauda equina roots (84). Clinically, spinal cord schistosomiasis may be classified into three classical forms; however, the disease can progress from one form to another (84). The most frequent form is meningomyeloradiculitis, followed by the medullary form involving the lumbosacral spine. The medullary form of schistosomiasis is generally associated with a rapid course and severe weakness and can manifest as meningomyeloradiculitis, transverse myelitis, spinal cord pseudotumor, anterior spinal artery syndrome, or radiculitis. The clinical triad of lumbar pain, paresthesias, and paresis of the inferior limbs is the most common initial manifestation of this condition. If not treated, it can evolve into a clinical picture of transverse myelitis. Although the clinical picture of neuroschistosomiasis is nonspecific, spinal schistosomiasis should be strongly considered in young patients presenting with acute paraplegia, myeloradicular pain syndrome, or CES with a positive epidemiologic origin. The clinical diagnosis becomes less likely when higher segments are affected or when the symptoms progress more slowly. Known epidemiology associated with blood eosinophilia, antibody levels, and the presence of parasite ova in the urine and/or stool may support the correct diagnosis (81). A rapid and pronounced improvement after treatment lends further support to diagnosis (84). The differential diagnosis of spinal schistosomiasis should include ependymoma, spinal cord astrocytoma, metastatic tumors, and vencongestion in a spinal dural arteriovenous fistula (81). Although the alterations observed in cases of spinal schistosomiasis are usually nonspecific, MRI greatly contributes to the diagnosis, easily demonstrating the abnormalities in the spinal cord and helping to rule out other possibilities. Although clinical forms usually coexist, the most common imaging findings are described in the medullary form and the conus syndrome, which is characterized by a patchy pattern hyperintensity on T2WI, enlargement of the spinal cord, and a remarkable heterogeneous contrast enhancement on T1WI, particularly in the lower cord and conus medullaris (Figs. 24.71–24.73) (80,81,84,85). This interesting multinodular enhancing pattern is associated with multiple schistosome eggs and granulomas in the spinal cord, peripheral contrast enhancement with eggs, and granulomas in the leptomeninges (85).

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FIGURE 24.71 Intramedullary Schistosoma mansoni infection in a 37-year-old man with bilateral lower extremity pain and paresthesias. Hyperintense intramedullary lesion (A) shows focal nodular enhancement (B). Schistosomiasis was confirmed by surgery.

FIGURE 24.72 Schistosoma mansoni infection in a 50-year-old paraparetic man without control of sphincter. The enzyme-linked immunosorbent assay in the cerebrospinal fluid was positive for schistosomiasis. Titer 1:128. A,B: Respective sagittal T1- and T2WIs of the cervicothoracic spine show multiple ill-defined hyperintense lesions in the lower cervical and high thoracic spinal cord. T1WI is negligible. C: Sagittal Gd-FS-T1WI of the thoracic spine shows several small areas of enhancement for the whole extension of the spinal cord, mainly on its periphery. D: Hematoxylin–eosin microscopy of S. mansoni circumscribed by lymphomononuclear infiltrate. (Courtesy of Dr. Fátima Aragão, Recife, PE, Brazil.)

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FIGURE 24.73 Schistosoma mansoni infection in a 25-year-old woman with a 6-month history of lumbar pain, paresis, and paresthesias at the inferior lower limbs. Sagittal T1WI (A), T2WI (B), and Gd-T1WI (C), and axial GdT1WI show swelling and signal heterogeneities affecting the conus medullaris and the lower thoracic cord. There is heterogeneous enhancement of the lesion. (Courtesy of Dr. Fátima Aragão, Recife, PE, Brazil.)

Occasionally, MRI may also display an intramedullary arborized appearance, which is highly suggestive of this disease in individuals from endemic schistosomiasis regions (56). In cases with a longer evolution, medullary atrophy can be observed (56). In the other clinical forms (myeloradicular and cauda equine), MRI demonstrates thickening of the spinal roots (especially the cauda equina roots) and a linear radicular contrast enhancement, representing eggs and granulomas on the surface of nerve roots (81,84,85). The granulomatous form of schistosomiasis results from an intense granulomatous inflammatory reaction around the eggs in association with gliosis and fibrosis. This reaction leads to the formation of focal expanding intra- or extra-axial lesions, which demonstrate a pattern of intense epidural enhancement adjacent to areas of medullary involvement (56). Extradural compromising (bilharzioma) is considered rare. Other even rarer forms, which may be revealed by imaging, include acute transverse myelitis (which may be hemorrhagic and necrotizing) and an acute, anterior spinal artery syndrome (27). Spinal Echinococcosis The larvae of the parasitic tapeworm T. echinococcus cause hydatid disease. Two main forms have been implicated in human infection: Echinococcus multilocularis and E. granulosus. Humans are secondarily infected via the ingestion of food or water contaminated by eggs of the parasite. The two most frequent clinical forms are cystic echinococcosis, caused by E. granulosus, and, less frequently, alveolar echinococcosis, caused by E. multilocularis. Hydatid disease remains a health problem in endemic areas of countries where veterinary control is precarious, mostly in the temperate zones. This disease is diagnosed by serologic and imaging tests. The most frequently involved organ is the liver, and CNS involvement is considered rare (1% to 2% of all cases), even in endemic areas (56,86). Spinal involvement in echinococcosis is very rare and, the thoracic segment of the spine is the most frequently affected region (50% of cases), followed by the lumbar (20%), sacral (20%), and cervical (10%) segments (86). Cysts of hydatid disease are always multilocular. Within cancellous bone the parasite develops as multiple small cysts that grow along the path of least resistance and, with time, may destroy the cortex and extend into the adjacent soft tissues. Even if the cortex is breached, the dura remains intact. The imaging and clinical presentation of spinal echinococcosis depends on the primarily involved anatomic structures (86). The plain radiographs show nonspecific bony destruction that may also be demonstrated by CT and MR. CT may be helpful, allowing better visualization of details of bone destruction and spinal canal involvement (Fig. 24.74). MR may detail the intraspinal extension to better advantage than CT (Figs. 24.75 and 24.76). This disease usually manifests as isointense cystic lesions without significant peripheral edema. The fibrous capsule is characteristically hypointense on T2WI and may display discrete peripheral contrast enhancement in the presence of active inflammation. Intramedullar echinococcosis is rare and intradural–extramedullary cysts are more commonly observed. These cysts usually grow eccentrically and follow the line of least resistance along the dural 1876

sack. Compared with extradural echinococcosis, they are more frequently limited to a single cyst and appear to present at a younger age (86). Intradural–extramedullar or intramedullar cysticerci may mimic echinococcosis. In addition, and even more rarely, cestode infections may also mimic spinal alveolar echinococcosis (E. multilocularis) and spinal sparganosis (Spirometra sp.). Spinal arachnoid cysts and spinal aneurysmal bone cysts are also potential differential diagnoses; however, known epidemiology associated with marked eosinophilia should be useful to raise a suspicion of the parasitic origin (86).

FIGURE 24.74 Surgically proven hydatid cyst. Axial computed tomography (A) shows a multiloculated hypodense mass expanding the left pedicle lamina and transverse apophysis of L3. B: Its surgical demonstration. The dural sac is indicated by black arrowheads. Multilocular cysts are seen at the posterior arch of L3. (Courtesy of Dr. Claudio Pitta Pinheiro, Porto Alegre, RS, Brazil.)

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FIGURE 24.75 Hydatid cyst. Young man with thoracic myelopathy. A,B: Sagittal T2WIs on both sides of the midline demonstrate multiloculated extradural cysts with intradural extension (arrow). C: Axial T1WI confirms these findings (arrows) and shows the cord compression to better advantage. (Courtesy of Dr. A. Hamzaoglu, Istanbul, Turkey.)

FIGURE 24.76 Hydatid cyst. A: Sagittal T1WI demonstrates a destructive lesion of L4 with a large anterior prevertebral mass (arrow). B: Axial computed tomography demonstrates the calcification in the periphery of the mass (arrow) not seen on magnetic resonance imaging. (Courtesy of M. Koby, Bethesda, MD.)

Preoperative diagnosis is difficult because of lack of characteristic radiographic features. In addition, successful management is also problematic because of the invasive nature of bone involvement and the variable anaphylactic reaction to the cyst fluid antigen (56). Toxoplasmosis Toxoplasma gondii is a protozoan that commonly infects mammals and birds throughout the world. This obligate intracellular parasite can cross all biologic barriers and finally invades the host CNS. The course 1878

of toxoplasmosis is well described for maternal primary infection during pregnancy, which can lead to various congenital defects and even abortion, and infection or reactivation of a pre-existing infection in immunocompromised individuals, often causing encephalitis. Numerous conditions that affect the immune system are associated with toxoplasmosis, more commonly related to reactivation of a latent infection. These include AIDS, Hodgkin disease, use of corticosteroids and other immunosuppressive agents, collagen vascular disorders, and organ transplantation. T. gondii has been recognized as the most common cause of focal brain lesions in patients with AIDS. Neurotoxoplasmosis is diagnosed upon clinical, serologic, CSF or imaging investigations. The highest sensitivity can be achieved by the application of polymerase chain reaction (PCR) methods in the serum or CSF, whereas ELISA or immunoblotting of the CSF demonstrates better specificity (56,80). Although few reports have been published describing spinal toxoplasmosis in humans, adult-acquired toxoplasmosis can also affect the spinal cord. This spinal cord pathology clinically manifests predominantly in severely immunocompromised patients, especially due to CD4 T-cell immune deficits associated with AIDS or T-cell leukemia/lymphoma. Depending on the parasite location (with respect to different segments of the spinal cord), the symptomatology is characterized by motor and sensory loss, urinary sphincter abnormalities, and pain. In AIDS setting, spinal lesions usually present as contrast-enhancing intramedullary lesions with an extensive mass effect and associated edema (Figs. 24.77 and 24.78). The presence of coexisting cerebral toxoplasma lesions frequently assists in diagnosing the spinal disease (27,56).

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Viral Diseases Nearly all of the major groups of animal viruses can infect the CNS. As a matter of fact, nervous system involvement, in most instances, is an uncommon complication of a relatively common systemic infection. This section discusses some of the viruses that most frequently affect the spine, such as herpesvirus (varicella-zoster virus [VZV], Epstein–Barr virus [EBV], cytomegalovirus [CMV], and herpes B virus), enterovirus (poliovirus), and retrovirus (HIV). Herpesvirus The family Herpesviridae is probably the most common viral cause of transverse myelitis, consisting of a large group of double-stranded DNA viruses, which includes herpes simplex virus type 1 (HSV1), herpes simplex virus type 2 (HSV2), CMV, EBV, VZV, herpes B virus, herpesvirus 6, and herpesvirus 7. In addition to producing infection when the host initially acquires the virus, an important property shared by these viruses is their ability to produce latent infection and to be later reactivated. Although encephalitis is the most common manifestation, some herpesviruses may produce myelitis and polyradiculitis. HERPES SIMPLEX. It may cause all forms of myelitis from mild with good recovery, recurrent, ascending, and necrotizing with permanent sequelae. About two-thirds of cases have an ascending presentation of neurologic manifestations. HSV1 more commonly causes myelitis in children while HSV2 is the more common agent in adults. Children may have fever and mild respiratory symptoms prior to the onset of myelitis. Less than half of adults have genital herpes prior to myelitis. MRI usually reveals unspecific hyperintensity on T2WI with swelling of the cord with lesions anywhere from the conus to the cervical cord (Fig. 24.79) that may enhance after intravenous contrast administration. Diagnosis is dependent on finding the virus DNA or direct IgM antibodies in the CSF. HERPES ZOSTER. Myelitis is a distinctly unusual manifestation of VZV infection, with most cases occurring in immunocompromised patients, which appears to be due to viral invasion of the spinal cord, as viral DNA is found in the CSF and specific antiviral therapy usually results in clinical improvement. Most patients have dermatomal zoster preceding the myelitis by few weeks. Although the etiology of VZV myelitis is not fully established, an allergic response, autoimmune vasculitis, demyelination, and direct viral invasion have been postulated. The myelitis is usually subacute in onset and asymmetric with the initial leg weakness ipsilateral to the zoster. MRI usually reveals unspecific spinal cord swelling visible as variable hyperintensities on T2WI, which can be patchy throughout the cord. Confirmation requires finding VZV-specific antibody or VZV DNA in the CSF. On serial MR, the degree of contrast enhancement changed from marked to none with corresponding clinical improvement (Fig. 24.80).

FIGURE 24.77 Intramedullary toxoplasmosis in a hemophiliac patient with acquired immunodeficiency syndrome. A: Sagittal T1WI suggests thickened nerve roots (arrow). B: Sagittal Gd-T1WI demonstrates intramedullary enhancement (open arrow) proved to represent toxoplasmosis at biopsy. Notice also the enhancement of the nerve roots (black arrow) and of the pia along the conus (small white arrows). (Courtesy of Mary K. Edwards, Indianapolis, IN.)

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FIGURE 24.78 Intramedullary toxoplasmosis in a 40-year-old, HIV-positive man with acute quadriparesis and high toxoplasmosis titers. A: Sagittal T1WI demonstrates expansion of the cord at the C2 level. B: Sagittal T2WI demonstrates expansion of the cord and increased signal intensity in the cord between C2 and C4 and a central hypointense center. C: Sagittal Gd-T1WI demonstrates a nodular enhancing lesion in the cord at the C2 level. D: Axial image demonstrates a well-defined lesion in the right aspect of the cord at the C2 level. This nodular enhancement has been associated with granulomatous infections or neoplasms rather than idiopathic or viralinduced transverse myelitis.

FIGURE 24.79 Viral myelitis. Sagittal FS-T2WI of the cervical spine (A), sagittal STIR of the thoracic spine (B) and axial T2WIs of respectively the cervical and the thoracic spine (C,D). A 42-year-old male. Herpes simplex type II confirmed by PCR of the CSF. Extensive nonspecific centrally located lesion affecting the cervical and the upper thoracic cord with swelling of the lower portion. There was no enhancement after gadolinium intravenous injection.

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FIGURE 24.80 Herpes zoster myelitis in a 41-year-old man with progressive urinary retention and bilateral leg weakness. The patient had concomitant herpes zoster skin papules in some of the involved dermatomes. Acyclovir therapy resulted in moderate clinical improvement. Note the extensive lesion on the T2WI (A, arrows) with irregular foci of enhancement (B,C). (From Gero B, Sze G, Sharif H. MR imaging of intradural inflammatory diseases of the spine. AJNR Am J Neuroradiol 1991;12:1009–1019, with permission.)

EPSTEIN–BARR VIRUS. EBV is the agent of infectious mononucleosis, an acute infection that when symptomatic includes fever, sore throat, lymphadenopathy, and lymphocytosis with splenomegaly. This infection occurs early in life in the less developed countries and is usually inapparent. In the more developed nations, EBV infections occur later in life, usually in older children and adolescents. Complications involving the CNS include GBS, Bell palsy, transverse myelitis, and meningoencephalitis. Imaging may reveal hyperintensity lesions on T2WI involving the spinal cord with variable contrast enhancing of the lesion and meninges. CYTOMEGALOVIRUS. CMV is a common opportunistic infection in AIDS patients and is associated with a spectrum of clinical manifestations, including chorioretinitis, pneumonia, adrenalitis, and gastrointestinal infection. It may also involve the CNS and/or peripheral nervous system in HIV-positive patients. CMV infection occurs mainly in those with cluster designation 4 (CD4+) cell counts lower than 100/μL. Since 1996, after the introduction of highly active antiretroviral therapy (HAART), the incidence and prevalence of CMV infections has declined significantly. CMV polyradiculomyelitis is an unusual syndrome consisting of radicular pain, rapidly progressive paraparesis, and urinary retention. It has been observed in both immunocompetent and immunocompromised patients. It is characterized by rapid development of a flaccid paraparesis that begins distally and ascends. The typical pathologic examination demonstrates cytomegalic cells and a dense mononuclear infiltrate involving primarily the ventral roots, with chromatolysis of anterior horn cells. There may be coexistence of acute and chronic inflammation. The subpial location is a frequent site of involvement on neuropathologic examination, especially at entry sites of ventral roots and motor cranial nerves. On the other hand, it was also showed no significant difference in the degree of pathologic involvement between dorsal and ventral roots. Severely affected areas of the cauda equina may show hemorrhage and parenchymal necrosis of the nerve roots. MR findings have been described in patients with the unusual syndrome of polyradiculomyelitis. Precontrast images demonstrated a thickened cauda equina, and the conus medullaris was ill defined. Postcontrast images showed diffuse enhancement of the cauda equina and enhancement along the surface of the conus and meninges (Fig. 24.81). The nerve roots were clumped and adherent to the walls of the thecal sac and to other nerve roots. A rare manifestation was described in a profoundly immunocompromised patient showing enlargement of the spinal cord, consistent with a space-occupying lesion with ring enhancement after gadolinium injection. Poliovirus There are three antigenically different strains of poliovirus (types 1, 2, and 3) that cause poliomyelitis. Poliomyelitis, also known as infantile paralysis, is an acute illness in which the polioviruses selectively destroy the motor neurons of the spinal cord and brainstem, causing flaccid asymmetric weakness. 1882

Paralysis is an infrequent complication of the infection by poliovirus, affecting only 1% to 2% of patients. Poliovirus replicates in the intestinal mucosa and disseminates through lymphatics and blood vessels and reaches the CNS, where it attacks mainly motor neurons of the spinal cord and brainstem. The paralytic form of the disease must be differentiated from the GBS and other predominantly motor neuropathies. Diagnosis can be established by isolation of virus from blood or CSF or by serologic evidence of acute poliovirus infection.

FIGURE 24.81 Cytomegalovirus polyradiculopathy in an HIV-infected patient. Sagittal precontrast T1WI was normal (not shown). Parasagittal (A,B) and axial Gd-T1WIs (C) demonstrate marked enhancement of the roots in the cauda equina (arrows). (Courtesy of Dr. Charles Lanzieri, Cleveland, OH.)

In necropsy, spinal cord segments from all patients who had poliomyelitis showed loss or atrophy of motor neurons, severe reactive gliosis disproportional to the neuronal loss, and a perivascular and intraparenchymal inflammation even in the chronic phase, up to 20 years after infection. In the acute to subacute phase (up to 8 weeks after acute illness), the ventral horns cells are characterized by a severe inflammation, neuronophagia, active gliosis, and destruction of the anterior horn cells. In the acute infection there is active inflammation, gliosis, and destruction of anterior horn cells, and the characteristic MR appearance described is that of local enlargement and abnormal signal in the ventral horns (Figs. 24.82 and 24.83) (87). Chronically, the spinal cord shows loss of anterior horn cells, severe reactive gliosis, and persistent inflammation. There are rare poliolike paralytic syndromes associated with other viruses, such as coxsackie virus, echovirus, and enterovirus (87), EBV (88), and flaviviruses (89), that may present with similar imaging picture. Spinal cord ischemia is also a cause of hyperintensity on T2WI that may also be associated with contrast enhancement, mainly in subacute stage. Human Immunodeficiency Virus HIV, cause of AIDS, is a retrovirus transmitted primarily through sexual contact, parenteral exposure to blood or blood products, and perinatally from infected mothers to their infants. The hallmark of HIV infection is progressive depletion of the CD4-helper inducer subset of lymphocytes. The immunologic deficits associated with HIV infections are widespread and include cellular and humoral elements (90).

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FIGURE 24.82 Vaccine-associated paralytic poliomyelitis in a 3-year-old child. The child presented with motor signs at the four limbs 72 hours after poliomyelitis vaccination. Sagittal T2WI (A) and axial Gd-T1WI (B) show hyperintensity on T2WI and enhancement of the anterior horns as well as enhancement of the anterior roots. (Courtesy of Dr. José Roberto Lopes Ferraz, S.J. do Rio Preto, Brazil.)

FIGURE 24.83 Late changes of poliomyelitis in a 54-year-old man who had the infection when he was 5 years old. Sagittal T2WI (A), and axial T2WI (B) images show focal atrophy and gliosis of the frontal horns. The arrow points to the high signal intensity.

Although the major neurologic complications occur in the late phase of HIV infection, patients may also be afflicted earlier, at the stage of seroconversion, by conditions that include focal or diffuse encephalopathy, myelopathy, meningitis, and peripheral nervous system disorders. During the clinically latent phase of the disease, several neurologic conditions have been reported, among them the GBS (91). The evolving and eventually severe impairment of immunity caused by HIV leaves the nervous system highly vulnerable to a broad spectrum of disorders (Table 24.17) (90). Today, we see far fewer cases of CNS disease in HIV AIDS. However, the list of nonneoplastic conditions that affect the spine and the spinal cord on AIDS patients can be divided into two main categories: 1. AIDS-associated myelopathy: HIV myelitis, vacuolar myelopathy, and tract pallor. 2. Opportunistic bacterial, mycobacterial, fungal, parasitic, and viral infections. Although we assume that most opportunistic infections can be diagnosed by clinical, imaging, or laboratory data, there are still some AIDS patients presenting a myelopathy unrelated to a neoplasm, opportunistic infection, or vascular disease. Because in such cases it is uncommon to obtain pathologic correlation, the actual cause of the clinical and MR findings remains undetermined, the term “AIDSassociated myelopathy” has been used to describe this uncertainty. TABLE 24.17 Spinal Cord Inflammatory Lesions in Patients with AIDS

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AIDS-RELATED MYELOPATHY. Vacuolar myelopathy is the most common chronic myelopathy associated with HIV infection, with prevalence between 15% and 30% (90). This condition most frequently presents late in the course of AIDS, when CD4+ lymphocyte counts are very low, often in conjunction with AIDS dementia complex, peripheral neuropathies, and opportunistic CNS and peripheral nervous system infections or malignancies (e.g., CMV, progressive multifocal leukoencephalopathy, lymphoma). Before the introduction of HAART, vacuolar myelopathy was seen in 5% to 20% of adult HIV patients in clinical studies and in 25% to 55% of adult HIV patients in histologic studies. Since the introduction of HAART, it is estimated that fewer than 10% of AIDS patients develop HIV myelopathy. It usually manifests as a slowly progressive paraparesis. Less commonly it can manifest as a monoparesis or tetraparesis with impaired vibration and position sense. There may be associated ataxia and spastic bladder. Mild cases may only have extensor plantar responses. Progressive dementia may also be found in some patients, but there was no correlation between the incidence and severity of the dementia and the severity of the myelopathy (90). Vacuolar myelopathy is characterized pathologically by vacuolation in the white matter of the spinal cord associated with lipid-laden macrophages. The vacuoles are surrounded by a thin myelin sheath appearing to arise from intramyelin sheath swelling. However, there is no demyelination. It affects the lateral and posterior columns of the thoracic cord more severely, although it can also involve the cervical spine. It is believed that the pathogenesis of vacuolar myelopathy involves a combination of several mechanisms acting synergistically. The persistent immune activation in the CNS that occurs in the late stages of HIV disease may lead to production of myelin- or membrane-damaging cytokines, toxins, or oxygen radicals (93). The requirement for methyl groups to repair membrane and myelin may lead to a condition similar to that observed in vitamin B12 deficiency, predisposing the cord to a pattern of degeneration like that observed in subacute combined degeneration of the cord. HIV myelitis is reported to occur in 5% to 8% of AIDS patients. In this condition, a few multinucleated giant cells may be found in either white or more commonly in the gray matter. When found in the white matter, these inflammatory lesions may be associated with severe vacuolation, which is distinguishable from vacuolar myelitis by the presence of HIV-immunoreactive microglial nodules and by its focal and nondiffuse nature. Although HIV encephalitis and vacuolar myelopathy have frequently been found in association, this is believed to be only a coincidence of the presence of both diseases in later stages of AIDS. Tract pallor is a condition associated with a sensory neuropathy in which there is loss of myelin staining without actual demyelination, vacuolation, or abnormal presence of macrophages. It affects the distal axonal gracile tract and is believed to be caused by degeneration of the dorsal root ganglion cells. The cause of this tract pallor is unknown, but human T-cell lymphotropic virus type 1 (HTLV-1), CMV, herpes simplex, or VZV infection have been implicated, among other causes, such as direct infection of the dorsal root by HIV. Typically, patients with tract pallor have a sensory neuropathy. Although it is already possible to characterize vacuolar myelopathy on cadaveric macroscopic and MR studies, in vivo MR is not yet so specific. In a postmortem MR study of the spinal cord in AIDS patients, a pattern was established of signal abnormality on T2-weighted and proton density–weighted images involving the white matter tracts laterally and symmetrically on multiple contiguous sections that was sufficiently distinct to differentiate vacuolar myelopathy from other spinal lesions associated with AIDS. However, other reports of the MR findings on AIDS patients with myelopathy, excluding spinal cord 1885

disease due to any cause other than HIV infection, showed MR findings of diffuse nonspecific hyperintensity of the spinal cord on long–repetition time sequences, without associated swelling and with no definite pattern of lateralizing distribution of the intrinsic spinal cord abnormality. Spinal cord swelling or contrast enhancement was not reported (28,90). Even considering the aforementioned limitations, MR plays an essential role in the evaluation of myelopathy in HIV-infected patients. The diagnosis of AIDS-associated myelopathy is one of exclusion, based on clinical, laboratory, and imaging findings. MR is essential to exclude other extrinsic or intrinsic processes, such as lymphoma, primary or metastatic neoplasm, tuberculosis, toxoplasmosis, and other opportunistic infections. In an AIDS patient with myelopathy, it is critical to determine whether a focal mass is present in the spinal canal so that a medical or surgical treatment may be chosen. The identification of a focal mass or focal signal change within the spinal cord is important because either a cord biopsy or medical treatment may be indicated. Toxoplasmosis and lymphoma can affect any part of the cord and may demonstrate vigorous contrast enhancement, depending on whether therapy has already been instituted. In contrast to HIV myelitis and vacuolar myelopathy, cord edema associated with toxoplasmosis or lymphoma can be significant as the involvement becomes more extensive and may result in multilevel cord swelling extending longitudinally from the epicenter of the lesions (94,95). The differential diagnosis of an enhancing lesion in the spinal cord in an AIDS patient must include CMV, herpes simplex virus, fungal myelitis, lymphoma, and other neoplasms. A hemorrhagic-enhancing lesion suggests HSV2 as the etiologic agent (90,94–96). Associated meningeal enhancement can be quite useful in establishing a differential diagnosis. CMV, M. tuberculosis, herpesvirus, neurosyphilis, candidiasis, aspergillosis, nocardiosis, toxoplasmosis, and lymphoma all can give meningeal enhancement with secondary cord involvement (96). Cryptococcal infection does not usually cause meningeal enhancement in the spinal cord. CMV, the most common opportunistic infection that affects the intraspinal content, can cause polyradiculitis or a myeloradiculitis. This inflammatory process can show striking nerve root enhancement with or without cord swelling and enhancement. MR of the brain may show subependymal enhancement of the ventricles. Tropical Spastic Paraparesis Tropical spastic paraparesis (TSP), HTLV-1–associated myelopathy (HAM), and chronic progressive myelopathy are the names given to the myelopathy associated with HTLV-1, which is a retrovirus associated with several human diseases, including adult T-cell leukemia, neurologic disorders, uveitis, and arthropathy. HTLV-1 infects 20 million individuals globally and is highly endemic in Japan and also prevalent in Melanesia, the Caribbean, and certain areas of Africa and Brazil (92). This virus is transmitted through breast-feeding, blood transfusion, sexual intercourse, and intravenous drug use. Approximately 2% to 5% of patients will develop a progressive myelopathy known as HAM, which overlaps with tropical spastic paraparesis. These manifestations usually have a slow onset with chronic progression, and neurologic impairment develops within the first 2 years (97). Akizuki et al. reported histopathologic findings in the spinal cord characterized by loss of myelin and axons was observed bilaterally, mainly in the lateral and anterior columns, and occurred mainly along the tracts (97a). In addition, perivascular and parenchymal infiltration with lymphocytes and macrophages, as well as astrocytosis, were observed in the white and gray matter of the entire spinal cord. These findings are quite different from those of vacuolar myelopathy. Punctate or confluent brain white matter lesions and spinal cord atrophy (74%) have been reported as MR findings of HAM (98). The progression of neurologic deficits can be accelerated (termed “acute HAM”) by a higher proviral load or prior blood transfusion, the involvement of extensive spinal cord lesions, which present as cord swelling, and vacuolation in the white matter (97,99,100). These imaging findings resemble those described in NMO; moreover, some patients may present antibodies directed against the water channel aquaporin-4 antigen (97). Nevertheless, acute HAM and that associated with the NMOSD are distinct clinical entities; however, it is possible that HTLV-1 worsens the evolution and leads to a worse prognosis in patients with NMO (92). HAM/TSP should be included in the differential diagnosis in cases of swelling of the entire length of the spinal cord, high signal on T2WI, and contrast enhancement on MR images (Fig. 24.84).

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FIGURE 24.84 Tropical spastic paraparesis (human T-cell lymphotropic virus type I myelopathy) in a 34-year-old man from Barbados who presented with progressive quadriparesis. Human T-cell lymphotropic virus type I infection was proved by cerebrospinal fluid titers. A: Sagittal T1WI shows diffuse swelling of the cervical spinal cord (arrows). B: Sagittal T2WI shows high intensity in the cord (arrows). (From Gero B, Sze G, Sharif H. MR imaging of intradural inflammatory diseases of the spine. AJNR Am J Neuroradiol 1991;12:1009, with permission.)

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PART

IV

Advanced Applications

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25 MR Angiography: Techniques and Clinical Applications Wende N. Gibbs and Joseph E. Heiserman

INTRODUCTION Flow-related phenomena were recognized early in the development of MR (1), well before imaging techniques were devised. Understanding the mechanisms of flow sensitivity and the appearance of flowing fluid is important for several reasons. First, the flow sensitivity can be exploited to provide diagnostic information. Since the initial publication by Wedeen et al. (2) showing intravascular flow as high signal intensity on in vivo MR images, intense scientific and clinical interest has focused on the development of MR angiography (MRA) and its applications to imaging cerebral vasculature and its pathology. Initially, two families of techniques, time of flight (TOF) and phase contrast (3,4), were developed. These rely on the inherent properties of blood and its motion. More recently, rapid acquisition three-dimensional (3D) imaging in combination with T1-shortening intravenous contrast agents was introduced (5). A foundation in the fundamental physical origins of these methods can aid in the interpretation and rational choice among these techniques and their many permutations. Second, the characteristics of the nuclear magnetic resonance (NMR) signal of flow can be quite variable, even in normal physiologic states. This can have a direct impact on the image appearance of flowing blood; the possibility of misinterpreting normal states as important pathologic conditions is reduced if one has a good understanding of the physical basis of flow effects. It is critically important that interpretation of MR-based flow studies is made with the fundamental understanding that these images depict the physiology of flow, rather than the morphology of the vessel lumen. This is very different from other radiologic methods, like CT angiography (CTA) or catheter angiography, which directly demonstrate the morphology of the patent lumen of a vessel by filling it with a contrast agent. Third, the variable signal often generates significant artifacts that can obscure anatomy and degrade images. An understanding of flow phenomena allows one to recognize these artifacts and alter protocols to eliminate or compensate for such effects. Fluid Flow, the Basics Start by considering the simplest case, an incompressible fluid without viscosity in a rigid circular pipe of constant size. This is known as an ideal or Euler fluid. For slow flow of a fluid approaching this limit, the motion is en masse down the pipe, a condition known as plug flow. Every small volume within the fluid moves at the same velocity. If now the diameter of the pipe changes, the speed of the flow needs to change in proportion to the change in cross-sectional area to ensure continuity of the fluid. This means that to keep the volume flow rate of fluid constant the velocity v of the fluid must change in proportion to the radius r of the pipe squared, We can also make a statement about conservation of energy for the flow, known as Bernoulli’s principle. In simplest form, the sum of the pressure p and kinetic energy per unit volume of the flow must be conserved: where ρ is the density of the fluid. To get a more realistic picture, add viscosity. Now we think of the flowing fluid as being composed of thin concentric circular sheets or laminae. The viscosity results in drag between these sheets, and 1892

between the outermost sheet and the wall. Again consider slow flow, let the drag force be proportional to the velocity, and let the velocity at the wall be zero. This is known as a Newtonian fluid. In this model, the fluid velocity decreases due to drag as we move from the center of the pipe out toward the wall. It turns out this results in a parabolic flow profile, known as laminar flow (Fig. 25.1). Because of the reduction in velocity peripherally, the volume flow rate Q is reduced, especially in smaller pipes, and depends on the fourth power of the radius. This is known as Poiseuille flow,

FIGURE 25.1 In well-ordered laminar flow, the velocity is constant on sets of shells or “laminae.” Because of friction due to viscosity between the fluid and the wall, the fluid velocity at the wall is zero. In a long cylindrical tube with rigid walls, the laminae are concentric cylinders. With steady flow, the velocity profile across the tube is parabolic, as shown by the dashed line. This case (steady flow in a long, rigid-walled, cylindrical vessel) is referred to as Poiseuille flow.

Because of this strong dependence on radius, changes in the vessel size in the vascular tree can effectively control flow. Next consider a smooth bend in the pipe. In steady flow, the fluid parcels resist the change in direction due to inertia. When centrifugal forces are large compared to viscous damping, this leads to a spiral motion of the fluid around the bend. In addition, slower moving peripheral fluid parcels are more easily accelerated, causing a more pluglike profile to develop. Even in relatively simple geometries, flow patterns can become complex. This is illustrated for the carotid bifurcation in Figure 25.2. In vivo vascular flow is associated with additional complexity. Arteries and veins are not rigid uniform pipes but are elastic with varying diameter and numerous branchings. In vivo flow is also pulsatile, and this is associated with variation of flow velocity with time and even at different points within vessels. When the unsteady forces associated with acceleration of flow are large compared to viscous damping, pulsatile flow will tend to be associated with a flatter, nonlaminar flow profile. Blood is not well modeled as a Newtonian fluid in smaller vessels because the cellular components lead to vessel diameter–dependent viscous forces. Because of these and other factors, in vivo flow is frequently not well modeled by a laminar profile, and may be complex and disordered, especially in the presence of pathology. As an example, Figure 25.3 shows flow patterns associated with an experimental stenosis. When flow becomes so complex that the flow velocity at any given point is random, the pattern is referred to as turbulent. In this case the viscous forces within the fluid are too small to damp the inertial motions of the fluid. This rarely occurs in the vascular system, even in high-flow regions distal to stenoses. However, flow within the vascular tree can become sufficiently disordered that even at a very small scale the direction of flow can vary from point to point.

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FIGURE 25.2 Flow patterns as shown by particle trajectories. These were measured with high-speed photography through a constant-flow phantom fashioned from cadaver specimens of the human carotid artery bifurcation. Re0 is a measure of the ratio of fluid inertia to viscous drag known as the Reynolds number, U0 is the average velocity, Q0, Q1, and Q2 are the flows in the common internal and external carotid arteries, respectively. Overlay numbers in the top illustration are the local flow velocity values. In the lower illustration, numbers within the flow channel show the peak velocity at a number of cross-sectional positions, and the values at the edge of the vessel are the local shear rate. (From Motomiya M, Karino T. Flow patterns in the human carotid artery bifurcation. Stroke 1984;15:50–56, with permission.)

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FIGURE 25.3 Visualization of the flow field through a 50% (by area) axisymmetric stenosis. The stenosis is visible at the left of each tube. The flow rate was temporally steady from left to right. Three flow conditions are shown, with flow velocity increasing from frame A to C. Visualization was performed by injecting hydrogen bubbles into the flowing fluid (63% by weight glycerol in water), illuminating the system with four lamps, and using optical photography. Note that at higher velocities the flow becomes quite complex. (From Ahmed SA, Giddens DP. Velocity measurements in steady flow through axisymmetric stenoses at moderate Reynolds numbers. J Biomech 1983;16:505–516, with permission.)

These simple models will provide sufficient framework for the understanding of most MR flow phenomena; however, the interested reader is referred to the literature for a more detailed picture of blood flow (6). Effects of Motion on MR Broadly speaking, motion may affect an MR signal by modifying its amplitude or its phase. A change in amplitude related to fluid motion is referred to as a TOF effect. Changes in phase are discussed in a later section. Time of Flight TOF effects arise due to the macroscopic motion of spins and their state of longitudinal magnetization. Typically, the magnetization of a bolus of blood is modified (with a radiofrequency [RF] pulse) at one location and detected at another. If the direction of flow is perpendicular to the imaging slice (or volume), partially saturated spins are replaced by the inflowing unsaturated (fully relaxed and magnetized) spins during the RF repetition time (TR). The degree of replacement of partially saturated spins is directly dependent on the flow velocity and slice thickness (Fig. 25.4). If the TR is short relative to the longitudinal relaxation time T1 of stationary tissue, the signal of the stationary material is saturated and therefore signal from this source is attenuated. Signal from the unsaturated inflowing blood entering the excitation volume between pulse sequence repetitions consequently has a high signal intensity compared to the surrounding stationary tissue. This is flow-related enhancement. In the simplest example, consider a volume of tissue being imaged using a pulse sequence with TR less than the T1 of blood. Assume for now that during the TR interval there is no RF excitation outside 1895

of the imaged volume (e.g., we are using a 3D sequence or a single-slice 2D sequence). We also assume that the transverse magnetization at the end of each TR is zero (e.g., because TR is significantly longer than T2). Static tissue, including static blood, will experience a long train of excitations (one per sequence repetition) and reach a steady-state signal that depends on parameters such as TR, flip angle, and echo time (TE). Because TR is less than T1, the magnetization of static spins will be partly saturated. Flowing spins, however, if flowing sufficiently rapidly, will not have seen the long train of excitations and therefore will be more fully magnetized. The signal from flowing fluid will depend on the sequence parameters but also on the amount of spin replacement.

FIGURE 25.4 Illustration of flow-related enhancement. The schematic shows the cross section of a vessel. The relaxed spins entering the image slice result in high signal intensity because of the inflow of fully magnetized blood into the excitation volume. Signal strength is proportional to the fractional replacement of saturated spins within the imaging volume.

The effect is the simplest if the excitation is with 90-degree pulses. Any intravascular volume element (voxel) will contain a mixture of two subpopulations, fully magnetized spins that are experiencing their first excitation and spins that have been previously excited. For a velocity v in the slice direction and a slice thickness of Δz, the fraction of fully magnetized spins is vTR/Δz (but no greater than 1). Therefore, as a function of v, the signal intensity will increase linearly until it plateaus at a velocity of v = Δz/TR, where there is full spin replacement and no further signal increase is possible. This signal increase (as compared with that normally expected from the NMR properties of the fluid) represents flow-related enhancement. Note that for typical flow profiles in which the velocity is not uniform across the diameter, the flow-related enhancement is nonuniform. The signal behavior of flowing fluid is somewhat more complicated with sequences that use a flip angle other than 90 degrees because the spins do not reach a longitudinal steady state after only one TR. For a given flow velocity, a voxel will contain some spins that are about to experience their first excitation, some that will see their second, and so on. For example, spins moving at 15 cm/s into the imaging volume travel 4.5 mm in a TR of 30 ms. With a 10-mm slice, there would be 45% (4.5/10) spin replacement per TR. Just before any RF pulse, therefore, 45% of the spins are fully magnetized, 45% have experienced one RF pulse, and 10% (the remainder) have experienced two RF pulses. The contrast (i.e., signal difference) between flowing blood and surrounding tissue depends on the signal behavior of the blood but is further affected by saturation of the magnetization of static spins. Higher flip angles and shorter TRs lead to more saturation and lower signal from static tissue and therefore higher contrast. As a result, maximum contrast is obtained at higher flip angles than predicted by the intravascular signal alone. In volumetric imaging, flow-related enhancement is stronger at the ends of the imaging volume. Well within the imaging volume, spins are likely to have been partly saturated by earlier excitation pulses. It should be kept in mind that this “entry slice” phenomenon occurs only for surfaces defined by selective excitation pulses (e.g., in the slice or slab direction). It will not be seen at the edges of the volume in the readout or phase-encoded directions. For any vessel, signal increases will be highest near the surface where that vessel enters the excitation volume. Pulsatile Flow A priori, we might assume that the average velocity determines the overall signal intensity changes from TOF effects. However in very short TR sequences, contrast in the image might be determined by data 1896

collected during a fraction of the cardiac cycle, and as a result, the image intensity may be dominated by the flow conditions during that fraction of the cycle. This can lead to different intravascular signal intensities in different images if they are not consistently synchronized to the cardiac cycle. In 2D TOF MRA, this can lead to inconsistent vessel intensity, which may be especially troublesome in computed projections. Synchronization between physiologic periodicity and signal acquisition may also undermine the assumption that the image intensity should reflect the average flow velocity. This synchronization may be accidental or intentional. For example, when the cardiac cycle has a period close to the TR (known as pseudogating), one slice in an interleaved multislice scan may be acquired predominantly during systole and another predominantly during diastole. This is more pronounced with intentional synchronization to the cardiac cycle (i.e., cardiac triggering). Tagging, Suppression, and Labeling Pulses Flow-related enhancement is caused by the inflow of fully magnetized spins into the imaging volume. A number of techniques deliberately alter the longitudinal magnetization of spins outside the imaging volume to affect their appearance when they are in the volume of interest. Saturation pulses can be selectively applied upstream from the imaged volume to reduce the longitudinal magnetization of fluid that will flow into the volume. To be effective, the presaturation pulses need to be applied frequently and/or in close temporal proximity to the slice excitation. In 2D TOF, this can be done by placing the saturation pulse always immediately adjacent to the slice being collected, this is known as a traveling presaturation pulse. In 3D TOF, the impact may be most visible in the entry slices. Phase Effects After a 90-degree pulse, the magnetization vector lies in the transverse plane and precesses at the local Larmor frequency. The phase of the MR signal can be visualized as the position of the transverse magnetization vector relative to some standard. A useful analogy is the position of the hand of a clock relative to the 12 o’clock position. Another class of flow effects results from changes in the phase of the transverse magnetization that occur when spins move along magnetic field gradients such as those used for position encoding in MR. This arises from local changes in the Larmor frequency due to the presence of the gradient. Moving spins change location during gradient play and as a consequence of this motion within the gradient field acquire additional phase changes. Consider first a stationary spin at position x0 subjected to a gradient of constant amplitude G and duration δ (25-5A). The phase change ϕ due to the presence of the gradient magnetic field is given by where γ is a constant known as the gyromagnetic ratio and x0 is the position of the stationary spin. For this simple case of a gradient of constant amplitude, the phase change is proportional to the factor Gδ which represents the “area” of the gradient play and is referred to as the zeroth moment. Consider now the case of motion. For a spin moving at constant speed v in the x direction, there is an additional velocity-related contribution to the phase, and the total change can be written as where T is the time between the excitation pulse and the center of the readout pulse. The factor GδT is referred to as the first moment.

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FIGURE 25.5 Three gradient waveforms used to explain motion-induced phase shifts (see text): (A) a phaseencoding gradient of amplitude G and duration δ centered at time T after the excitation pulse, (B) a bipolar lobe composed of two pulses of duration δ and center-to-center spacing Δ but opposite amplitudes ±G, and (C) a waveform with a first moment of zero.

Consider now a more complex gradient with a negative going component (lobe) of duration δ followed by a positive lobe of equal amplitude and duration, with a center-to-center spacing of Δ (255B). This is known as a bipolar gradient pair. Because the two lobes have equal but opposite area, the net area is effectively zero. Because the (position-dependent) phase change introduced by the first lobe is cancelled by the second lobe of identical size and duration but opposite polarity, the zeroth moment is zero and stationary spins experience a net phase change of zero. However, the contribution from the moving spins is nonzero, and the phase change for times after the end of the bipolar gradient (and for constant-velocity motion) becomes An intuitive way to interpret this is as follows. The first lobe imposes a phase shift of (−γGδ) on the spins at the time of the center of this first lobe. The second lobe imposes an additional phase shift of (+γGδ) times the position of the spins at the time of the center of the second lobe. The net effect is a phase shift of (γGδ) times the distance the spins traveled during the time between the center of one lobe and the center of the other. With constant-velocity motion, this displacement is vΔ, making the net phase shift (γGδ)(vΔ). Bipolar gradients can be used to reduce the velocity sensitivity (or even set it to zero). In Figure 23.5C, a bipolar lobe (filled in with the diagonal pattern) is preceded by a bipolar lobe of opposite amplitude. The two act on the spins in succession. The first (filled in with the dotted pattern) introduces a phase shift proportional to velocity. The second bipolar lobe (filled in with the diagonal pattern) introduces an opposing velocity-induced phase shift. As a whole, this waveform has a first moment of zero and therefore no velocity sensitivity. The dotted pattern lobe was used to alter the velocity sensitivity that would have been present had the second lobe been used by itself. This approach is used to alter the velocity sensitivity of pulse sequences, for example, in gradient moment nulling. Although the waveform of Figure 25.5C is insensitive to velocity (because it has a zero first moment), it is sensitive to acceleration. This sensitivity can be understood, as before, by realizing that the first part of the waveform introduces a phase shift dependent on the velocity at one time point (the center of the first bipolar lobe), whereas the second portion removes a phase shift depending on the velocity at the second time point (the center of the second bipolar lobe). If the velocity is the same at the two times, the net phase shift is zero. Otherwise, the net phase shift is proportional to the change in velocity (i.e., the acceleration). Similar considerations apply to even higher-order moments. Pulse Sequence Considerations A spin-echo (SE) sequence typically begins with a 90-degree RF pulse followed by a 180-degree refocusing pulse. Both pulses are slice selective. Consequently, flowing blood within the slice during the 90-degree pulse will be labeled, but will have exited the slice and be at a new location during the 180degree pulse and readout. The blood within the slice at these later times does not contribute signal, and 1898

so the vessels appear as signal voids for sufficiently rapid flow. This is referred to as high-velocity signal loss. The TR chosen for an SE sequence must also be long enough to allow the time interval needed for formation of an echo. Gradient-echo (GE) sequences dispense with the 180-degree pulse. The refocusing gradient is nonslice selective, and so even signal from sufficiently rapidly flowing blood is recovered and vessels appear bright, part of the basis of flow-related enhancement. With flip angles less than 90 degrees and short TR, image data can be rapidly acquired. Dephasing of residual transverse magnetization can be accomplished with RF or GE spoiling pulses, resulting in T1-weighted (spoiled gradient-recalled acquisition in the steady state [SPGR], T1-weighted fast field echo [T1 FFE], fast lowangle shot [FLASH]). These benefits are important factors in the choice of GE-based sequences for most angiographic applications. Flow-Related Artifacts The basic motion effects (TOF and phase shift effects) can cause increases or decreases in the MR signal amplitude and phase of moving spins. If these signal amplitude changes are consistent throughout the scan, the impact on the image is simply due to the corresponding signal amplitude and/or phase change in intravascular voxels. Consistent flow-related enhancement, for example, causes an increase in intravascular signal in GE images. Consistent phase shifts are harnessed in phase-contrast angiography to depict regions of flow. The most powerful way to ensure that the motion effects are consistent is to ensure that the velocity distributions are temporally steady during the scan time or that the system is synchronized to the variability. If the signal changes are not consistent throughout the scan, the modulation of the raw data will cause artifacts. Specifically, they will cause some of the signal that actually belongs in one pixel to be dispersed or spread to other image pixels. Gradient Moment Reduction and Nulling As has been discussed, motion in the presence of magnetic field gradients causes a phase shift in the transverse magnetization as compared with that of identical static spins at the same location. Through this mechanism, nonuniform velocity within a voxel can lead to nonuniform phase and consequently loss of signal (intravoxel dephasing). If the velocity distribution is not steady in time, ghost artifacts can result due to phase modulation of the average signal from a voxel or from amplitude variations due to time-dependent intravoxel dephasing. Although some of these artifacts are caused by gradients produced by inhomogeneity of the static magnetic field, the strongest effects are due to the magnetic field gradients intentionally applied during the imaging process. The effect of these gradients depends on the details of the waveforms. A very basic and quite effective method of reducing gradient moments is to reduce the area of the corresponding gradient pulses. There are two important examples of this in MR imaging (MRI)—the use of fractional echoes for frequency encoding in GE imaging and the use of slab excitation and 3D volume imaging rather than acquisition of multiple thin slices. Offsetting the echo within the acquisition window toward the beginning of the readout reduces the area of the dephasing gradient pulse and also allows the time between the center of the dephasing lobe and the center of the echo to be decreased. This technique is also known as “asymmetric” or “partial echo” sampling. The reduction of the first moment can be proportional to the square of the offset, one factor deriving from each of the decrease in area and the decrease in spacing. These design options are often used to obtain a shorter TE, in order to minimize intravoxel dephasing. The improvement is due to both the reduction in gradient moment and TE reduction, but the dominant contribution is the reduction in gradient. The difference between 3D and 2D multislice imaging results from the fact that selective excitation of a thin slice requires very strong gradients. For a constant RF bandwidth, the gradient strength for slice selection is inversely related to slice thickness. Therefore, excitation of a thick slab (for 3D) can be performed with a weaker gradient and a shorter refocusing lobe, both leading to a lower gradient first moment. In addition, 3D images tend to have smaller voxels, leading to less heterogeneity of flow velocities within the voxel and therefore less intravoxel dephasing. It is also possible to change the gradient moments without altering the spatial encoding lobes. This is generally done by inserting bipolar lobes or by altering the size of other lobes to change the first moment while leaving the net area (zeroth moment) unchanged. Most commercial systems offer firstorder gradient moment nulling, a feature that essentially eliminates the phase effects due to constantvelocity motion. Because the first moment is zero, the phase accrual due to the velocity term is zero regardless of the actual velocity. This will greatly decrease intravoxel dephasing, leading to higher 1899

signal from flowing spins. Moment nulling also tends to reduce inconsistencies due to pulsatile flow. Note that first-order moment nulling only eliminates the effect of constant-velocity motion. It may be surprising, then, that it can be effective for pulsatile flow, which by definition exhibits acceleration. However, we need to note that the requirement for first-order nulling to be successful is that the velocity be relatively constant during a single sequence execution. This is easily satisfied, especially for short sequences. Moment nulling reduces the inconsistent phase shift among all the sequence repetitions in the scan from changes in average velocity and thereby leads to artifact reductions (Fig. 25.6).

IMAGING BLOOD FLOW The TOF and phase shift effects discussed previously, although considered primarily in terms of their interference with image interpretation, can be exploited so that both qualitative and quantitative flow information can be extracted from MRI. A wide variety of techniques can accomplish the general goal of flow detection and blood vessel imaging. Many of the techniques can be divided along the same categories used for discussing basic flow effects: TOF and phase-based methods. In addition, the advent of fast MRI methods has enabled the use of exogenous contrast agents, specifically the arterial phase of the contrast agent transit, to image the vasculature. Some basic aspects of this technique are described in what follows as well.

FIGURE 25.6 First-order gradient moment nulling effect on cerebrospinal fluid (CSF) flow. Long–TR/TE image of cervical spine and cord without gradient moment nulling (A) shows signal loss, as well as several ghost images from CSF motion. The artifacts, which degrade the image and obscure the definition of cord from CSF, are virtually eliminated by first-order gradient moment nulling (B), allowing CSF to be seen as high-intensity fluid surrounding the cord.

Time-of-Flight MR Angiography By far the most popular TOF MRA methods are based on flow-related enhancement (7). The typical characteristics of these MRA techniques include use of a short TR, partial flip angle GE sequence, coverage of an anatomic volume rather than a single slice, viewing of the data using computed projections, and nonsubtractive imaging, that is, a single acquisition rather than subtraction of two datasets. In these methods, blood flowing into the region being imaged with the short TR sequence appears as high-contrast “bright blood” signal. The pulse sequence and scanning parameters are selected with consideration given to the expected speed and direction of flow, the vessel tortuosity, and desired field of view (FOV) and spatial resolution. The volumetric acquisition can be executed by sequential scanning of adjacent or even overlapped 2D sections (2D TOF), by imaging the entire volume using a single 3D scan (3D TOF), or by sequential 3D imaging of overlapping slabs. In all three methods, the result is a 3D image array in which, one hopes, the pixels with intravascular blood have the highest signal and the volume is generally viewed using computed projections through the volume. 1900

Two-Dimensional Time of Flight 2D TOF sequences image the 3D volume as a stack of slices that are acquired sequentially (Fig. 25.7). Typically, the orientation of the imaging planes is selected to be perpendicular to the main direction of flow (e.g., axial slices for carotid imaging). Use of thin slices that are relatively perpendicular to the flow produces a high level of spin replacement. In this case a relatively large flip angle yields strong inflow enhancement and good vascular contrast. The amount of spin replacement increases with increasing velocity, increasing TR, and decreasing slice thickness. Without the use of preparation pulses, inflowing blood is bright regardless of flow direction. It is common to use spatial presaturation to select for flow in one direction or the other (i.e., to image arteries vs. veins). Note that this assumes that the flow directions are dependable; errors could be made in regions of retrograde flow. The saturation region is generally moved along with the imaging plane as the multiple slices are sequentially scanned. In all TOF techniques, including 2D TOF, the use of fractional echo methods and a short echo delay (TE) is desirable to minimize phase shifts that can produce regions of signal loss (intravoxel dephasing). The use of first moment nulling is also beneficial even when a penalty in TE is incurred.

FIGURE 25.7 Sequential two-dimensional time-of-flight technique. Axial gradient-echo images are obtained in a craniocaudad direction with a superiorly placed traveling (tracking) saturation pulse to eliminate inferior flowing venous signal. The direction of acquisition opposing carotid flow minimizes the saturation from a previous slice.

FIGURE 25.8 Three-dimensional (3D) time-of-flight technique. In this case, the 3D volume is acquired with a ramped radiofrequency (RF) pulse to avoid progressive saturation of blood as it travels cephalad through the 3D volume. Note that the flip angle of the RF excitation (α) increases across the volume. The superior saturation pulse suppresses signal from inflowing unsaturated venous blood.

Three-Dimensional Time of Flight In 3D TOF the entire volume is imaged in a single acquisition by using phase encoding in two directions (in-plane direction and slice direction) (Fig. 25.8). Flow-related enhancement is maximized by orienting the imaging volume perpendicular to inflowing blood, optimizing the TR and flip angle (Fig. 25.9), and using a transmit/receive head coil to avoid excitation and therefore saturation of flowing spins outside the imaging volume. Flow compensation for acceleration or higher-order motion terms technically is possible with complex gradient configurations; however, in practice, using compensation gradients for 1901

first-order flow (constant velocity) alone in combination with a very short TE generally is more effective than higher-order flow compensation, which slightly but detrimentally increases the echo time. Using this technique, it is possible to produce 3D datasets with voxel dimensions of less than 0.8 mm. These small voxels coupled with the relatively weaker gradient play and shorter TE result in less intravoxel dephasing than in the 2D technique. However, the relatively thick imaging slabs are associated with intravascular signal loss as blood proceeds through the slab. This accounts for the decreased sensitivity to slow flow seen with the 3D method compared to 2D. Overlapping Slab Acquisition This approach represents a compromise between the 2D thin-slice acquisition and the single 3D volumetric scan (Fig. 25.10). The volume is divided into multiple overlapping thin slabs [MOTSA], [multichunk], [multislab]). For each thin slab, a dedicated 3D acquisition with relatively few phase encodes is used. The data from the multiple slabs are combined to depict the entire volume of interest. Because each thin slab is acquired using a thinner excited region than in 3D TOF, more reliable flowrelated enhancement can be expected. As compared with 2D TOF, this sequence can achieve better spatial resolution in the slice direction and better signal-to-noise ratio (SNR).

FIGURE 25.9 With gradient-echo sequences flow-related enhancement relative to the T1 relaxation of the surrounding soft tissues can be varied through choice of repetition time and flip angle. Fast, low-angle shot images (FLASH) for (A) a 100-ms repetition time and (B) a 200-ms repetition time. The respective flip angles are represented by the values in each image frame. With increasing repetition time, the flow-related enhancement extends farther along the neck, even as the echo time increases. Notice that the background also increases. (From Masaryk TJ, Tkach J, Glicklich M. Flow, radiofrequency pulse sequences, and gradient magnetic fields: basic interactions and adaptations to angiographic imaging. Top Magn Reson Imaging 1991;3(3):1–11, with permission.)

Methods to Improve Contrast The basic techniques described previously rely solely on flow-related enhancement to produce contrast 1902

between static tissues and moving blood. The achieved contrast depends on the degree of spin replacement, TR, and flip angle. Several methods are available to further improve the image contrast. Magnetization transfer contrast can be used to decrease the signal from normal brain more than that of blood, thereby increasing the contrast between them. It is particularly effective in 3D TOF imaging. The use of a lower flip angle can be utilized to save some of the longitudinal magnetization so it can be used when the spins are deeper into the excitation region. In the cases analyzed earlier, it was assumed that the flip angle is uniform throughout the excitation volume, but this need not be so. Selective pulses can be designed to produce a lower flip angle at one end of the slab as opposed to the other. At the cranial end of the slab, the spins are not expected to remain within the imaged volume much longer, and a larger flip angle uses the remaining longitudinal magnetization more rapidly and efficiently.

FIGURE 25.10 Multiple overlapping three-dimensional (3D) time-of-flight slab acquisition. This technique incorporates advantages of both sequential 2D Fourier transform and 3D Fourier transform exams. The axially oriented partitions maximize flow-related enhancement. The smaller 3D slabs allow thin contiguous slices, to avoid flow saturation. Note that the slabs are acquired in a craniocaudad direction to avoid saturation effects. With the implementation of a ramped radiofrequency pulse, larger 3D volumes are used because flow saturation is reduced with this technique. A superior saturation suppresses venous signal.

TOF MRA: Artifacts and Limitations Despite the success of TOF methods, care is required in the acquisition and interpretation of these studies to avoid errors. Both 2D and 3D TOF are associated with distinctive artifacts. Because the strong gradient play required to specify the thin slice in 2D TOF limits the minimum-achievable TE, signal loss in regions of disordered flow due to intravoxel dephasing is a characteristic of this method. This can obscure focal stenoses but also can contribute to overestimation of stenosis. In this regard, 3D TOF and MOTSA-style acquisitions benefit from reduced gradient play and shorter echo times to achieve less intravoxel dephasing. However, because of the relatively large slab thickness, 3D methods are characterized by signal loss arising from saturation. In the presence of slow flow, signal loss could result in an incorrect diagnosis of occlusion and can reduce flow signal within aneurysms. Characteristic signal loss can also be seen in the presence of accelerated flow, such as within tortuous vascular segments. Numerical simulations of flow in vessels and pathologic structures such as aneurysms have shed considerable light on the physical basis of these artifacts (8,9). In addition to these sources of error, local magnetic field distortions arising from metal or air or bone and tissue interfaces can result in local dephasing (Fig. 25.11), sometimes simulating stenosis (10). Because of the relatively nonoverlapping nature of the spectrum of artifacts, 2D and 3D TOF can be considered complementary methods, and, in some applications, such as evaluation of the cervical arteries, a combination of the two approaches increases accuracy.

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FIGURE 25.11 A: Digital subtraction catheter angiogram and three-dimensional Fourier transform (3DFT) time-offlight (TOF) magnetic resonance angiography of the carotid bifurcation. Notice the surgical clips overlying and adjacent to the carotid artery (black arrow) on the catheter angiogram, which results in a susceptibility artifact (white arrow) and signal loss on the 3D TOF angiogram (B), resulting in diminished signal intensity.

Strategies for Optimizing Performance of Time-of-Flight MRA The broad goal of TOF MRA is to provide an accurate depiction of vascular structures noninvasively, and these methods have been largely successful in meeting this challenge. The best results are achieved when an appropriate method is matched to each clinical application. Optimization of sequence parameters and in some cases use of supplementary techniques can improve diagnostic accuracy. Reductions in flow-related enhancement can be thought of as being due to saturation effects, dependent on the T1 recovery time of blood, and transverse dephasing, dependent on T2 and T2* decay times. Saturation effects are important in the setting of slow or in-plane flow, and can be minimized by using thinner slices, smaller flip angles, and relatively long TR. Thus 2D TOF excels in the setting of slow flow and is often the technique of choice for venous imaging (Fig. 25.12). It also has a role in evaluation of cervical carotid stenosis in detecting slow flow distal to a high-grade stenosis. Transverse dephasing is minimized by small voxels to minimize intravoxel phase cancellation, and especially by reductions in echo time. For TE greater than about 1 ms, flow compensation gradients can also reduce this source of signal loss. Because of their intrinsically high-resolution and short echo times, 3D TOF sequences are less limited by this source of signal loss.

FIGURE 25.12 Sequential two-dimensional time-of-flight magnetic resonance venography. Coronal acquisition, oblique coronal maximum intensity projection. Excellent slow-flow sensitivity of the two-dimensional time-of-flight technique minimizes this source of signal loss.

Innovative supplementary methods have also been developed to reduce saturation and improve vessel conspicuity relative to background. Second-order chemical shift effects can be used to suppress background soft tissues (Table 25.1 and Fig. 25.13). Because of the small difference in Larmor frequency between fat and water resonances, there is a phase shift between the fat and water signal contributions to a given voxel, which varies as a function of TE. Choosing a TE at which fat and water are out of phase can provide fat suppression, contributing to vessel conspicuity. However, the benefit in 1904

background soft tissue suppression is usually more than offset by the increase in intravoxel dephasing and consequent signal loss in areas of disturbed flow that accompanies the increase in TE above the minimum value. As a general rule, TE should be minimized at the expense of other considerations because of the increase in intravoxel dephasing that accompanies increases in TE. Magnetization transfer contrast sequences have been used to enhance the ratio of vessel to background signal intensity (Fig. 25.14). Fat suppression can also be incorporated for this purpose. Spatially variable RF pulses are designed to increase linearly along the major axis of flow so a lower flip angle is applied where the flowing spins enter the volume and higher flip angles are applied distally where the vessel/soft tissue contrast would normally be limiting. Compared to the conventional MRA pulse sequences, distal small-vessel visualization is improved because of the background suppression and the improvements related to the specialized RF pulses intracranially (Fig. 25.13). This is most obvious when intracranial studies are reconstructed at matrices of 512. Great progress has been made in minimizing the effects of nonuniform flow in MRA. However, areas of tight stenosis continue to display flow-induced signal loss at and immediately following the luminal narrowing. The larger slice-select gradients necessary for the sequential 2D sequences generally prolong the minimum TE relative to comparable 3D techniques. An additional challenge relates to inflow in 3D methods. Bright signal requires not only flow, but also unsaturated spins. A disadvantage to the use of such a thick slab of excitation/saturation is that, depending on the speed of flow (i.e., residence time within the volume) and frequency of RF pulses (i.e., TR), one may lose vascular contrast deep in the volume secondary to saturation effects. Although rapid arterial blood flow can retain sufficient flowrelated enhancement to be successfully imaged over small regions of interest (such as the intracranial circulation or cervical carotid arteries), slowly moving venous, peripheral arterial, or pathologically slowed arterial flow may become sufficiently saturated over even small imaging volumes to prevent visualization. Thus, inflow-enhanced 3D methods appear limited to relatively small regions of rapid flow (i.e., arteries of the head and neck). Care must be taken when using the 3DFT methods to allow for adequate inflow through choice of repetition time, flip angle, and volume thickness. An inappropriate selection of parameters may result in a false appearance of vessel tapering. The use of MOTSA-style acquisitions may be the most effective method for reducing the problem of spin saturation. In effect, this technique combines the 2D advantages of reduced spin saturation and the short TEs and small voxels of the 3D TOF MRAs, at the expense of a time penalty depending on the degree of overlap. Careful parameter selection is needed to minimize discontinuity at slab boundaries, which can produce a characteristic “venetian blind” artifact. When combined with the spatially variable RF pulses, it is possible to increase the size of the volumes, reduce the degree of overlap between the volumes, and reduce the number of volumes necessary to cover the region of interest. Postprocessing and Display Because background soft tissues are generally well suppressed, the source data in MRA are easily postprocessed to provide clinically useful representations of the vascular structures. As a first step, 3D imaging data are often interpolated or zero filled. Although this does not improve spatial resolution, it does minimize partial volume artifacts and can improve diagnostic accuracy (11). Following this, source data images can be manipulated to make detection and evaluation of abnormalities easier and more accurate. 3D or contiguous 2D data constitute a volumetric representation. Such data can be reformatted into more appropriate planes for evaluation. Vascular structures can also be segmented from the stationary tissues and projection images resembling conventional angiograms produced. The most popular algorithm, maximum intensity projection (MIP), is produced by casting a ray through the dataset along the desired projection angle and selecting the most intense pixel along the ray, discarding the rest (Fig. 25.15). More recently, 3D volume-rendering algorithms have become available, and, when used on a workstation, they allow interactive real-time evaluation (Fig. 25.16). This is particularly useful for depicting suspicious areas for more detailed evaluation. TABLE 25.1 Second-Order Chemical Shift Effect

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FIGURE 25.13 Second-order chemical-shift artifact seen on gradient-echo images results from the transverse magnetization of both fat and water lying in phase. Because water and fat precess at slightly different rates as dictated by the main magnetic field, there are times during the decay that fat and water will be in or out of phase. A,B: Axial three-dimensional time-of-flight images at 1.5 T with an echo time of 5.0 and 7.0 ms, respectively. Note the orbital and subcutaneous fat high signal intensity with the in-phase and low-signal intensity with the out-of-phase acquisition with an echo time of 7.0 ms. The lateral projections (C,D) illustrate the image degradation by the overlapping fat.

FIGURE 25.14 Effect of magnetization transfer. All imaging parameters were held the same. A: Three-dimensional time-of-flight magnetic resonance angiography axial image. B: The same image with application of magnetization transfer. Notice the superior background suppression of the brain tissue; however, the fat within the orbits and scalp now is accentuated. Note that because of the superior background suppression, the visibility of the intracranial

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vessels is increased. C: Application of magnetization transfer and fat suppression. Notice on this image the superior delineation of the vessels resulting from the superior background suppression from both magnetization transfer and fat suppression. (From Lin W, Tkach JA, Haacke EM, et al. Intracranial MR angiography: application of magnetization transfer contrast and fat saturation to short gradient-echo, velocity-compensated sequences. Radiology 1993;186:753–761, with permission.)

FIGURE 25.15 Maximum intensity projection (MIP). This is the most commonly used postprocessing method for magnetic resonance angiography (MRA). A: For any given projection, a ray is cast through the dataset at the chosen angle, and the pixel along the ray with the maximum intensity is chosen; all other pixels are set to zero intensity. The method works best with data in which vessel signal intensity greatly exceeds background signal and the signal-tonoise ratio is adequate. B: Base projection of intracranial three-dimensional time-of-flight MRA at 3 T. Excellent background suppression results in faithful MIP of even small-vessel detail. (Panel A: From Edelman RR, Wentz KU, Mattle H, et al. Projection arteriography and venography: initial clinical results with MR. Radiology 1989;172:351– 357, with permission.)

Although these representation methods are often useful and can improve detection of abnormalities (12), postprocessing generally involves loss of data and can introduce artifacts. For example, MIP images often overestimate the degree of stenosis, partially due to poor detection of signal from slower flow along the margins of vessels and disordered flow in and around stenoses. Hyperintensity on the source images not related to flow—for example, subacute blood products or fat—can also appear in postprocessed representations and mimic regions of flow (Figs. 25.17–25.19). For these reasons, correlation of abnormalities seen on postprocessed representations with source images improves accuracy. When quantitative measurements are made, such as residual lumen or percentage stenosis, highest accuracy results from performing the measurements on source images or pixel-thickness orthogonal reformats (13). Phase-Contrast Imaging As described previously, at TE immediately following a symmetric bipolar gradient pair the phase of stationary spins is unchanged; however, moving spins will acquire a phase shift. In the simplified case of constant velocity, the phase shift is proportional to the velocity. In this case, if a second sequence with gradient moment nulling is acquired, and the two sequences are subtracted, signal intensity within the resulting difference image is proportional to velocity on a pixelwise basis. This is the basis of PC MRA (7). A 2D version of this approach can be coupled with different forms of cardiac gating or retrospective sorting to produce velocity data throughout the cardiac cycle. Stationary soft tissue signal appearing on both sequences is absent, resulting in good background suppression. With increasing velocity, the phaserelated signal intensity increases sinusoidally but eventually starts to decrease with increasing velocity. Consequently, the phase-related signal intensity is not single valued. For this reason, a maximum anticipated encoding velocity (venc) must be specified to prevent aliasing artifacts.

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FIGURE 25.16 Postprocessing by volume rendering. This method can be used in real time to study subvolumes of a magnetic resonance angiography dataset in detail. Optimal projection angles often depict subtle abnormalities to best advantage, as in this subtle posterior cerebral artery narrowing, seen with volume rendering (A) and maximum intensity projection (B).

Advantages of these phase-sensitive methods include their high sensitivity to slow flow, such as venous blood, as well as high vascular contrast resulting from excellent stationary tissue subtraction. Since a separate acquisition is required for each direction of flow to be encoded, with three encoding acquisitions and a mask sequence required for full volumetric data, this technique tends to be time intensive when performed with standard GE sequences. Images may be integrated into a single acquisition by alternating (i.e., interleaving) phase-sensitive y-steps. This interleaved approach helps to reduce misregistration artifact secondary to motion between acquisitions.

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FIGURE 25.17 Right petrous apex cholesterol cyst. A: Note the high signal intensity on the T2-weighted spin-echo image just posterior to the right carotid canal (arrow). B: Axial three-dimensional Fourier transform time-of-flight magnetic resonance angiography demonstrates the high signal intensity just posterior to the petrous portion of the right internal carotid artery (arrow). C: The maximum intensity projection incorporates the high signal intensity from the cholesterol cyst into the angiogram, simulating a petrous carotid aneurysm (arrow).

Artifacts and Limitations Implementation of flow-sensitive gradients requires additional time before signal sampling, thus prolonging TE. This is particularly disadvantageous in regions of fast nonuniform motion and in GE sequences that are sensitive to other T2* effects that may degrade image quality. The phase-based techniques are particularly sensitive to image degradation from pulsatile flow, as well as instrument imperfections such as eddy currents. Signal phase aliasing also is a problem in vessels with complex or rapid flow. Emerging concepts are addressing some of these shortcomings of PC MRA. An example is the phase-contrast variant of VIPR (PC VIPR) (14). This addresses the relatively long acquisition times associated with high-resolution PC MRA by using a novel radial scheme of data collection.

FIGURE 25.18 Catheter digital subtraction angiogram and three-dimensional (3D) Fourier transform time-of-flight (TOF) magnetic resonance angiography (MRA) of the carotid bifurcation. A: The catheter angiogram demonstrates a very severe stenosis (long arrow). The two facing short arrows demonstrate the normal arterial vessel segment diameter that would be used for calculation of the percentage of stenosis using the North American Carotid

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Endarterectomy Trial criteria. B: Notice that the 3D TOF MRA does not resemble the catheter angiogram because of incorporation of high signal intensity from a mural hematoma (hemorrhagic plaque) in the angiogram. This is one of the potential pitfalls of MRA of the carotids. This tends to be less of a problem with 2D TOF because background soft tissue is more effectively suppressed.

FIGURE 25.19 Acute occlusion of the right internal carotid artery and hemorrhagic infarction of the right lentiform nucleus. A: The T2-weighted spin-echo image demonstrates the hemorrhagic infarction within the lentiform nucleus. B, C: Three-dimensional Fourier transform time-of-flight magnetic resonance angiography demonstrates minimal signal in the right carotid siphon, most likely resulting from retrograde flow (open arrow). Note the slightly diminished signal intensity in the middle cerebral artery branches on the right when compared to the left from the slower flow. In addition, there has been incorporation of high-signal products of hemorrhage into the maximum intensity projection angiogram (arrow). Notice the patent posterior communicating artery on the right side (arrowhead).

Black Blood Angiography Despite the use of short echo times, gradient refocusing, and small voxels, the inflow or “bright blood” MRA techniques still suffer from signal loss in regions of complex flow secondary to superimposed spinphase phenomena. This can produce signal loss, leading to overestimation of stenoses or signal dropout. One approach is to adopt the appearance of SE series and generate images in which blood does not contribute signal to the image. Arterial spins can be intentionally dephased as they flow along the imaging gradients by using relatively long echo times. These “black blood” images are immune to the effects of dephasing and can result in good contrast with the surrounding soft tissues. Projection angiograms can be produced using a “minimum-intensity” projection method analogous to the “maximum-intensity” algorithm described for so-called bright blood methods. This technique is frequently incorporated into MR protocols intended for plaque characterization. Contrast-Enhanced Magnetic Resonance Angiography The signal loss related to saturation in TOF MRA can be addressed by rapidly acquiring T1-weighted images during the bolus administration of gadolinium-based intravenous contrast material, known as contrast-enhanced (CE) MRA (15). At high intravascular concentrations, most of the intravascular signal results from the T1 shortening of blood (from 1.2 seconds down to 50 to 100 ms) associated with the contrast. To minimize venous signal, accurate bolus timing and very rapid image acquisition are needed. Several methods for bolus timing have been investigated, including timing estimates, test bolus, automatic triggering, bolus tagging, and fluoroscopic triggering (Fig. 25.20). In the standard methods, 1910

images are generally acquired using fast spoiled gradient-recalled echo (GRE)-based sequences (FSPGR, 3D FFE, FLASH). When these are implemented on MR systems fitted with high-performance gradients, repetition times of 3 ms with minimum echo times of about 1 ms are available. These sequences can be combined with novel k-space acquisition and phase-ordering schemes, such as elliptical-centric phase ordering (16) to achieve total acquisition times ranging from 10 seconds to 1 minute, depending on the desired resolution. Although CE MRA addresses the undesirable saturation effects associated with TOF, it is still subject to signal loss associated with sources of transverse dephasing. In addition, phase ghosts from pulsatile flow are more prominent due to the shorter T1 (higher signal) of incoming blood (Fig. 25.21). The primary limitation of CE 3D MRA is the k-space acquisition speed and thus the achievable resolution during the time-limited first pass of contrast agent. In addition, the fast spoiled GE sequence is intrinsically limited in signal-to-noise ratio (SNR) because of fractional RF, fractional echo, and increased bandwidth considerations. Fain et al. (17) analyzed the theoretical limits of spatial resolution in elliptical-centric CE 3D MRA. They demonstrated that maximum attainable resolution relates to the TR, FOV, trigger time, and bolus profile characteristics. FOV dependence is isotropic in this view order, that is, reducing the FOV in either phase-encoding direction improves resolution in both of the phaseencoding directions. Reduced TR also results in improved resolution because SNR penalties dictated by decreased voxel size and short TR at small FOV will be compensated by more favorable k-space weighting, assuming long scan times with a prolonged contrast enhancement tail.

FIGURE 25.20 Contrast-enhanced magnetic resonance angiography (MRA) acquisition schemes. A: A series of fast three-dimensional (3D) measurements is simultaneously acquired with the contrast injection. B: Contrast-enhanced MRA with subtraction. Pre- and postcontrast images are acquired, and stationary tissue is removed by subtraction. C: Fluoroscopically triggered contrast-enhanced MRA. Contrast arrival is monitored by a 2D sequence, and 3D

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sequence is initiated immediately after. (From Laub G. Principles of contrast-enhanced MR angiography. Basic and clinical applications. Magn Reson Imaging Clin N Am 1999;7:783–795, with permission.)

The use of gadolinium-based contrast agents for CE MRA has become a powerful tool for vascular imaging. These methods address some of the weaknesses of TOF and also result in short imaging times. This can be beneficial, particularly in the less cooperative patient, although total imaging times may not be significantly reduced when the preparation time for contrast injection is factored in. However, the use of these intravenous agents is not without risk. Apart from the potential complications and discomfort of venipuncture, the gadolinium-based contrast agents are themselves associated with uncommon associated morbidity, such as anaphylactoid reactions and nephrogenic systemic fibrosis (18). For this reason, when evaluating these methods in comparison to alternatives such as TOF MRA, the additional risk needs to be taken into account. k-Space Acquisition Schemes Data collected at low spatial frequencies or central phase-encoding steps are the primary determinants of overall contrast in an image, whereas the data collected at high spatial frequencies primarily determine edge definition and have proportionately less impact on contrast. The range of spatial frequency components in an image defines k-space, and this concept can be used to understand different methods of data acquisition. Various k-space sampling orders can be used in 3D imaging, and these have different imaging characteristics. In a standard 3D Fourier acquisition, one line of 3D k-space is acquired per TR interval. During this TR interval, the readout gradient causes a traversal in one k-space direction (e.g., kx). The location of the k-space line in the other two directions (ky and kz) is controlled using phase encoding. During the scan, all the needed values of ky and kz must be sampled. Considering only the ky and kz directions, each TR samples one (ky, kz) pair. The order in which ky and kz are sampled is completely under control of the pulse sequence.

FIGURE 25.21 A–C: Precontrast T1, (A), postcontrast T1 (B), and gradient-echo image (C) all demonstrate partially thrombosed giant aneurysm. Note the phase ghosting artifact along phase-encoding axis emanating from pulsatile flow in patent portion of lumen (A). This artifact is significantly more obvious after gadolinium administration (B). GRE image before contrast injection (C) shows how signal from flowing blood is recovered and vessels appear bright, due to the nonslice selectivity of the refocusing gradient.

In sequential k-space sampling, ky moves from one edge to the other of k-space over the course of the scan. At each ky location, the kz values progress in a similar edge-to-edge fashion. Thus, the kx traversal is most rapid, kz is slower, and ky is slower still. With this ordering, the acquisition of the center of kspace occurs during a fairly long period of time (due to the slow ky traversal) in the middle of the scan. This can impact the scan in various ways. In a CE MRA acquisition, to produce optimal arterial enhancement, the contrast administration should be timed so that the midpoint of the bolus arrives in the arteries approximately at the midpoint of the acquisition. If the transit time, Ttrans, between the point of injection and the arteries of interest is known or measured using a test injection, if the infusion time is Tinf, and if the scan time is Tscan, the optimal delay time is However, note that even if the optimal delay is used, if the infusion is too short (or the scan time is too long), the data acquired at the beginning of the scan could have suboptimal contrast enhancement because the bolus has not yet arrived, leading to some resolution loss. 1912

An alternative sampling strategy has been referred to as elliptical centric ordering. In this case, the (ky, kz) sampling is ordered so that data acquisition begins at the k-space center and moves progressively farther outward over the course of the scan. This is illustrated in Figure 25.22. The advantage of this technique is that if the bolus administration has been timed to arrive at the anatomy of interest at the start of the scan, the contrast is likely to be present during the entire examination. This can also lead to better arterial and venous separation, especially in areas such as the carotid arteries, where the short transit time of the cerebral circulation can cause rapid venous enhancement. With elliptical centric ordering, contrast should be in the venous system only during the acquisition of the outer portions of k-space. As a result, only the edges of veins may show enhancement in the final image. In a similar fashion, this scheme can also be advantageous for studies requiring suspended respiration. Subjects that are unable to complete an entire breath-hold are likely to begin breathing at the end of the study. Therefore, any resulting motion artifacts will originate only from the edges of the imaged anatomy.

FIGURE 25.22 Linear asymmetric (A) and elliptical–centric (B) k-space ordering schemes. (From Laub G. Principles of contrast-enhanced MR angiography. Basic and clinical applications. Magn Reson Imaging Clin N Am 1999;7:783– 795, with permission.)

TABLE 25.2 Comparison of Time-of-Flight, Phase-Contrast, and Contrast-Enhanced MRA

Dynamic Imaging Arguably, the ideal CE MRA technique not only would provide high spatial resolution but also would depict the dynamic enhancement pattern with sufficient temporal resolution to separate arterial from venous phases and depict regions of delayed or retrograde inflow, much like x-ray angiography. At present, 3D imaging is not fast enough to provide the ideal spatial and temporal resolution and spatial coverage simultaneously. Nonetheless, even if trade-offs among spatial resolution, temporal resolution, and slice coverage need to be made, dynamic 3D CE MRA could be very useful. If each time frame image is completely independent of any other time frame, a full sampling of kspace is needed for each. However, each time frame is clearly not independent of all others, and it is reasonable to propose that it should be possible to exploit this property to reduce the required sampling and therefore alter the trade-off among the imaging parameters. If images can be obtained very rapidly, 1913

on the order of 1 frame per second, then time-resolved MRA becomes possible (19). This allows information regarding the kinetics of contrast inflow to be obtained, analogous to conventional angiography. To achieve this, trade-offs are necessary, usually resulting in reduced spatial resolution or SNR. There are a number of ways to implement this strategy. One technique utilizes a variant of the keyhole method. In 3D time-resolved imaging of contrast kinetics (TRICKS), the central portion of kspace is acquired more frequently than the periphery. Each acquisition of the center of k-space is then combined with recent data from the periphery to produce a time series of images with good spatial and temporal resolution (20). A variant known as TREAT (time-resolved echo-shared acquisition technique), employing a less discontinuous mapping of k-space, has also been described (21). In another approach being explored, vastly under sampled isotropic projection reconstruction (VIPR), radial rather than Cartesian sampling of k-space is used, with a narrow acquisition window for the central portion of kspace and a wider window for the peripheral portions (22). A summary of the MRA methods commonly used in clinical practice is given in Table 25.2. Parallel Imaging and MRA The time required to acquire a conventional MR sequence depends linearly on the number of phaseencoding steps required to fill k-space. Reducing the number of phase encodes to reduce scan time will adversely affect spatial resolution. Parallel imaging addresses this problem by using information available from multiple-channel receive coils to replace some of the phase-encoding steps, allowing a reduction of scan time. In essence, the difference in signal received by coil elements at different locations around the body part being scanned can be used for localization (23). The cost of this benefit is primarily decreased in SNR due to the reduction in number of phase encodes, and, ignoring potential gains from increased coil efficiency, is proportional to the square root of the scan time reduction factor, with factors of two and four being commonly employed with eight-channel head coils. In some cases, aliasing artifacts may also be introduced. The processing of the information from the differential coil sensitivity can be performed in the image domain, that is, after Fourier transformation (sensitivity encoding [SENSE], array spatial sensitivity encoding technique [ASSET]), or in the frequency domain before Fourier transform (FT) (simultaneous acquisition of spatial harmonics [SMASH], generalized autocalibrating partially parallel acquisition [GRAPPA]) (24). From a clinical point of view, the two approaches yield similar results. Because they typically have very high SNR, MRA sequences are natural candidates for application of parallel imaging. The benefits can be realized either as improved resolution or reduced scan time. Timeresolved MRA sequences in particular benefit from incorporation of parallel imaging. Parallel imaging obtains an acceleration factor (here specified by the reduction factor, R) by acquiring only a fraction (1/R) of the needed phase-encoding steps. The factor R cannot be greater than, and is typically somewhat smaller than, the number of coils in the array. The reconstruction algorithm uses the spatial information from the coil array to compensate for the missing data that would normally cause aliasing artifacts. This approach offers the possibility of great reductions in scan time, which is clearly beneficial to vascular imaging. As with all fast scanning techniques, the reduction in scan time directly affects the SNR of the subsequent images. Therefore, parallel imaging should only be considered if there is adequate SNR in the fully sampled data. Specifically, the SNR in parallel imaging is approximately

where SNRp and SNRf are the SNRs obtained with a reduced and full set of phase encodings, respectively, R is the reduction factor, and g is the so-called geometry factor, which is spatially dependent and also depends on R and the coil array being used. The g-factor is always greater than or equal to 1, and increases as the reduction factor increases due to fundamental electrodynamic interactions between the coil elements. Equation (8) describes the noise in a series of parallel images obtained using the signal magnitude. In phase-contrast imaging, the noise in the reconstructed velocity images from a two-point acquisition can be shown to be (25)

This equation is valid unless there is a significant amount of aliasing in the reconstructed images. This can occur if the measured velocities are too close to the chosen velocity encoding, the reduction factor is too large, or the geometry factor is too great at the spatial location of the flow. 1914

Rapid Imaging Through Undersampling Reducing the number of sequence repetitions needed to form an image has obvious benefits in terms of imaging speed. With the Cartesian (linear and orthogonal) sampling of k-space that is normally used, if the number of phase-encoding steps is reduced, one has to reduce either the spatial resolution or the FOV, and if the object is larger than the FOV, aliasing artifacts result. For this reason, Cartesian k-space sampling is not very robust in the face of undersampling. Projection reconstruction (PR) techniques sample k-space in a radial pattern. The spatial resolution in PR is determined by the resolution in each projection and is independent of the number of projections used. If the PR data are undersampled (i.e., if the number of projections is reduced), artifacts in the form of streaks emanating from high-signal regions can be observed. If one is interested in subtle details in moderate- or low-signal regions, the artifacts from high-signal regions could be very troublesome. However, under the right circumstances, PR lends itself well to angular undersampling because the resulting aliasing artifacts can be benign. Specifically, if the highest-signal portions of the image are the ones of interest, the streaking artifacts from undersampling may be quite tolerable. This is the case, for example, in CE MRA, where the magnetization of background tissues is saturated while the signal from intravascular blood is intense. Even larger undersampling reduction factors can be obtained if the PR trajectory is extended to all three dimensions. In situations in which the image is “sparse,” that is, when the image is composed of a few, rather separated high-intensity structures, significantly higher reduction rates can be obtained. Examples of applications in which the image is sparse are angiography and phase-contrast measurements because the nonvascular image regions have low intensity or can be suppressed by subtraction. In these cases PR imaging can be coupled with a highly constrained back projection reconstruction (HYPR) algorithm to increase the temporal resolution of dynamic acquisitions to only a few TR intervals (26). This scheme requires a high-fidelity nondynamic image to use as a sort of mask and hugely undersampled dynamic projection data. Individual time frames are produced by multiplying the nondynamic image by back projections of the dynamic projections. The technique essentially only allows the dynamic projections to affect the high-intensity structures in the mask image and thereby suppresses streak artifacts. Furthermore, the SNR of the individual time frames is essentially determined by the SNR of the product image. A variant of this approach utilizes a sequence known as vastly undersampled isotropic projection reconstruction (VIPR). A sparsely sampled radial acquisition is performed producing time-resolved images with submillimeter voxel dimensions and subsecond time resolution. There are CE as well as nonenhanced TOF and PC versions. The undersampling factor is typically on the order of 100. This decreased sampling rate leads to a reduction of signal-to-noise (SNR) ratio in proportion to the square root of the undersampling factor. This is addressed in postprocessing. In outline, the concept is to constrain the time-resolved images using a high-resolution image with good SNR. This results in a time series of angiographic images of diagnostic quality. The constraint can be a composite of the time-series images themselves, however, could also be a separate set of images acquired before or after the time series. This approach is known generically as HYPR. There are many variants. After HYPR postprocessing, the SNR is given by the same expression as parallel imaging (Equation 8); however, the g factor for HYPR is less than 0.5, allowing large acceleration factors. The approach is not limited to time-resolved angiographic sequences. Variants which allow the mapping of intravascular velocity and pressure fields, wall shear stress and streamline distribution have also been described (Fig. 25.23). Thus, these novel sequences unlock the potential of MR-based angiographic sequences to provide physiologic information in addition to vessel morphology as suggested in the introduction to this chapter. Excellent reviews of this emerging technology are available (27). Alternative Approaches to Angiographic Imaging A number of other innovative methods have been developed to address specific challenges in angiographic imaging and applied to clinical questions involving the peripheral vasculature. The reader interested in these currently nonneurovascular applications is referred to the literature (28). MR Angiography at Higher Fields The widespread availability of clinical 3-T whole-body scanners provides access to a number of benefits for MRI. Fundamentally, a move from 1.5 to 3 T results in a factor-of-two increase in SNR; however, a number of other changes also occur, which may be beneficial or detrimental, depending on the details of the imaging sequence of interest. From the point of view of TOF MRA, three changes are of 1915

particular interest. The increase in SNR can be used to shorten scan time at equal resolution, to increase resolution at fixed scan time, or for a combination of the two. An approximately 30% prolongation of T1 for soft tissues (but not for blood) results in improved stationary tissue suppression. Finally, depending on the value of TE employed, relative fat–water phase differences may provide additional background suppression (Table 25.1). On the negative side, the increase in susceptibility effects can potentially result in increased artifacts, particularly near the bone/soft tissue and air interfaces at the skull base. The higher field is also associated with an increase in RF power deposition within the patient, quantified by specific absorption rate (SAR), and this source of heating may be limiting in some cases. Comparisons of intracranial TOF MRA at 3.0 and 1.5 T have been promising (28). The increased SNR can be used to achieve voxel dimensions less than 1 mm3. Improved suppression of background soft tissues reduces artifacts on postprocessed projection and rendered images. Improved vessel contour rendition and superior small-vessel detection are very noticeable compared to 1.5 T. Imaging options have also been evaluated at 3 T. Magnetization transfer contrast improves the (already very good) stationary tissue suppression, although the implementation of MT pulses lengthens scan time and so is not implemented in many 3-T 3D TOF protocols. The MT pulse sequence is also associated with increased SAR and associated soft tissue heating, although the RF power deposition can be controlled by specially tailored MT pulse sequences (29). Destructive interference from the RF can adversely alter the ramp shape in standard ramped RF excitation for 3D TOF; however, this can also be modified to make this technique useful at 3 T (30).

FIGURE 25.23 Phase contrast HYPR-Flow derived images of (left) flow directional map in the X/Y plane, (center)relative pressure map, and (right) relative wall shear stress. Red represents the largest values of each quantity shown. (From Wu YJ, Johnson KM, Velikina J, et al. Clinical experience of HYPR Flow. In: Proceedings of the 16th Annual Meeting of the ISMRM, Toronto, Ontario, Canada, 2008 (Abstract 110). Used with permission of ISMRM.)

The additional SNR available at 3.0 T also makes parallel imaging a natural choice. This can be implemented in such a way that near-isotropic submillimeter voxel dimensions are possible with an acceptable scan time, and further improvements in vessel detection and characterization are realized (31). The benefits of using a 3.0-T field strength also lead to improvements in CE MRA, particularly by reducing acquisition times. Increased conspicuity of contrast enhancement should be associated with increased intravascular signal compared to background. Parallel imaging at 3 T is of particular interest for time-resolved CE MRA. For MRA, the prolonged T1 relaxation times at higher fields are an advantage. For TOF MRA, the longer T1 of static tissues leads to higher saturation of these spins as compared with inflowing blood and therefore stronger flow-related enhancement. A longer T1 relaxation time is also of benefit for CE MRA. The T1 difference between CE arterial blood and static spins (and unenhanced venous blood) is more marked at higher fields. However, these advantages arising solely from relaxation time lengthening at higher field are fairly modest. The exact impact on TOF MRA depends on the T1 of static and moving spins, flow conditions, and so on, but is on the order of 5% to 10% for a field increase from 1.5 to 3 T. The impact on CE MRA depends on the T1, the contrast agent concentration, and the fielddependent relaxivity, but is on the order of 3% to 5% for the same field change. Thus, the main benefit to MRA at higher fields is simply the increased SNR. All other factors being equal, then, the contrast-tonoise ratio (CNR) of MRA at 3 T in practice is about twice that at 1.5 T. Although not currently approved by the FDA for clinical use, early results of MRA performed at 7 T are being reported by research laboratories. The expected increase in SNR has been confirmed, along 1916

with prolongation of soft tissue T1 values. For example, the T1 of white matter is 840 ms at 3 T, increasing to 1,130 ms at 7 T. These changes lead to further improved resolution and background suppression. There are, however, a number of technical challenges at this increased field strength. Increased dielectric effects lead to increased signal inhomogeneity across the FOV, susceptibility artifacts are increased, and increased SAR leads to pulse sequence limitations, particularly affecting the use of saturation pulses. Preliminary studies suggest that traditional TOF sequences can be SAR limited; however, magnetization prepared rapid GE-type sequences such as MPRAGE as either TOF or CE angiographic acquisitions appears to perform well at 7 T (32). Specially, tailored saturation pulses with reduced flip angle are being investigated to address SAR limitations (33). Clinical Applications Extracranial Circulation CAROTID ARTERIES. The cervical segment of the carotid artery is a site of several pathologies; however, in adults atherosclerosis is the primary concern. Since there are medical and surgical options for treatment, imaging is needed for screening and diagnosis as well as characterization of lesions. Disease may be focal or diffuse but occurs most commonly in the region of the carotid bifurcation. Atherosclerotic plaque can produce symptoms by serving as a source of emboli which propagate distally and lead to narrowing or occlusion of cerebral arteries, or less commonly as a cause of flow restriction due to narrowing or occlusion of the cervical carotids themselves. Carotid Flow and Atherosclerosis Even at the normal adult carotid bifurcation, flow is disturbed by the presence of a flow divider, vessel curvature, changes in luminal diameter, and commonly the presence of a proximal dilatation of the internal carotid artery (ICA) known as the carotid bulb. These factors dictate a relatively complex flow pattern, with helical secondary flows and flow separation with stagnant or even oscillating or reversed flow within the posterior bulb (Fig. 25.2).

FIGURE 25.24 Carotid stenosis, three-dimensional (3D) versus two-dimensional (2D) TOF. The 2D TOF magnetic resonance angiography (A) shows near complete signal loss (a flow gap), implying tight stenosis in the proximal internal carotid artery. High-resolution 3D TOF (B) demonstrates moderate narrowing, which more closely matches the catheter angiogram (C).

In the presence of atherosclerotic plaque, flow can become even more complex (34). Plaque typically forms in areas where the wall shear stress (force per unit area along the wall) due to the viscosity of the flowing fluid is low. At the carotid bifurcation, this is found along the posterior bulb. This can lead to irregular wall contour and ultimately luminal narrowing. These factors can disturb the pattern of flow, introducing disordered flow patterns at multiple scales (Fig. 25.3). Carotid Stenosis Treatment The feared complication of carotid atherosclerosis is stroke. Multiple large clinical trials performed in the 1990s identified a correlation between atherosclerotic carotid narrowing and response to combined medical and surgical versus nonsurgical medical therapies available at the time (35). Certain subgroups were identified who enjoy a marked benefit, particularly symptomatic patients with high-grade stenosis. Subsequently, both modes of therapy have evolved, and an additional option, transluminal angioplasty and stenting, has been added. Because of these changes, recommendations for treatment are evolving 1917

and some controversies have arisen (36). Ongoing trials particularly regarding asymptomatic individuals will help to clarify these issues (37). Carotid Screening An individual’s stroke risk due to carotid bifurcation disease is related to a number of factors, including the presence of vulnerable plaque or ulceration, as well as hemodynamic factors including stenosis. For purposes of many of the carotid therapy trials, carotid stenosis was used as an imaging surrogate for these multiple morphologic and hemodynamic factors. Determination of the degree of carotid stenosis in most of the endarterectomy trials was based on measurement of the percent diameter stenosis determined by catheter angiography on the projection image depicting the maximum stenosis. Based on this, individuals were stratified into groups based on the degree of stenosis. The most commonly used classification is the North American Symptomatic Carotid Endarterectomy Trial (NASCET). Individuals were divided into groups based on percent stenosis: mild (70%). Most of the less invasive alternatives to catheter angiography can accurately stratify individuals but are not sufficiently sensitive to assign precise values for percent stenosis. The available modalities include Doppler ultrasound (DUS), CTA, and multiple MRA techniques. All of these techniques have achieved sensitivity and specificity for identification of severe stenosis in the 80% to 95% range in multiple studies comparing them to catheter angiography. They are all reasonably accurate for the exclusion of mild disease. The accuracy for the characterization of moderate range stenosis is slightly lower (38). TOF MRA is a reasonable choice for screening the carotid bifurcation in at risk, particularly symptomatic individuals. Advantages include the lack of need for contrast enhancement and the ability to easily perform additional imaging to assess the cerebral vasculature and the brain parenchyma. 2D TOF provides excellent slow-flow sensitivity and extensive coverage for an overview of the cervical arteries; however, signal loss associated with recirculation at the carotid bulb and also disordered flow in the poststenotic region may lead to overestimation of stenosis. The “flow gap” seen in the poststenotic region can be distinguished from occlusion by the reconstitution of flow seen in the more distal segment of the artery (Fig. 25.24). This can be differentiated from collateral or retrograde filling due to the lack of side branches of the cervical internal carotid and the directional nature of flow visualization on 2D TOF. A tendency to overestimation does make the exam very sensitive for exclusion of significant pathology when the appearance is essentially normal. To optimize performance, TE should be chosen as short as possible. 3D TOF is less sensitive to slow flow and provides less coverage; however, the smaller voxels and shorter echo times achievable with this technique limit intravoxel dephasing and give a more accurate depiction of the degree of stenosis. Slow flow can contribute to poor visualization of the posterior bulb, simulating stenosis. This can be limited by reduction in spin saturation associated with a ramped RF pulse (Fig. 25.25). Even the 3D method will demonstrate some overestimation of stenosis due to dephasing in severe narrowing (Fig. 25.26). The differences between 2D and 3D TOF make the two techniques complementary, and both sequences can be obtained and interpreted with an increase in accuracy. Overlapping slab acquisitions combine some of the benefits of 2D and 3D TOF, and can also be effective for carotid imaging (Fig. 25.27). CE MRA is also frequently employed for evaluation of the carotid bifurcation, and is at least as commonly employed for screening purposes as TOF. Advantages include lack of flow dependence, rapid acquisition, and good depiction of the luminal contour (Fig. 25.28). CE sequences are still affected by signal loss from intravoxel dephasing (Fig. 25.29); however, the accuracy of luminal diameter and degree of stenosis are generally superior to TOF. Disadvantages include the need for an intravenous injection of contrast, which entails cost and time as well as some risk for the patient. Suboptimal bolus timing can result in a less accurate or even nondiagnostic exam.

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FIGURE 25.25 Normal carotid artery bifurcation. A: Digital subtraction angiogram. B: Three-dimensional Fourier transform (3DFT) time-of-flight (TOF) magnetic resonance (MRA) angiography. C: 3D TOF MRA with ramped radiofrequency (RF) pulse. Notice the subtle loss of signal intensity in the carotid bulb (white arrowhead) resulting from the disturbed flow and recirculation from progressive spin saturation. With the application of the ramped RF pulse, not only is there an improvement of the spin saturation in the distal internal carotid artery, but, in addition, signal loss in the carotid bulb is not as striking (arrow).

FIGURE 25.26 Catheter carotid angiogram (A) and three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA) (B) of the carotids (echo time = 7.5 ms) demonstrate a moderately long segment stenosis of the proximal internal carotid artery. Notice the outpouching along the margin of the stenosis on the conventional angiogram (arrow). The 3D TOF MRA accurately depicts the length of the stenosis; however, the severity of the stenosis is overestimated (open arrow). The outpouching is not visualized primarily due to flow stagnation.

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FIGURE 25.27 Multiple overlapping slab technique. A: A single 3D TOF slab demonstrating progressive flow saturation as the image extends higher in the volume, as evidenced by the vessel tapering and the loss of signal intensity. B: Multiple overlapping thin-slab acquisition, demonstrating the “venetian blind” artifact. Because of the use of the smaller imaging volumes, the effect of spin saturation is not evident. C: Multiple overlapping thick-slab acquisition with the use of a ramped radiofrequency (RF) pulse and manual integration of the slabs. Again, a “venetian blind” artifact can be seen in two locations with the integration of the three slabs. Note the uniform signal intensity and the lack of spin saturation through the use of the ramped RF pulse. D: Multiple overlapping thick-slab acquisition with an automated algorithm integrating the three slabs. No demonstrable “venetian blind” artifact is seen. There is no loss of signal intensity as a result of spin saturation.

Phase-contrast MRA has been evaluated for bifurcation screening; however, the 3D technique entails long scan times. It is possible to obtain cardiac gated quantitative flow data with 2D PC in a reasonable time, if a clinical question can be addressed by this data. Time-resolved MRA has also been evaluated. The principal benefit is lack of venous filling in the arterial phase images; however, the lower spatial resolution is a significant disadvantage. As previously mentioned, two additional methods are commonly used for carotid stenosis evaluation, DUS, and CTA. Ultrasound B mode and Doppler standards have been correlated with percent stenosis measurements. The exam is inexpensive, widely available, and well tolerated. It is commonly used for initial screening. The primary drawbacks are operator dependence and poor visualization of the target artery in the presence of calcified atherosclerotic plaque. With modern multi-detector scanners, CTA offers a high-resolution, rapid, minimally invasive, and comprehensive evaluation of the neck vessels. Disadvantages include contrast administration, radiation dose, contrast bolus mistiming, and poor visualization of the bifurcation due to beam hardening artifact in the presence of bulky atherosclerotic calcifications. Although plaque ulceration is a risk factor for stroke, none of the available imaging modalities are sensitive for the detection of small ulcerations, which could be the source of clinically important emboli. In fact, even catheter angiography is relatively insensitive for detection of associated small contour abnormalities. This is an important motivation for the development of dedicated plaque imaging, described below. Clinical Evaluation There are a number of commonly used algorithms for screening, although apart from test efficacy studies, there are few studies examining the usefulness of these schemes at the outcome levels (39). In asymptomatic patients, DUS followed by CE MRA or CTA for confirmation of pathology and morphologic evaluation prior to therapy is widely used. In symptomatic patients, MRI of the brain with diffusion and possibly perfusion imaging along with TOF MRA of the neck and brain provides a more comprehensive evaluation of the vessels and brain parenchyma. In the setting of acute stroke, CT scan of the brain along with CTA of the neck and brain and possibly CT perfusion (CTP) imaging rapidly provides information needed for decision-making regarding possible intravenous or arterial thrombolysis.

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FIGURE 25.28 Three-dimensional (3D) time-of-flight (A) and 3D contrast-enhanced (B) magnetic resonance angiography (MRA) of the carotid bifurcations of a patient who had previous endarterectomy and vein graft. There is markedly improved signal in panel B from minimized signal loss in contrast-enhanced MRA.

FIGURE 25.29 In patient with a tight stenosis of the internal carotid origin, note that the CTA shows the accurate patent lumen, the plaque, and the calcification (arrow). The contrast-enhanced MRA demonstrates patency of the lumen inferred from the flow signal, but exaggerates the stenosis and does not show the true morphology of the stenotic plaque (arrow).

After endarterectomy, MRA can be useful in evaluating patency and excluding dissection related to surgery when this is a concern. After angioplasty, MRA can confirm stent patency, however, depending on the composition of the stent, susceptibility artifact may limit the usefulness of MRA in evaluating in stent restenosis. In these patients, CTA is more accurate for evaluating narrowing within the stent (Figs. 25.30 and 25.31). Vertebral Stenosis Atherosclerotic change of the vertebral arteries is a more difficult diagnostic challenge owing to the small size of the vertebral arteries, their tortuous course, and the presence of adjacent bony structures. A typical vertebral artery (VA) is about 3 mm in diameter; however, many individuals possess an asymmetric vertebral system, in which case the nondominant artery may be very small. The midcervical, V2 segment of the vertebral artery passes through the foramina transverseria and so is encircled at these levels by bone. This can be a source of beam-hardening artifact for CTA and susceptibility artifact for MRA, limiting accuracy of evaluation. The distal cervical, V3 segment is tortuous, and horizontally oriented segments can be difficult to evaluate on axial sections. Multiplanar reformats are helpful in better depicting pathology within these segments. The horizontal course can also create in-plane flow-related signal loss, decreasing accuracy for TOF MRA. The origins of the vertebral arteries are frequently tortuous. Since this is a common site of narrowing, careful evaluation is needed. Multiplanar reformats and 3D postprocessing can be helpful. The location of the origins from the subclavian arteries is subject to respiratory artifacts in many individuals, which is a challenge for TOF MRA methods. Dedicated neurovascular coils are helpful in limiting this effect. The small size of the artery also poses a challenge. Conventional angiography is associated with a spatial resolution of 1921

approximately 0.2 mm. A typical value for current CTA exams is 0.5 mm, and MRA resolution lies in the 0.7 to 1 mm range depending on the technique and field strength. With a 0.5 mm isotropic voxel size, a 2-mm diameter artery is spanned by only 4 pixels in axial projection, limiting the accuracy of percent diameter stenosis determinations.

FIGURE 25.30 Multiplanar reformat from CT angiogram (A) demonstrates in-stent restenosis, which was confirmed on digital subtraction angiogram (B). Due to susceptibility effects, stenosis adjacent to or within a stent lumen is not well evaluated with magnetic resonance angiographic methods. (Figure courtesy of Barrow Neurological Institute, used with permission.)

FIGURE 25.31 CTA depicts the patent lumen in this stent (circle) but views of contrast-enhanced MRA do not, despite proving the presence of patency.

There are few studies evaluating the accuracy of noninvasive methods for evaluation of vertebral artery stenosis. Criteria for DUS evaluation of proximal stenosis have been published (40). Analysis of existing studies suggests that CE MRA and CTA may yield best accuracy. In many clinical settings, CTA is preferred, due to the short imaging time and resolution. CE MRA is also frequently employed. Accurate bolus timing and limiting motion are needed to optimize diagnostic accuracy. Differential diagnosis includes compression of the vertebral artery associated with cervical spondylosis. Due to the bony findings, CTA is optimal. Cases of positional posterior fossa symptoms may be initially evaluated with static cross-sectional imaging; however, conventional angiography is indicated for dynamic evaluation in these cases. Plaque Imaging Carotid stenosis provides a convenient and accessible imaging surrogate for atherosclerotic changes; however, it is evident that the association of stroke and atherosclerosis is more complex. Highresolution MR studies utilizing dedicated surface coils can image atherosclerotic plaques in vivo (41). These plaques consist of multiple components, typically a fibrous cap, lipid core, and foci of intraplaque hemorrhage and calcification. Foci of inflammation with associated neovascularity may also be present. In order to detect and characterize these components, a multispectral approach is adopted. A typical protocol includes both black and bright blood acquisitions, with 3D TOF, T1-, proton density (PD)-, and T2-weighted sequences (Fig. 25.32). A postcontrast acquisition is sometimes included. All of these sequences are obtained at high resolution, typically 0.25 mm after zero filling. Given the need for high resolution, 3-T imaging is advantageous. Differences in signal intensity among the plaque components 1922

allow them to be differentiated, and help to distinguish from other pathologies such as dissection. The goal is identification of potentially symptomatic plaques, described as unstable, vulnerable or high risk. The typical high-risk plaque is characterized by a prominent lipid-rich necrotic core, intraplaque hemorrhage, and a thin or ruptured fibrous cap. Postcontrast images may demonstrate enhancing areas of neovascularity associated with inflammation. The presence of these elements is predictive of future ischemic events independent of carotid stenosis (42). In the future, hemodynamic information available from rapid phase-contrast MRA methods such as HYPR may also contribute to plaque imaging and characterization. Low or oscillatory wall shear stress is associated with plaque formation, and could be assessed as a factor for plaque growth. Wall tensile stress reflects local pressure and may be a factor in plaque rupture. Future developments in this evolving area will also likely include rapid higher-resolution exams with improvements in dedicated surface coils and novel pulse sequence designs. Preliminary studies at 7 T have demonstrated the capability to image the normal vessel wall and differentiate the vascular lumen; however, correlation of signal intensity patterns with histopathologic plaque components needs to be performed (43).

FIGURE 25.32 Transverse carotid plaque images and coronally acquired CE MR angiogram of the left carotid artery in an asymptomatic 61-year-old woman. A: Maximum-intensity projection of the CE MRA demonstrates 74% stenosis at the left internal carotid artery. The horizontal line indicates the level of the transverse carotid plaque images shown in B. B: Transverse image of a TOF angiogram demonstrates a smooth luminal surface and a dark juxtaluminal band indicating an intact thick fibrous cap. The thick fibrous cap is easier to appreciate as a high-intensity band (arrows) on the CE T1-weighted (T1W) and T2W images. An isointense area on TOF and T1W images, an isointense to lowintensity area on the T2W image, and a low-intensity area on the CE T1W image indicate a lipid-rich necrotic core (LRNC) without hemorrhage occupying 29% of the wall area (arrowheads). Notice that the LRNC is easiest to appreciate on the CE T1W image. Asymptomatic plaques tend to have a smaller LRNC without hemorrhage as well as a thick fibrous cap. (Reprinted with permission from Demarco JK, Ota H, Underhill HR, et al. MR carotid plaque imaging and contrast-enhanced MR angiography identifies lesions associated with recent ipsilateral thromboembolic symptoms: an in vivo study at 3 T. AJNR Am J Neuroradiol 2010;31:1395–1402. © by American Society of Neuroradiology.)

Subclavian Steal Retrograde flow within the vertebral arteries is classically demonstrated with catheter angiography and rapid filming. The diagnosis can be established noninvasively by ultrasound, and CTA can demonstrate retrograde filling by sequential imaging at a fixed location during bolus administration of contrast (4D CTA). The diagnosis can often be established by MRA as well. On 2D TOF imaging with the usual traveling superior saturation band, the antegrade flow within one vertebral artery will be evident, but the retrograde flow will not be seen. If the flow is sufficiently rapid, both vertebrals will be seen on a 3D TOF sequence without directional encoding by saturating pulses. The combination of these two findings can be diagnostic of a steal. If the diagnosis is suspected, a pair of 2D TOF sequences with superior and inferior saturation bands, respectively, can elegantly display the abnormal flow. With sufficient time resolution, or evaluation of contrast kinetics, time-resolved CE MRA could also make this 1923

diagnosis. Carotid and Vertebral Artery Dissection Craniocervical dissections are typically classified as traumatic or spontaneous. Traumatic dissections are usually associated with blunt craniocervical trauma. Spontaneous dissections are uncommon; however, they are the etiology of a significant number of ischemic strokes in young individuals. The clinical presentation of dissection is wide ranging, and can include headache, nausea, vertigo, neck pain, cranial nerve palsies, and ischemic stroke. A fraction of spontaneous dissections are associated with underlying connective tissue disorder or other cause of vasculopathy (Fig. 25.33). In a typical dissection, an injury to the arterial intima allows blood to enter the media and form a mural hematoma in a pseudolumen (44). This hematoma may enlarge, leading to stenosis or occlusion of the adjacent true lumen. In a more severe intimal injury, an intimal flap may form, potentially also impeding flow. If the injury extends to the adventitia, a pseudoaneurysm may form. Dissections of the cervical arteries occur most commonly near the skull base. The carotid arteries are more commonly affected than the vertebral, multiple arteries can be affected. Intracranial extension and purely intracranial lesions are uncommon. However, intracranial dissections can be associated with severe sequelae including subarachnoid hemorrhage. Many imaging appearances are associated with dissection of the cervical arteries (44). A common angiographic appearance is smooth, eccentric, long segment narrowing of the distal internal carotid. Identification of an intimal defect, although uncommon, is very specific. Pseudoaneurysms can be focal outpouchings or appear as long segment fusiform enlargement of the artery (Fig. 25.34). Although catheter angiography is considered the reference standard for diagnosis of dissection due primarily to the high resolution of these studies, important information regarding the artery wall is available with cross-sectional imaging studies (45). Although ultrasound can detect the mural thickening associated with dissection, the deeper and more distal portions of the cervical arteries are not well seen and, consequently, this modality is not commonly used for evaluation of dissection. However, several other imaging options demonstrate high sensitivity and specificity. CTA demonstrates the opacified true lumen and also wall thickening associated with the mural hematoma. Intimal flaps and pseudoaneurysms are also typically well depicted. However, subtle dissection may appear with essentially no luminal narrowing, in these cases the only diagnostic clue is wall thickening. Poor bolus timing and patient motion will decrease sensitivity. A number of artifacts, such as beam hardening from adjacent bone or dense contrast, can obscure findings or simulate dissection (46). A combination of T1-weighted MRI and 3D TOF MRA has also been evaluated. In the setting of acute dissection, mural hematoma is similar in signal intensity to adjacent soft tissue on T1-weighted images, and so this sequence is relatively insensitive. MRA in this period can be helpful in evaluating for narrowing of the vascular lumen. With subacute blood products, seen at about 1 week following the acute event, thin-section T1-weighted images with fat saturation are an excellent choice for detection of hyperintense subacute blood products associated with mural hematoma (44). The characteristic appearance of a crescent-shaped T1 hyperintense margin adjacent to a narrowed segment of the distal internal carotid is very specific for dissection (Fig. 25.35). T1-weighted fast spin-echo (FSE) imaging with fat saturation allows very thin sections which can display the findings on several serial images (47). CE MRA has also been evaluated and is associated with high sensitivity and specificity. Detection of vertebral artery dissection can be challenging owing to the factors discussed above in the section on vertebral stenosis. Since most dissections occur within the distal cervical (V3) segments, the tortuosity of the artery poses a particular challenge. Multiplanar reformats are useful in tracking the course of the vessel. As with the carotid arteries, multiple imaging findings may be present in vertebral dissection (48). The perivascular venous plexus associated with the vertebral artery can be hyperintense on fat-saturated T1-weighted images, an imaging pitfall that can resemble dissection (46).

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FIGURE 25.33 Vertebral artery dissection with pseudoaneurysm in a 29-year-old with Marfan’s disease. Markedly tortuous large vessels are clearly abnormal for a young adult, and close inspection shows an irregular pseudoaneurysm in the vertebral artery from a prior dissection (arrows).

FIGURE 25.34 Pseudoaneurysm of the internal carotid artery. Catheter angiogram (A), 2D TOF (B), and 3D TOF (C) magnetic resonance angiograms of the carotid arteries. Notice the pseudoaneurysm in a patient who had a carotid artery dissection 1 month prior (arrow). The lower spatial resolution of the 2D TOF MRA image of the carotid artery pseudoaneurysm does not define the neck of the aneurysm completely (open arrow). The 3D TOF MRA image better demonstrates the association of the aneurysm to the carotid artery.

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FIGURE 25.35 Spontaneous carotid artery dissection. A: Spin-echo T2-weighted image demonstrating normal flow void in the left carotid artery and a halo of hyperintensity from a mural hematoma (arrow). B: Individual partitions from three-dimensional time-of-flight magnetic resonance angiography demonstrating the normal hyperintense signal associated with flow-related enhancement in the lumen of the left internal carotid artery with a less hyperintense crescent-shaped rim, representing mural hematoma (arrow). C: Maximum intensity projection (MIP) image of the internal carotid arteries demonstrating the surrounding slightly hyperintense focus adjacent to the left internal carotid artery (arrow), representing methemoglobin in the vessel wall that has been incorporated into the image by the MIP algorithm.

For craniocervical dissection, CTA and MRA are similar in sensitivity and specificity, although some authors consider CTA to be slightly more sensitive. As in many settings, the two examinations are often complementary. For traumatic dissection, CTA allows a rapid evaluation with high sensitivity. MRA with T1-weighted fat-saturated imaging can be used to confirm the diagnosis if needed. For evaluation of suspected spontaneous dissection, MRI and MRA provide a comprehensive cerebrovascular examination and are often the first choice. Particularly for vertebral dissection, CE MRA is likely more sensitive for detection of subtle contour abnormalities than TOF. Cross-sectional studies may in fact be more sensitive than conventional angiography for detection of subtle dissection.

THE INTRACRANIAL CIRCULATION MR Imaging of Stroke Stroke is the third leading cause of death and one of the leading causes of adult disability in North America, Europe, and Asia. In the setting of acute stroke, neuroimaging has evolved from a purely diagnostic tool to an important component of stroke evaluation and management. Imaging contributes to rapid, accurate diagnosis, appropriate triage, prognosis, and improved outcome. Diagnosis and Triage The most beneficial therapeutic intervention in acute ischemic stroke is the early restoration of cerebral blood flow, which is closely related to functional outcome. Utilization of stroke treatments including intravenous recombinant tissue plasminogen activator (rtPA), intra-arterial thrombolysis, and endovascular mechanical recanalization are based on treatment time after onset and features of stroke defined on imaging studies, such as the presence of hemorrhage, location of vessel occlusion, the volume of infarcted brain tissue, and estimation of ischemic core and penumbra. Intracranial hemorrhage is an absolute contraindication for reperfusion therapy. Noncontrast1926

enhanced CT (NECT) is the accepted standard for detection intracranial hemorrhage. Gradient echo imaging (GRE) and susceptibility-weighted imaging (SWI) MRI sequences have equal or greater sensitivity than NECT. However, the significance of small foci of susceptibility artifact (presumably reflecting petechial hemorrhage) seen on these sequences, but not seen on CT, is uncertain. Parenchymal signs of infarct on NECT appear in 3 to 6 hours in slightly over half of cases. Diffusionweighted imaging (DWI) is four times more sensitive than CT for detecting acute stroke, with visible changes in less than 60 minutes. Despite the greater sensitivity of MR, the benefits of CT, primarily speed and convenience, likely outweigh any additional diagnostic benefit of MRI in the acute setting. Identifying candidates for endovascular treatment relies on vascular imaging with DSA, CTA, or MRA. Distal intracranial arterial occlusions are more likely to recanalize than proximal occlusions in patients treated with intravenous rtPA. The recanalization rates of intravenous rtPA for proximal arterial occlusions range from less than 10% for ICA occlusion to 30% for proximal middle cerebral artery (MCA) occlusion and 44% for distal MCA occlusion (49). Endovascular therapy may be more successful for proximal occlusions: stent retrievers have reported recanalization rates greater than 85% (50). Location and volume of clot and proximal and leptomeningeal collateral circulation status are also of great importance in treatment planning. MRA and CTA have high diagnostic accuracy for detecting large vessel occlusion when compared with DSA. Both modalities can measure stenosis in large extracranial vessels, as discussed previously. The sensitivity of TOF MRA decreases for intracranial vessels. Stenosis can be overestimated in regions of slow or disorganized flow, requiring careful interpretation of lumen caliber. Assessment of Viable Brain Tissue Evaluation of tissue viability may extend the therapeutic time window in some acute stroke patients. The ischemic penumbra is critically hypoperfused tissue that can be salvaged from infarction by early reperfusion after acute ischemia. If early reperfusion fails or neuroprotective intervention does not occur, the infarct core will expand and the penumbra will be incorporated into the final infarct volume. Penumbra salvage depends upon early reperfusion as the result of successful intervention, time elapsed after ischemia onset, the severity of cerebral blood flow reduction, and the presence of adequate collateral blood flow. Perfusion imaging may be performed with CT or MRI, with visualization of intravascular contrast as it passes through the capillary bed, producing increased density on CT and decreased signal intensity on MR. CTP can provide quantitative assessment of cerebral blood flow, blood volume, and mean transit time. The ischemic core demonstrates hypoperfusion, decreased blood volume, and elevated mean transit time. In contrast, blood volume is preserved and mean transit time (MTT) is prolonged in the viable penumbra. A mismatch between cerebral blood volume (CBV) with threshold of 1980

—to the diffusion coefficient, D, appearing in Fick’s first law and the diffusion time, τ: (In three dimensions, the coefficient 2 should be replaced by 6.) Thus, the larger the diffusion coefficient, D, the greater the distance a particle is expected to travel on average during the same diffusion time.

FIGURE 27.1 The Fickian picture of diffusion is best understood by considering the behavior of the diffusion cell, schematically represented here, in which the particle concentration is different in two compartments that are separated by a permeable membrane.

FIGURE 27.2 The Brownian picture of diffusion is best epitomized by this sketch illustrating a possible path taken by a molecule that is released at point r0 at time t = 0 and moves to position r at a later time t. The molecule undergoes a “drunken walk” whose displacement is characterized by a probability distribution.

Classic NMR measurements of (translational) molecular diffusion were based on the Brownian rather than the Fickian picture. The distinction is important because the Brownian description enables one to measure a molecular diffusion coefficient without using exogenous tracers. In essence, in the NMR measurement of diffusion, the diffusivity is inferred from the phase dispersion of the magnetization (loss in signal) caused by the assumed random displacements of spin-labeled molecules. Moreover, the Brownian pictures can treat diffusion as a process that can occur at thermodynamic equilibrium. One no longer needs to set up concentration gradients to observe diffusion. The first person to understand and describe the effect of molecular diffusion on the NMR signal was Erwin Hahn (8). The first measurements of the self-diffusivity of water (and of other liquids) using NMR methods were reported in the 1950s (9). In a series of classic experiments, Carr and Purcell used the NMR spin echo, also discovered by Hahn (8), to measure the self-diffusion coefficient of water and other solvents (9). Carr and Purcell first showed that the NMR spin echo could be sensitized specifically to the translational motion of a spin-labeled species by subjecting it to a static magnetic field gradient. An example of their NMR sequence is given in Figure 27.3A. They then showed that the random motions (net displacements) caused by diffusion reduce the amplitude of the NMR spin echo. The larger the diffusivity of the spin-labeled molecules, the greater the phase dispersion and the larger the attenuation of the magnitude signal they observed. By using a Brownian, probabilistic description of molecular displacements of the spin system subjected to a uniform magnetic field gradient, they derived an analytic expression relating the NMR signal attenuation and the molecular diffusion coefficient. Their conceptual framework is the basis for modern diffusion MRI studies. Their work also established the nonperturbing and highly accurate NMR measurement of the self-diffusion coefficient of water and other solvents as a “gold standard.” Two years later, Torrey incorporated the diffusion of magnetized spins explicitly into the Bloch (magnetization transport) equations (10), showing how it leads to additional attenuation, the NMR signal (11). Analytic solutions to this equation followed for freely diffusing species during a spin-echo experiment (12) and, later, for diffusion in various restricted geometries (13–15), in which the diffusing species were confined within pores of varying shapes. The next key innovation in the evolution of NMR diffusion measurements was the development and 1981

use of pulsed-field gradient methods (16). By applying two appropriately placed short-duration magnetic field gradient pulses rather than one that is constant in time, the NMR diffusion experiment could be performed more accurately and with an ability to control independently the diffusion time and length scale that is probed (14). An example of a pulsed gradient sequence is shown in Figure 27.3B. Using their new pulsed gradient sequence, Stejskal and Tanner extended the findings of Carr and Purcell, showing that uniformly translating spins produce a net phase shift that is proportional to their velocity and that diffusing spins produce no net phase shift but a change in the height of the phase distribution (16). They generalized the mathematical framework of McCall et al. (17) for relating the signal attenuation, A/A0; the conditional displacement distribution, P(r2, Δ|r1, 0); the pulse duration, δ; the pulse strength, G; the gyromagnetic ratio, γ; and the time between pulses, Δ: where the assumption is also made that δ is infinitesimally short so that negligible molecular displacements occur during the pulse period as compared with during the diffusion time, that is, δ Rt, left and right asymmetry; MDD, major depressive disorder; mI, myo-inositol; OC, occipital cortex; OCD, obsessive–compulsive disorder; OFC, orbitofrontal cortex; PCr, phosphocreatine; PDEs, phosphodiesters; PMEs, phosphomonoesters; PN, panic disorder; PTSD, posttraumatic stress disorder; SPR, schizophrenia; Temp, temporal cortex; Thal, thalamus.

TABLE 29.2 Structural Magnetic Resonance Imaging Findings in Individuals with Autism Spectrum Disorder

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Deficits in the theory of mind, which is important for understanding others and other social cognition skills, may be associated with mirror neuron system (MNS). Children with ASD showed no MNS activity when they imitate and observe emotional facial expressions of others (41). Language and Communication Language and communication impairments are common in individuals with ASD, especially in young children. Abnormal right-lateralized temporal cortex activities to language and reduced left hemisphere responses to speech sounds were observed in both children with ASD and children at risk for ASD under 4 years of age (42,43). In various language-related tasks including sentence comprehension, semantic judgments, verbal fluency, and language comprehension, children with ASD had decreased function in brain regions processing language and activated function in brain regions that are not typically related to language processing (44). Individuals with ASD depend on visualization for language processing, using different regions of the brain compared to healthy controls. Occipitoparietal and ventral temporal regions got activated in individuals with high-functioning autism, whereas frontal and temporal language regions got activated in controls during a pictorial reasoning paradigm (45). Parietal and occipital lobes were associated with imagery in comprehending imagery sentencing (46), and bilateral extrastriate visual cortex was related to visual imagery in semantic processing (47). These findings suggest that individuals with ASD rely more on visualization to support language comprehension than in healthy controls. Executive Function Deficits in executive functions, including inhibition and planning, may lead to behavioral control problems and repetitive symptoms frequently observed in individuals with ASD (48). Increased activation of the putamen and decreased activation of inferior parietal lobe (IPL) on the anti-saccade task, a measurement of inhibitory control, was shown in adolescents and adults with ASD (84), showing developmental differences of inhibitory control system related to the brain circuit. Reduced ACC reactivity during response inhibition tasks and weakened functional connectivity between inhibition network including ACC and the right middle and inferior frontal and right parietal regions were observed in adults with ASD compared to healthy controls, indicating atypical and less synchronized inhibition circuitry (85). Reduced connectivity between frontal and parietal areas were observed during the “Tower of London” task in adults with ASD, indicating possible association between abnormalities in integration of information and problems in executive functions (86). Neurochemistry 2034

MRS studies of ASD have generally measured metabolites including NAA, Cr, and Glx in various brain regions (87,88). Decreased NAA levels in the parietal regions and cerebellum were observed in individuals with ASD and in ACC for both adults and children with ASD, with lower values in adults than in children, indicating the age effects of metabolite levels and the regions (87). Decreased level of NAA indicates abnormalities in neurogenesis and in neuronal metabolites, bringing up the major symptoms of the disease (89). Both increase and decrease levels of Cr depending on the age and the brain regions were shown. Cr concentrations were more detected in the temporal lobes in adults, but were less detected in the occipital lobes in children with ASD (87). As Cr plays an important role in energy storage in the brain, abnormalities in Cr may lead to language problems or mental retardation (90). Decreased Glx levels in the basal ganglia were also observed in adults with ASD, which were also correlated with increased deficits in social communication, indicating an association between Glx transmission and social development (88). NAA and Cr levels were also reduced in this region in addition to in DLPFC (88). Attention-Deficit/Hyperactivity Disorder ADHD is one of the most common neurodevelopmental disorders, which affects 5% of children worldwide and 11% of children 4 to 17 years of age in the United States (5,91). The percentage of children diagnosed with ADHD continues to increase, which reflects the increasing awareness of the disorder (60,91). It is more commonly diagnosed in boys than in girls, and a significant number of children diagnosed with ADHD continue to experience the disorder as adults (61). The main symptoms include inattention, having difficulty organizing tasks or failing to pay close attention in details, or hyperactivity and impulsivity, talking excessively or having difficulty remaining steadily in appropriate situations (5). These characteristics of the disorder lead to various degrees of functional impairment in individuals, which may be associated with oppositional defiant disorder, learning disabilities, conduct disorder, depression, mood disorders, anxiety disorders, and substance use disorders (62,63). Structural Neuroimaging Studies using VBM aim to identify neuroanatomical correlates of ADHD. Several MRI findings have reported structural abnormalities in different areas of the brain in children and adults with ADHD. The most consistently reported abnormalities in individuals with ADHD include reduced volumes of the frontal lobes, basal ganglia, and cerebellum (64). Specifically in children with ADHD, studies have shown volume and GM reduction in the right globus pallidus, putamen, and bilateral caudate, implying less control of subconscious voluntary movements (65,66). GM deficits in the right-sided frontoparietal brain circuits and left DLPFC were also detected in children with ADHD, implying poor performance in executive function tasks, attention, and behavioral inhibition (67,68). Children with ADHD also have delay in cortical maturation, reaching peak of their brain development around 10 to 11 years of age, compared to typically developing children, reaching around 7 to 8 years of age (69). This may be linked to smaller total brain volumes in children with ADHD (67). Adult samples show greater changes in the ACC rather than in the basal ganglia, which might be related to symptoms of disorganization or regulation of the disorder (66). Reduction in the cerebellar volume, especially in the medial hemispheric zone observed in individuals with ADHD, was associated with motor, executive, and emotional functions (70). Diffusion tensor imaging (DTI) studies in ADHD children have consistently reported the WM abnormalities in the frontostriatal and frontocerebellar circuity (71).The disrupted WM was also found in adults with ADHD, including smaller FA values in the cingulum bundle and superior longitudinal fascicle II, compared to the healthy controls (72–74). Functional Neuroimaging Disrupted Inhibitory Control There have been a number of studies using fMRI to better understand the brain functional abnormalities associated with ADHD. Several studies have found reduced blood flow in the frontal regions and frontostriatal networks in children and adolescents with ADHD compared to healthy controls (75,92,93). Recently, Arnsten (94) also summarized the important role of the PFC in attention with a review of the PFC region in the primate brain with connection to striatum and cerebellum (Fig. 29.2). Depue and others (92) showed reduced activity in the right lateral prefrontal cortex (rLPFC) and the right inferior 2035

frontal gyrus (rIFG) during a cognitive control task performance (Think/No Think [TNT] task) in young adults with ADHD compared to controls, indicating decreased ability to inhibit motor responses. Dickstein and others (93) also found summative information of frontal hypoactivity in individuals with ADHD (the ACC, DLPFC, IPC, and other related regions including the thalamus, basal ganglia, and other parietal cortex portions), suggesting dysregulated neural activity within the frontostriatal and frontoparietal circuits. Furthermore, increased levels of deactivation in the ACC and parietal cortical structures were negatively correlated with symptom severity of ADHD, suggesting the association between symptom severity and frontal dysfunction.

FIGURE 29.2 Brain regions involved in the regulation of attention in the primate brain as shown on the lateral surface. The basal ganglia circuits are not evident from this view. The basal ganglia are believed to contribute to the automatic planning, selection, initiation, and execution of complex movements and thoughts.

Altered Functional Connectivity Moreover, numerous task-related fMRI studies other than cognitive control tasks have demonstrated the trends of deactivation in the frontal regions. Rubia and others (95) found that children with ADHD during a reward performance task exhibited hypoactivation and weakened functional interconnectivity in bilateral fronto-striato-parieto-cerebellar networks. Lower connectivity in the frontoparietal and fronto-striato-parieto-cerebellar networks was also observed in adolescents and adults with ADHD during interference inhibition and the simpler attention allocation tasks as compared to controls (96,97). In addition to task-related fMRI, resting-state fMRI (rs-fcMRI) has been the target of many studies with individuals with ADHD, measuring the connectivity and organization of neural circuits (Table 29.3). Functional connectivity studies have found reduced or absent functional connectivity within the default mode network (DMN) in individuals with ADHD compared to controls (98). Cao and others (99) revealed decreased inverse connectivity between the putamen and DMN regions, and Castellanos and others (100) found abnormally reduced connectivity within the DMN, the precuneus, posterior cingulate cortex (PCC), and the MPFC. Some individuals with ADHD had difficulties suppressing the DMN during a task-related mental process (101). TABLE 29.3 Resting State Functional Magnetic Resonance Imaging Findings in Individuals with Attention-Deficit/Hyperactivity Disorder

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Neurochemistry Previous MRS studies in individuals with ADHD have investigated the concentration of various metabolites, such as NAA, Cho, Glx, Cr, and Ins, especially in the striatum and frontal brain regions (112,113). One 1H MRS study in adults with ADHD revealed reduced Glx, Cr, NAA concentrations in the basal ganglia, suggesting the dysregulated attention, and lower concentration of Cr in the DLPFC, implying lessened executive control network (114). Similarly, changes of Cho were found in the left striatum and right frontal lobe in children with ADHD and in the left and right ACC in adults with ADHD (112). In addition, significant differences of Glx/Cr ratio in the right posterior cingulate (RPC) and Ins/Cr and NAA/Cr ratio in the right striatum were noticed in individuals with ADHD (115). Furthermore, below-normal levels of Cr, Cho, mI, and N-acetylaspartate + N-acetylaspartylglutamate (tNAA) were found in the MFG of children and adolescents with ADHD as compared to controls, indicating attentional or executive impairments (116,117). Mood Disorders 2037

MAJOR DEPRESSIVE DISORDER. MDD as one of the continuously growing leading reasons of disability in the world is characterized by persistent and pervasive low feelings associated with depression and inability to experience positive feelings from normally enjoyable activities, which can develop at any age (5,118). Symptoms include fatigues, guilty thoughts, sleeping problems, and eating problems. Affecting approximately 5% of the population, MDD is more commonly in women than in men with a younger age of onset (119,120). It is comorbid with anxiety disorders, eating disorders, and substance use disorders (120,121). Structural Neuroimaging Volume differences are most commonly shown in various brain regions related to the emotional experiences including hippocampus, basal ganglia, and OFC particularly in gyrus rectus in individuals with MDD (122). Reduced volumes of the right and left hippocampus were observed in the children, middle-aged, and older adults, but not in young adults with MDD (123). Decreased volume of the bilateral hippocampal tail, right hippocampal head, and whole right hippocampus were generally shown in adults with MDD (124). Individuals who suffer multiple depressive episodes and who have suicide attempts are more prone to smaller size of hippocampus, related to the stressful events, experiences, and the plasticity of hippocampus (125,126). Volumetric reduction of basal ganglia and frontal lobe including OFC and subgenual PFC were also observed in individuals with MDD, severity depending on the number of depressive episodes and the duration of illness (122,127). These affected regions crucial in memory, emotion, and executive function are, therefore, related to major symptoms of MDD. Individuals with MDD have also shown ventricular enlargements and increased rates of subcortical GM hyperintensities in addition to increased lesions in both subcortical and total WM hyperintensities (WMHs) especially with anger attacks (122,128). WMHs might have disrupted connections between cortical regions involved in emotion, mood regulation, and cognition that might have resulted in depressive moods. Recent DTI studies have suggested that there is a stronger association between MDD and reduced FA in various brain regions, emphasizing WM microstructural abnormalities (Table 29.4). Reduced FA was observed in both individuals with early life–onset depression and with late-life depression in the frontal and temporal lobes (129,130). The loss of frontal and temporal WM fiber tract integrity is, therefore, associated with abnormalities in neuroanatomical circuits related to MDD. Decreased FA was also found in various regions important in emotional regulation including internal capsules, striatum, cingulate cortex, and CC (129,131,132), indicating major emotional symptoms related to the disorder. Functional Neuroimaging Emotional Stimuli Impairments in distinguishing and processing facial expressions are commonly observed in individuals with MDD, affecting their interpersonal functioning (152). As ambiguous, and even positive actions tend to be perceived negatively in individuals with MDD, responses to happy and sad facial expressions, or negative and positive affective pictures were generally measured related to neural responses (153–155). Increased responses in putamen, parahippocampal gyrus, amygdala, and fusiform gyrus (FFG) related to increasing sadness were observed during the happy versus sad face tasks, indicating negative cognitions which might lead to poor social interactions in individuals with MDD (153). Enhanced responses in anterior cingulum, and right middle and superior frontal gyrus were additionally seen during the emotional expression tasks in individuals with MDD compared to healthy controls (154). Increased activation of the amygdala and hippocampus with negative stimuli and negative information processing were also shown in individuals with MDD (156). Reduced activation in the insula, temporal, and occipital cortices were shown during the emotional face tasks, and orbitofrontal area activation was associated with anxiety symptoms and severity of the disorder (155,157). Abnormal activation of these regions might be related to increased perception of negative or sad emotional stimuli, paying more attention to sad stimuli than to happy stimuli. MDD, therefore, might be due to the abnormal interactions between or among brain regions. Strengthened functional connectivity between the amygdala, hippocampus, and putamen regions, and decreased connectivity between the amygdala and prefrontal area were found during emotion processing, showing disconnectivity in limbic and frontal brain regions (72,158). As the neural circuit for mood regulation and emotion contains hippocampus, amygdala, basal ganglia, prefrontal cortex, and insula, impairments in these brain regions are strongly related to symptoms of MDD. 2038

Resting State Resting-state fMRI, not using a task, explains neural systems related to functional connectivity in individuals with MDD. Abnormalities in various regions including the cerebellum, thalamus, ACC, DLPFC, amygdala, and insula have been reported in individuals with MDD (159). Soares and Mann (32) proposed specific frontosubcortical circuits that regulate mood based on the findings in those with mood disorders (Fig. 29.3). A limbic–cortical model of depression has been also suggested (Fig. 29.4) (160,161). As cerebellum also plays a role in emotion regulation in addition to motor coordination, decreased regional homogeneities in the right insula and in the left cerebellum were observed in individuals with MDD in the resting state, suggesting pathophysiology of MDD (162). Decreased connectivity in pregenual ACC and dorsomedial thalamus were also observed in both individuals with MDD and with bipolar disorder, suggesting abnormalities in decreased connectivity (163). Increased functional connectivity between subgenual cingulate and thalamic was seen in individuals with MDD compared to healthy controls (164).

FIGURE 29.3 The main neuroanatomic circuits that have been proposed to participate in the pathophysiology of mood disorder.

TABLE 29.4 Diffusion Tensor Imaging Findings in Individuals with Major Depressive Disorder

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FIGURE 29.4 A limbic–cortical model of depression. It involves three compartments: a dorsal, a ventral, and a rostral compartment. dACC, dorsal anterior cingulate; rACC, rostral anterior cingulate. (Adapted and modified from Mayberg HS, Liotti M, Brannan SK, et al. Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry 1999;156:675–682.)(160)

Strengthened functional connectivity in the cognitive control network (CCN), DMN, and affective network (AN) has been identified in the dorsomedial prefrontal cortex (DMPFC) with individuals with MDD in the resting state (165,166). CCN, important in decision-making and conflict resolution; DMN, in planning, remembering, and evaluating; and AN, in emotional processing and regulation of fear and vigilance through connections with other regions, have influenced symptoms of the disorder. 2041

Neurochemistry MRS studies of MDD have generally measured metabolites including NAA, Cr, Cho, Glu, and Glx in various brain regions (167). Lower level of Glu concentrations were found in the ACC, and lower level of Glx in all brain regions in individuals with the current episode of depression (167). Decreased levels of Glu and Glx, which are important in brain function and development, in ACC, affecting various functions including emotional–motivational behaviors, cognitive functioning, and motor behaviors, therefore, affect depressive symptoms of MDD. Decreased level of gamma-aminobutyric acid (GABA) concentrations were observed in occipital cortex, DMPFC, and dorsal anterolateral PFC in individuals with MDD, and GABA levels in the ACC were negatively correlated with anhedonia, one of the major symptoms of MDD (168,169). In addition, lower NAA/Cr ratio was shown in both left and right WM prefrontal lobes in individuals with MDD, indicating abnormalities in neuronal viability (170). Changes in the levels of other metabolites in specific brain regions are represented in Figure 29.1 (171). Bipolar Disorder Bipolar disorder (BD) is a mood disorder characterized by emotional dysregulation associated with abnormal periods of depression and elevated mood, appearing in the late teenage or early adult years (5). Symptoms associated with periods of depression include loss of interests, sadness, hopelessness, anxiety, and suicidal thoughts or behaviors. During the periods of elevated mood, so-called mania or hypomania stages, depending on the changes in the activity, energy, and severity, the symptoms of euphoria, agitation, and poor judgments are observed (5). Moreover, BD individuals also undergo euthymia stage with stable unfluctuating mood (5). BD approximately affects 2.4% of the population, with high suicide rates (172,173). BD is comorbid with anxiety disorders, disruptive behavior disorders, and substance use disorders (174,175). Structural Neuroimaging Structural MRI studies in BD have suggested volumetric alterations in diffuse brain regions including the GM atrophy in the prefrontal cortex, limbic structure, and WM reductions (122,176). Reduced subgenual ACG volume, enlarged lateral ventricles, larger amygdala volumes, and smaller CC have been observed. First, reduced GM volumes in the frontal regions, mainly in ventral PFC, perigenual and subgenual ACG, and insular–inferior frontal cortices were commonly found in individuals with BD compared to healthy controls through a number of VBM meta-analyses (102,103). In addition, BD individuals have shown enlarged lateral ventricles and accelerated rates of GM hyperintensities in the subcortical regions (176). The limbic structures including the amygdala and CSP have been suggested as possible neural substrates for BD pathology. The studies on amygdala volume changes in BD individuals, involved in cognitive and emotional control, have not yet reached consensus. Even though children and adolescents with BD exhibited smaller left amygdala, the amygdala volume of BD adults was comparable to those with healthy controls (104). Enlarged lateral and putamen were distinctive morphologic abnormalities commonly found in those with BD. Abnormally enlarged CSP was associated with earlier onset of BD, and more of individuals with BD have shown abnormal enlargement (105). Dysfunctional expansion of CSP, important as a developmental marker, disrupts the early maturation process, possibly leading to the development of BD (105). Moreover, the cortical thickness and shape analyses in BD have revealed distinctive differences. Lyoo et al. (106) investigated the cortical thickness of diffuse brain regions in BD individuals and found reduced cortical thickness in the left cingulate cortex, bilateral middle frontal cortex, left middle occipital cortex, right medial frontal cortex, right angular cortex, right fusiform cortex, and bilateral postcentral cortices as compared to healthy controls. These regions are implicated in dysfunctions of cognitive, sensory, and emotional processing in individuals with BD (106). Hwang et al. (107) have also found out the shape differences in subcortical regions including the anterior regions of both caudates and the anterior and ventral surfaces of the striatum, prominently in the right side in BD individuals, associated with executive, visuospatial, and attention deficits, and slowed information processing. The bilateral vermi and right crus of posterior cerebellar regions, involved in processing emotion and connected to anterior limbic regions, were positively associated with longer duration of BD progress (108). Smaller CC observed in BD individuals implicates disrupted interhemispheric connections for BD pathophysiology (109). Abnormalities not only in volumes or structures, but also in WM connectivity were observed in BD individuals using DTI. Higher and lower FA values in different regions among individuals with BD were 2042

shown, showing WM abnormalities particularly in the frontolimbic circuitry, and the frontotemporal regions (110,111). Few studies have also suggested abnormalities of WM integrity in the frontal cerebral region related to the pathophysiology of BD. Longer the duration of illness and earlier the age of onset, lower the FA values and higher the MD in diverse brain regions (177,178). Higher FA values in the bilateral frontal WM and lower FA values in the left cerebellar WM were found in individuals with BD, showing different fibers and crossing tracts between BD individuals and healthy controls (179). Reduced FA values in the right uncinate fasciculus and increased values in the left uncinate fasciculus, left optic radiation, and right anterior thalamic radiation were also found, which suggest the asymmetry of WM tracts which connect prefrontal regions with limbic regions (177). Similar to adults, FA reductions in the superior frontal regions anterior corona radiata (ACR) that connects prefrontal regions and brainstem were observed in adolescents with BD (180,181). Functional Neuroimaging Emotional Processing Deficits The altered activation patterns of the OFC and amygdala, involved in emotional regulation, have been consistently suggested by the fMRI studies in BD. The amygdala activation patterns of BD individuals are mood dependent as compared with healthy controls. The OFC, involved in emotional integration and regulation, exhibited increased activity throughout the all stages, suggesting its role in mood fluctuations in BD individuals (181). Specifically, BD individuals have shown attenuated reactivity of the right OFC during emotional Stroop tasks and sad face processing tasks and DLPFC during other cognitive tasks, implying dysfunctional emotional processing due to impaired top-down control of limbic systems (182,183). Working Memory and Verbal Fluency Diminished activations of the right DLPFC and right parietal cortex have been found in BD individuals throughout all three stages, manic, euthymic, and depressed, when performing working memory tests including n-back tests, implying right frontal dysfunctions as possible neural substrates for working memory deficits in BD individuals (184). Diminished activity in euthymic individuals with BD was also observed in the hippocampus and parahippocampus when tested on working memory for both delay and recall (185,186). Moreover, increased IFG, DLPFC, and lingual gyrus activation during word-generation tasks were found in both euthymic and depressed BD individuals with variations depending on tasks (187). Resting State Weakened corticolimbic functional connectivity including the pregenual ACG, bilateral thalamus, amygdala, and left pallidostriatum during resting states was found in both manic and depressed BD individuals. This illustrates the difficulty of balancing cognitive and emotional functions with prefrontal and limbic regions even in the resting state (155). Similarly, reduced left VLPFC–left amygdala connectivity and strengthened left and right VLPFC connectivity including the ventral striatum and ACG were observed in manic, depressed, and euthymic individuals with BD (188). Neurochemistry Neurochemical alterations in NAA, Glu, Cr, and Cho concentrations were consistently found in MRS studies in BD associated with mitochondrial dysfunction as well as the abnormalities in neuronal and glial cells (Table 29.5) (Fig. 29.1) (33). Particularly, diminished NAA level in various brain regions including basal ganglia and caudate reflects mitochondrial function and neuronal metabolism, suggesting mitochondrial dysfunction related to the pathophysiology of BD (33,189). Heightened concentration of Glx suggests the increased need for energy, which may underlie sudden alternations of moods in BD individuals (190). Increased concentration of Glx could imply the increase of NAA related to the increase of Glu levels (191). Increased Glu level implies disturbed neuronal–glial interactions and altered glutamate–glutamine cycle, affecting Glx (192). In a comprehensive series of studies, Kato’s group clearly demonstrated that frontal lobe PME levels vary with mood states in BD individuals (Fig. 29.5) (193–196). TABLE 29.5 Magnetic Resonance Spectroscopy Findings in Individuals with Bipolar Disorder 2043

FIGURE 29.5 Magnetic resonance spectroscopy (MRS) measure as a function of mood state in bipolar I disorder. PME, phosphomonoester.

Anxiety Disorders SPECIFIC PHOBIA. Specific phobia (SP) is characterized by consistently heightened fear responses to 2044

any of various stimuli or situations. Those responses include fear, anxiety, and avoidance behavior. The degree of fear and anxiety is so unreasonable and excessive that a person’s daily living is interfered (5). The lifetime prevalence of SP is different depending on the types of phobia including phobias of animal, natural environment, situational, and blood-injection-injury (BII) ranging from 3.2% to 11.6% (206). The overall prevalence across types of phobia is higher among women than men (206). Structural Neuroimaging Several structural MRI studies have consistently found decreased volume of the amygdala and ACC and increased volume of the insula, cingulate cortex, and visual cortex in individuals with SP. One study compared the amygdala volume between individuals with spider phobia and healthy controls. It was found that the left amygdala volume of the spider phobia individuals compared to healthy controls was smaller, which is negatively correlated with the severity of spider phobic symptoms (133). In another study, the cortical thickness of the ACC was reduced among individuals with spider phobia compared to healthy controls (121). In addition, Rauch et al. (134) investigated the differences of cortical thickness between individuals with animal phobia and healthy volunteers. They reported greater cortical thickness of the insular bilateral cortex, bilateral pregenual anterior cingulum, bilateral PCC, and left visual cortex in the phobia group contrasting findings that individuals with animal phobia and healthy controls did not show difference in the thickness and volume of the insula imply difficulty to reach consistent results and possible limitations in the structural MRI studies (135). Functional Neuroimaging In order to find out the underlying mechanisms, various fMRI studies have investigated the changes in activation patterns of certain brain regions in response to specific cues possibly implying phobia (Table 29.6). Individuals with SP when confronted phobia-related stimuli showed enhanced activations of the amygdala, ACC, insula, and PFC compared to controls (136–142). Exaggerated Frontolimbic Fear Network Specifically, Lipka et al. (139) found that individuals with spider phobia showed abnormal hyperactivity of the bilateral amygdala in response to the stimuli of spiders compared to neutral targets during both supraliminal and subliminal conditions. This finding suggests that intense fear to spiders is present during both unconscious and conscious perception of spider-related stimuli, implying the dominance of exaggerated distress over consciousness and unconsciousness. The individuals with specific animal phobia (SAP) showed greater activation in the right rACC than controls in response to the phobiarelated cues compared to neutral words during emotional counting (ecStroop) task (140). Also, the strengthened functional connectivity between the rACC and left amygdala in response to phobia-related words relative to neutral words was noticed in the SAP group. In addition to these findings, elevated activations of the frontolimbic fear network (ACC, OFC, mPFC–amygdala, insula) illustrate that dysregulated conflict management and learning (ACC) and decision-making systems (OFC, mPFC) lead to abnormally exaggerated fear (amygdala, insula). With regard to dental phobias compared to controls, Hilbert and colleagues (136) also found the increased activity in the frontotemporal regions for auditory stimuli (the ACC, insula, thalamus, inferior frontal gyrus, hippocampus, precuneus, postcentral gyrus, and calcarine sulcus) and in the vermis for visual stimulus. Dysfunctional Cognitive System A number of fMRI studies have indicated attenuated activations of the frontal regions involved in cognitive control including the PFC and ACC, responsible for phobic provocation in those with phobias. Specifically, Killgore and colleagues (137) demonstrated the reduced activity in the vmPFC as well as the increased activity in the left amygdala in SP on a masked fear perception task. Hermann et al. (138) examined the association of habitual cognitive reappraisal usage in dental phobias with brain activation patterns during phobic compared to neutral stimuli provocation. The dmPFC activation was strongly reduced in frequent reappraisals in the phobia group. The dispositional cognitive reappraisal was also associated with the reduced activation of the vmPFC in the phobia group. Moreover, Hermann et al. (141) studied the brain structures of automatic emotion regulation deficits and the dysregulation of phobic compared to nonphobic emotional responses in those with spider phobias. Downregulation of emotional responses to phobic pictures resulted in diminished activation of the insula and the dACC in comparison with simply looking at the pictures. Also, downregulation of phobic emotional responses led 2045

to an increased regulation effort and reduced activation of the right rACC and the dmPFC compared to aversive emotional responses. Distinct Neural Mechanism for Each Phobia Type Neural responses to phobia-specific symptom provocation were also compared among subtypes of phobia (143,144). First, the potential differences of neural activation patterns between snake and dental phobias were examined (143). In response to phobogenic stimulus processing, anxiety-related brain regions (amygdala, insula, and ACC) were activated in snake phobias, while cognitive control-related regions (PFC, OFC) were stimulated in dental phobias (143). This result interestingly suggests that dysfunctional emotional and cognitive systems are responsible for snake and dental phobias, respectively. TABLE 29.6 Functional Magnetic Resonance Imaging Findings in Individuals with Specific Phobia

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Moreover, Caceras et al. (144) compared those with spider phobias and BII phobias, and controls. Individuals with spider phobia showed exaggerated activation in the dACC bilaterally, anterior insula, inferior frontal gyrus, visual cortex, and cerebellum compared to healthy controls and hyperactivations in the dACC and anterior insula compared to BII phobias, suggesting disrupted cognitive system in those with spider phobias (144). Additionally, reduced activation of the medial frontal gyrus extending posteriorly to the rACC was observed in those with spider phobias in comparison with both controls and BII phobias (144). The BII phobia group compared to controls and spider phobia groups exhibited increased activation in the bilateral occipitoparietal regions and the thalamus, suggesting the role of visual stimuli in fear conditioning of BII. Neurochemistry Few studies have investigated metabolic abnormalities possibly present in SP. Linares et al. (142) attempted to assess the alteration in NAA concentrations that could be associated with the high level of anxiety in SP. The research indicated that there were no metabolite alterations in the cingulate cortex in individuals with spider phobia and healthy controls. Panic Disorder Panic disorder (PD) has a lifetime prevalence of 4.7% to 5.1% and 12-month prevalence of 2.1% to 2.8% (145,146). It is characterized by recurrent sudden panic attacks, followed by at least 1 month of consistent worry about additional attacks, concern about the outcomes of the attacks, or maladaptive behavioral change brought by the attacks. The symptoms of panic attacks cover a variety of physical signs including accelerated heart rate, smothering, sweating, nausea, chest pain, depersonalization, and fear of losing control (5). An individual with PD will be put on a high risk of having a comorbid disorder including mood disorders or another anxiety disorder. Among these disorders, major depression tends to occur very commonly with PD, with an estimate of 35% to 40% (145). Structural Neuroimaging Using MRI, structural brain irregularities in PD have been speculated in the limbic structures (amygdala, ACC, hippocampus, and insula) and cortical and subcortical structures (frontal and temporal areas and basal ganglia) since the amygdala plays a key role in regulating fear and stress responses and has reciprocal interactions with the mPFC, hippocampus, and the temporal lobe. This is supported by a recent meta-analysis by Dresler et al. (147), indicating that PD individuals tended to show 2047

neuromorphologic abnormalities in the limbic systems, frontal and temporal lobes, basal ganglia, and brain stem. Del Casale et al. (148) also demonstrated that PD individuals showed smaller amygdala volume compared to healthy controls, decreased ACC volume along with increased FA, and volumetric changes in the hippocampus, parahippocampal gyrus, insula, and temporal lobes. Additionally, Lai (149) exhibited that individuals with PD had reduced GM volume in the right caudate head and right parahippocampal gyrus. GM volume deficits in the basal ganglia of individuals with PD and the negative interaction between putaminal GM volume and the severity of panic symptoms were also observed (150). Kim et al. (151) investigated the role of the amygdala in dealing with fear and anxiety, processed in relation with cortical and subcortical areas. The review demonstrated the amygdala volume reduction in PD individuals consistently reported through MRI studies. Hayano et al. (218) also showed that volumes of the bilateral amygdala were diminished in PD and that the volume of left amygdala was inversely correlated with the score for trait and state anxiety in PD individuals relative to healthy controls. Moreover, smaller GM volume in the insular cortex, right ACC, bilateral dmPFC, right vmPFC, as well as amygdala in individuals with PD was noticed compared to sex-matched healthy controls (219). Shinoura et al. (220) indicated that the damage to the right dACC was correlated with the development of PD in two individuals; one who experienced a panic attack during surgery and the other who had PD after the surgery and radiotherapy. It was revealed that they had diminished dACC size at 6 months after surgery and the absence of the dACC at 2 years after surgery. In addition, mood state evaluation showed that the common abnormal symptom in two individuals before and after surgery was tension– anxiety. Lai and Wu (221) observed first-episode, treatment-free, and very late-onset panic disorder individuals and found that they had smaller GM volumes in the left OFC, IFC, STG, and right insula, as compared to controls. With regard to DTI studies, the WM connectivity alterations in PD individuals were discovered in the ACC and PCC (222). The research indicated that individuals with PD had greater WM connectivity in the left ACC and right PCC relative to healthy controls, which also had a positive correlation with the severity of panic symptoms. Functional Neuroimaging Altered Functional Connectivity Heightened activity in the hippocampus and amygdala, and recently extended to the ACC, basal ganglia, and other cortical lobes in PD individuals, has been consistent by a number of fMRI studies. Restingstate functional connectivity studies have suggested abnormalities observed in the limbic network and salience network as a possible pathophysiology of PD. Shin et al. (223) indicated that individuals with PD had greater resting-state functional connectivity between the ACC and the precuneus relative to controls. Pannekoek and others (224) also demonstrated that PD individuals showed strengthened resting-state functional connectivity between the right amygdala and the bilateral precuneus, possibly leading to disturbance of self-processing activities related to symptoms of panic attacks such as depersonalization. Moreover, the dACC was irregularly connected with frontal, parietal, and occipital areas in individuals with PD. Neural Mechanisms Responsible for Panic Attacks In case studies of spontaneous panic attacks which are valuable to shed a light on neural substrates of human anxiety, Pfleiderer et al. (225) reported increased activation in the right amygdala, parahippocampal gyrus, and putamen in a PD individual during the last block of an auditory habituation paradigm. Another study indicated that heart rate of an individual with panic attacks was negatively correlated with activation in the left middle temporal gyrus (226). Moreover, amygdala and insula activity was positively correlated with heart rate when panic attacks began. Dresler and others (227) reported that an individual with PD had a decreased activity in PFC in response to emotional faces, suggesting damage on top-down control over limbic areas. Altered Amygdala Reactivity Sakai et al. (228) employed PET with 18F-fluorodeoxyglucose to assess cerebral glucose metabolism in PD individuals. Higher glucose utilization was found in the fear network including the amygdala, hippocampus, thalamus, and midbrain in PD individuals compared to controls while they did not experience panic attacks during scanning, which indicated the dispositional hyperactivity of the 2048

amygdala. In line with this, Wittmann et al. (229) provided the activation of fear circuit including the amygdala, insula, and hippocampus in PD individuals with agoraphobia during fMRI with anxietyinducing pictures. Even though there have been numerous studies emphasizing the hyperactivity of the amygdala, Pillay et al. (230) revealed that individuals with PD produced lower amygdala and cingulate cortex activity in response to fearful faces relative to controls. Also, Boshuisen et al. (231) demonstrated the hypoactivity in the right amygdala in PD individuals compared to controls during anticipatory anxiety by means of H215O PET scan. Neurochemistry Spectroscopic studies have reported neurochemical alterations in the hippocampus, ACC, basal ganglia, and visual cortex in relation to the development of panic attacks (Table 29.7) (Fig. 29.1) (171). In the hippocampus, the levels of NAA were lower in PD individuals relative to controls. Trzesniak et al. (232) supported using 1H MRSI that PD individuals compared to controls showed less NAA/Cr in the left hippocampus, suggesting impairment in neuronal integrity in the hippocampus which plays a role in inhibiting stress responses. Atmaca et al. (233) also demonstrated the lower levels of NAA, Cho, and Cr in the hippocampus in PD individuals compared to controls. With respect to the change in the ACC and basal ganglia, the levels of GABA which is the major inhibitory neurotransmitter were decreased in individuals with PD as opposed to controls (234). Long et al. (235) also showed that GABA relative to total creatine was lower in the ACC in PD group. Moreover, the GABA concentration of the ACC was negatively correlated with the functional connectivity between the ACC and precuneus (223). However, Hasler et al. (201) found no difference in GABA concentrations in the vmPFC or dorsomedial/dorsal anterolateral PFC including the ACC between unmedicated PD individuals and controls. In addition to the neurochemical changes in the fear network, Maddock et al. (246) observed greater brain lactate responses in occipital cortex in individuals with PD. The increase of brain lactate affects the brain acidity and acid-sensitive circuits involved in the fear-related processing, which may be related to panic attacks. A following study by Maddock et al. (247) also showed the exaggerated activitydependent brain lactate accumulation in primary visual cortex in both remitted and symptomatic PD individuals relative to healthy controls. Furthermore, since lactate responses to neuronal activity are considered to reflect glutamatergic function, there will be metabolic dysregulation of glutamate and glutamine (glx) in PD. Zwanzger and others (248) conducted experimental provocation of panic attacks elicited by CCK-4, revealing that PD individuals compared to controls had an increased level of brain Glx/Cr in the bilateral ACC. In contrast, Maddock and colleagues (247) demonstrated that PD groups had smaller activity-dependent alterations in Glx than controls, even though both groups showed Glx level increases in response to visual stimulation. TABLE 29.7 Magnetic Resonance Spectroscopy Findings in Individuals with Panic Disorder

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Obsessive–Compulsive Disorder OCD is characterized by whether obsessions and/or compulsions exist or not. Obsessions are marked by recurrent and persistent urges (e.g., to stab someone) and thoughts (e.g., of contamination) that distress a person during the disturbance. The person tried to avoid, suppress, or compensate for such urges and thoughts by doing another actions (e.g., performing a compulsion). Compulsions are defined by repetitive behaviors (e.g., checking, handwashing, ordering) in response to an obsession. A person feels strongly that the behavior must be done in order to end or reduce intense suffering from obsessions. For a diagnosis of OCD, obsessions and compulsions must take more than 1 hour per day or generate clinically significant distress and functional impairment in a society and workplace. The 12-month prevalence of OCD is 1.2% in the United States and 1.1% to 1.8% internationally (5). Structural Neuroimaging By employing DTI, a number of structural studies conducted in OCD have focused on microstructural network putatively implicated in the pathophysiology of the disorder (Table 29.8). The major site of the abnormal microstructure in OCD is speculated in the cortical-striatal-thalamic loop. According to the meta-analysis by Piras et al. (249), the alterations of WM integrity in the network were found in the cingulum and in the anterior and posterior limbs of the internal capsule, albeit inconsistent FA values. Fitzgerald et al. (250) provided the evidence of abnormal development of frontal-striatal-thalamic circuitry in pediatric OCD. The finding said that FA values in anterior CC, anterior cingulum bundle, and anterior limb of the internal capsule arouse related with age in young individuals with OCD compared to age-matched healthy controls. Fontenelle et al. (251) also supported the WM connectivity change in the posterior limb of the internal capsule and superior longitudinal fascicule in OCD individuals compared to controls. 2050

TABLE 29.8 Diffusion Tensor Imaging Findings in Individuals with Obsessive-Compulsive Disorder

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The alteration of diffusivity along the axon measured by axial diffusivity (AD) was detected in the cingulate WM in OCD compared to controls (271). Likewise, Jayarajan et al. (272) found increased AD in the superior and inferior longitudinal fascicule, cingulum, and internal capsule, and increased RD in the longitudinal and uncinate fascicule and anterior thalamic radiations, which is connected with an axonal loss or myelination decline. 2052

The microstructural changes of frontal–striatal circuitry in OCD were described along with the clinical variables. Fitzgerald et al. (250) found that OCD individuals showed the positive relationship of FA in anterior cingulum bundle with the OCD symptom severity after controlling for age, suggesting that the irregularities of WM in the region may exert an impact on the OCD symptom expression. Fontenelle et al. (251) reported the fiber directionality change within the internal capsule along with the symptom severity. Recently, not only the classic model of microstructural abnormalities in OCD discussed above, a more widespread circuitry also seems to be altered. Li et al. (273) discovered the difference in WM regions between OCD individuals and controls, resulting in WM microstructural abnormalities in the occipital and temporal areas as well as frontal regions and cingulum bundle in OCD. Meta-analysis by Peng et al. (274) demonstrated a reduced FA in the cingulum bundles, inferior fronto-occipital fasciculus (IFOF) and SLF, and increased FA in the left uncinate fasciculus. Furthermore, OCD individuals exhibited increased MD in the left dorsal anterior cingulate, insula, thalamus, and parahippocampal gyrus (275). They also had decreased FA in the left SLF and the CC (275). Koch et al. (276) observed the irregular microstructure related with symptom severity in OCD. The decreased FA in the visual processing tract (right interior FOF and the right optic radiation) was correlated with ordering symptom severity. The lower value of FA in the CC and cingulate bundle was related with obsessing symptom severity. Lazaro et al. (277) compared young OCD individuals with healthy controls, finding that OCD individuals with the harm/checking dimension had the decreased FA in the CC and in the left anterior cingulate gyrus and caudate nucleus. OCD individuals with predominant contamination/washing dimension showed the decreased FA in the left midbrain, lentiform nucleus, insula, and thalamus. Functional Neuroimaging Cognitive Inflexibility Various studies in OCD have consistently suggested the dysregulation in the “frontostriatal network” as the neural correlates, which contribute to the pathology of OCD. The frontostriatal brain circuits, which are involved in conflict management, self-regulation, serial processing, have been focused in many tasks of fMRI studies. Based on these observations, the models explaining the pathophysiology of OCD have been developed (Fig. 29.6) (278,279). Specifically, OCD individuals when asked to perform conflicting stimuli in Simon Spatial Incompatibility tasks showed hyperactivated right hemisphere including the inferior frontal gyrus, insula, and putamen, more stressed in those with severe doubt or checking problems (280). These activation patterns and increased putamen- other frontostriatal regions functional connectivity were observed when switching between congruent and incongruent stimuli, implicating cognitive inflexibility, deficient self-regulation, and conflict resolution deficits in OCD individuals (280). In addition, hyperactive striatal–cortical connections (caudate nucleus–precentral gyrus/middle cingulate cortex) and other striatal abnormalities illustrate failure to monitor error and inhibit responses, leading to stereotyped and compulsive behaviors in OCD individuals (281,282). Hypoactive cingulate cortex and basal ganglia while asked for inhibitory tasks were in line with the finding that symptom severity was positively associated with diminished activation in the left caudate and ACC and hyperactive corticocerebellar regions for those with checking and washing symptoms, respectively (282,283).

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FIGURE 29.6 Model of obsessive–compulsive disorder (OCD) pathophysiology: imbalance of direct greater than indirect pathway “tone.” OCD symptomatology may be the result of a “captured” signal in the direct orbitofrontal– subcortical pathway, a positive feedback loop. Excess tone in the direct relative to the indirect basal ganglia pathway may allow obsessive concerns and their attendant compulsive behaviors to rivet attention to themselves and result in an inability to switch to other behavior. Red arrows denote positive influence of one brain area on the other and blue arrows denote negative influence. GPi, globus pallidus interna; SNR, substantia nigra, pars reticulate.

Planning Dysregulation Moreover, frontal–striatal network dysfunction may support planning deficits observed in OCD individuals. As OCD individuals exhibited decreased dorsal frontal–striatal activation and increased limbic and ventral frontal–striatal activity, problems in planning occurred along with lower Tower of London performance (284). As abnormal activation patterns of the DLPFC in OCD individuals have been explored, so-called “the dorsolateral prefrontostriatal circuit” have been defined and proposed (285). When OCD individuals face the situations of symptom provocations including the need to check or clean, abnormal patterns of the DLPFC, VLPFC, and IFG were noticed in OCD individuals, implying abnormalities in attentional set-shifting, response inhibition, and decision-making among OCD individuals (103,286). In addition, reduced connectivity within the limbic regions including the amygdala and hippocampus were found in individuals with OCD as compared to healthy controls, suggesting neurocognitive deficits in expectation and implicit learning (287). Deficit Fear Extinction Weakened connections between the limbic regions and executive/attention network and increased connectivity within the executive network may underlie why OCD individuals cannot properly deal with intrusive thoughts of uncertainty and threat (287). Reduced connectivity in executive or attention network and DMN, leading to excessively checking thoughts, was positively correlated with OCD symptom severity (287,288). Also, disconnected limbic–default mode networks (amygdala– frontoparietal regions) and abnormally hyperactive lateral OFC and medial PFC illustrate dysfunctions in reevaluating potentially intrusive or threatening thoughts in individuals with OCD (281,288). In addition, decreased connectivity between the limbic regions and basal ganglia network and reduced connectivity within the limbic network implies disrupted emotional processing and disrupted judgment of reward and punishment (288). Nevertheless, negative associations between fear extinction deficiency and Yale–Brown obsessive compulsive scale scores suggested other pathologic factors, in addition to deficient fear extinction (289). Decreased activity in the vmPFC during training extinction recalls, in the hippocampus and caudate during fear conditioning, and putamen, cerebellum, and posterior cingulate while extinction recall were found in those with OCD, associated with greater symptom severity (289). Neurochemistry MRS studies have shown various abnormalities of metabolites including NAA, Cho, and Cr in different brain regions in children, adolescents, and adults with OCD (Fig. 29.1) (171,290). Higher levels of Cho and NAA were found in right prefrontal WM in children and adolescents with OCD, and increased right prefrontal WM levels of NAA, Cr, and mI were also positively correlated with severity of OCD symptoms (290). Separately working cortico-subcortical loops in OCD brain, resulting in cognitive processing deficits in OCD, play an important part in asymmetric differences in right and left prefrontal WM results (291). As NAA and Cho are also important in neuronal integrity and myelination processes, increased levels of these metabolite indicate abnormalities in basic process in the brain related to symptoms of the disorder (290). In adults with OCD, lower NAA levels in the frontal cortex and NAA/Cr ratio in the ACC were observed, indicating biochemical involvement of the frontal area in the pathophysiology of OCD (197,292). Positive correlation between NAA reduction and symptom severity of OCD also indicates neurochemical alteration in those areas directly related to abnormal behavior of OCD (292). Trauma- and Stressor-Related Disorders POSTTRAUMATIC STRESS DISORDER. Posttraumatic stress disorder (PTSD) is triggered by exposure to negative experiences including sexual violation, serious injury, or death. Individuals will develop PTSD by witnessing traumatic events in person, learning that traumatic events occurred to close people, or being extremely exposed to aversive aspects of the events not through media, pictures, or movies. Four diagnostic categories of behavioral symptoms of PTSD are described in DSM-V such as re2054

experiencing (recurrent memories of the traumatic event and nightmares about the event or flashbacks), negative thoughts and mood (persistent guilt and blame for others numbing and loss of interest in activities, impaired memories of the events), arousal (aggressive behaviors and hypervigilance), and avoidance (avoiding thoughts or feelings about the trauma, or reminders of the trauma) (5). PTSD is associated with high rates of comorbidity and suicides. The prevalence estimate has been reported at 0.5% among men and 1.2% among women. Arnberg et al. (198) investigated the prevalence of PTSD in survivors 6 years after the natural disaster. The point prevalence of PTSD was 4.2% and the incidence of PTSD during 6 years was 11.3% (198). Also, the study showed that the high rates of suicidal ideation were related to PTSD after the event from 14 months to 6 years (198). Structural Neuroimaging It has been well known that the structural brain alterations of PTSD are found in the amygdala, hippocampus, and MPFC albeit those findings are somewhat inconsistent (Table 29.9). Morey et al. (199) investigated decreased amygdala volume in a large cohort of combat veterans with PTSD compared to combat-exposed veterans without PTSD. In a study using voxel-based and surface-based morphometry, PTSD veterans with mild traumatic brain injury showed reduced amygdala volume which is the predictor of poor performance on inhibitory tasks, increased impulsivity, and more severe PTSD symptoms (200). Diminished amygdala volumes in police officers were also related to higher arousal responses to negative pictures and higher re-experiencing scores (202). In contrast, Kuo et al. (203) indicated enlarged amygdala volumes in military veterans with PTSD compared to combat-exposed veterans without PTSD. Moreover, Woon and Hedges (204) demonstrated that there were no volumetric differences in bilateral amygdala in individuals with PTSD compared to both nontraumatized controls and trauma-exposed controls without PTSD. This suggests that a traumatic event alone may not predict a volume change in the amygdala. Numerous structural studies in individuals with either trauma experience or PTSD have consistently reported reduced hippocampus volume. Zhang et al. (205) showed the smaller bilateral hippocampi GM volumes in individuals with gas explosion–related PTSD compared to controls. In addition, the volumetric reduction of the hippocampus observed in PTSD individuals including police officers compared to trauma-exposed individuals without PTSD illustrate overgeneralization of negative context and difficulty differentiating negative from novel conditions, which may account for re-experiencing symptoms in individuals with PTSD (202,302,303). A meta-analysis also showed smaller right hippocampus in chronic combat-related PTSD individuals than in the trauma-exposed individuals without PTSD (304). Interestingly, the other meta-analysis of structural brain alterations in PTSD revealed that smaller volumes in the bilateral hippocampi were associated with trauma-exposed groups regardless of PTSD diagnosis relative to controls unexposed to trauma (305). This suggests that the hippocampal volume reduction may be a result of trauma, not a risk factor of PTSD. It remains controversial whether smaller hippocampal volume in PTSD is dependent on other comorbidities, current and lifetime PTSD history, or duration. In a study accounting for alcoholism which is regarded as one of main comorbidities, Hedges and Woon (306) demonstrated that PTSD individuals with no lifetime history of alcoholism had bilateral hippocampal volume reduction compared to controls, suggesting that the hippocampal volume deficits in PTSD may be independent of alcoholrelated problems. Some studies also indicated that the smaller right hippocampal volume is related to current and lifetime PTSD and longer PTSD duration (307,308). On the other hand, Apfel et al. (309) found that volumetric reduction in the hippocampus appeared only to individuals with current PTSD symptoms, not lifetime PTSD symptoms, suggesting the plasticity of hippocampus volume depending on PTSD symptom severity. Nevertheless, some studies failed to replicate hippocampal volume deficits but newly found the alterations in the frontal regions related to PTSD. No differences in hippocampal volume were noticed between highly traumatized refugees without comorbidities such as alcohol or substance abuse and veterans with and without PTSD (207,208). Structural studies have shown that individuals with general PTSD, urban violence victims, and victims exposed to urban violence during adulthood exhibited diminished volume of the mPFC, perigenual ACC, and right rACC, respectively, compared to both trauma-exposed individuals without PTSD and nontraumatized individuals (209–211). Moreover, Lyoo et al. (212) indicated that disaster survivors with PTSD in comparison with controls exhibited greater cortical thickness in DLPFC at 1.42 years and normalized thickness with recovery. Greater DLPFC thickness was suggested to play a key role in recovery from PTSD (212).

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TABLE 29.9 Structural Magnetic Resonance Imaging Findings in Individuals with Posttraumatic Stress Disorder

DTI studies have found reduced FA in the frontal regions and tracts in PTSD individuals. Specifically, veterans with PTSD exhibited the inverse relationship between FA in the right ACR and PTSD severity (213). In addition, veterans with PTSD showed reduced WM integrity along with low FA values in the prefrontal regions including the ACC and PFC (214). PTSD survivors from a severe coal mine accident exhibited FA reduction in the right anterior cingulate gyrus compared to generalized anxiety disorder survivors with the accident, indicating the specific role of the ACC in the pathophysiology of PTSD (215). Asymmetrical abnormalities of the cingulum were found in DTI studies in PTSD individuals. A metaanalysis revealed that individuals with adult-onset PTSD individuals showed reductions in the leftlateralized posterior part and bilateral anterior parts of the cingulum (216). The WM tract integrity in PTSD individuals showed disrupted WM tract integrity not in the right section but in the left section of rostral, subgenual, and dorsal cingulum bundle as opposed to controls (217). These left-lateralized alterations may be related to the verbal or nonverbal memory function in PTSD. Functional Neuroimaging Dysregulated Emotional Processing in Neutral Stimuli Numerous fMRI studies in PTSD have shown alterations in regional activation patterns and disrupted functional connectivity. Disaster survivors with PTSD exhibited reduced rACC functioning during an emotional processing interference and trauma-unrelated emotional conflicts as compared to healthy controls and trauma-exposed non-PTSD individuals, respectively (310,311). rACC activation was 2056

negatively associated with greater PTSD symptom severity and re-experiencing symptom severity in PTSD individuals (310,311). Additionally, it has been suggested that an amygdala–locus coeruleus– anterior cingulate circuit may be associated with chronic noradrenergic activation in PTSD individuals (Fig. 29.7) (312). The efferent noradrenergic projections from the locus coeruleus would cause the failure of anterior cingulate function (312). These results suggest that less rACC function in PTSD may show a general abnormality in emotional processing even in response to trauma-unrelated stimuli.

FIGURE 29.7 The anterior cingulate “brake” for gating external stimuli or extinguishing internal ones. Reduced anterior cingulate function would facilitate both the external and internal pathways. Chronic, exaggerated noradrenergic activity in posttraumatic stress disorder (PTSD) as mediated by efferent projections from the locus coeruleus may dampen the anterior cingulate. Thus, kindling of this amygdale–locus coeruleus–anterior cingulate loop would allow a myriad of externally or internally driven stimuli to facilitate the dysfunctional behavior responses characteristic of PTSD. (Reprinted with permission from Hamner MB, Lorberbaum JP, George MS. Potential role of the anterior cingulate cortex in PTSD: review and hypothesis. Depress Anxiety 1999;9:1–14.) (312)

Hyperactive Control System in Response to Trauma-Related Stimuli Distinctive regions of activation in PTSD individuals relative to healthy controls have been suggested as the right ACC, right PCC, and left precuneus, which was activated during trauma-script imagery and involved in conflict management and memory retrieval regulation to consciously suppress painful visuospatial episodes (313). Similarly, PTSD participants rather than healthy controls showed neural activity in the midline retrosplenial cortex and precuneus and enhanced activation of the pregenual and anterior cingulate gyrus and bilateral amygdala when confronted with trauma-related stimuli in comparison to neutral stimuli (314). Bruce et al. (315) examined that using an attentional distracting task, women with interpersonal trauma-related PTSD relatively showed hyperactive amygdala and insula as well as dorsal lateral and ventral PFC compared to controls. Inhibitory Deficits Dysfunctions in inhibitory control system and attenuated network have been observed in PTSD individuals during cognitive control tasks. Individuals with PTSD as compared to healthy controls showed reduced activation of the vmPFC and dorsal ACC during No Go stimuli requiring conflict management in a Go/No Go task, indicating impaired inhibition of fear (316,317). Additionally, weakened PTSD symptom severity was related to heightened activation of the mPFC during inhibitory control task (317). Weakened Frontolimbic Connectivity Functional hypoconnectivity between the amygdala and vmPFC has been suggested as responsible for exaggerated right amygdala responses in response to fearful compared to neutral faces in highly traumatized women with PTSD (318). In line with this, Cisler et al. (319) demonstrated that the frontocingulate network during emotion processing (fearful versus neutral facial expression images) was greatly activated in response to trauma-related stimuli such as assaultive violence. Within this network, the reduced functional connectivity between the left amygdala and the perigenual ACC was related to PTSD severity among the assaulted group, underlying impaired ability to control emotional responses (319). Neurochemistry 2057

The hippocampus, involved in the biologic response to stress, has been targeted in many studies using H-MRS to find the neuronal abnormalities in PTSD (Fig. 29.1) (171). Li et al. (320) demonstrated that fire accident victims with recent-onset PTSD exhibited the reduced ratio of NAA and Cr in the left hippocampus relative to the accident victims without PTSD, but not in the right side of the hippocampus. Schuff and others (321) also supported that PTSD was associated with reduced ratio of NAA to Cr in the hippocampus independent of hippocampal volume deficits. Compared to healthy controls, survivors with PTSD showed decreased NAA levels in the ACC and bilateral hippocampus and also correlated with re-experiencing symptom in survivors with PTSD (322). This finding suggests that weakened neuronal viabilities in the ACC and bilateral hippocampus may underlie the pathophysiology of PTSD. Moreover, PTSD individuals had decreased NAA and glutamate concentrations in the ACC and Cho concentration reductions in left hippocampus as compared to trauma-unexposed and traumaexposed non-PTSD groups (321,323). Meyerhoff and others (238) revealed that the concentrations of glutamate as well as NAA in the ACC were negatively correlated with arousal scores. Personality Disorders Personality disorders are relatively common psychiatric disorders, characterized by maladaptive and inflexible personality traits. These traits are so dysfunctional compared to culturally accepted and expected range, causing subjective stress and impairments in occupational and social functioning (5). Approximately between 10% and 13% of the general population are affected by personality disorders although cultural variations clearly exist (324). Borderline Personality Disorder Borderline personality disorder (BPD) is a relatively common psychiatric disorder with a lifetime prevalence of 5.9% along with no significant difference between men (5.6%) and women (6.2%) (325). This disorder is characterized by a serious dysregulation of affect, interpersonal relationships, behavioral control, and self-identity (5). Thus, individuals diagnosed with BPD tend to be impulsive, antagonistic, and emotionally insecure due to impairments in disinhibition, theory-of-mind, and emotional control, and these symptoms eventually lead to disrupted activities of daily living (5). As BDP individuals experience severe functional disruptions such as a high suicide rate of 10%, a substantial amount of treatment and mental health resources for a large subset of psychiatric inpatients and outpatients have been necessitated in our society (5,326). Structural Neuroimaging The recent progression of VBM has allowed an unbiased investigation of whole-brainwise structural properties rather than selected regions-of-interest approach. The application of VBM analysis explored diverse brain regions and newly found their correlations with specific BPD symptoms. Individuals with BPD compared to healthy controls showed GM atrophy in the bilateral fronto-temporal-limbic regions, associated with mood dysregulation, aggression, and impulsivity (327–329). GM abnormalities in the ACC and DLPFC of BPD individuals were associated with impulsivity and suicidality (198,330). One study found larger third ventricle, shorter adhesio interthalamica, negative correlations between the right anterior insular volume and impulsivity score in teenagers with first-presentation BPD as compared to controls (236,331). Recent meta-analyses reported diminished GM volumes in the bilateral amygdala (13%) and hippocampus (11%) (237). Interestingly, neither comorbid psychopathology such as depression, substance use disorders, and PTSD nor treatment experience with psychotropic medications was associated with these volumetric changes of GM. Thus, smaller volume of these key limbic structures was once suggested as “candidate endophenotypes” for BPD (237). Studies on structural WM integrity in BPD have implied that a large-scale network of emotion processing is disrupted in individuals with BPD. Maier-Hein et al. (239) investigated BPD-specific WM alterations in association bundles interconnecting the heteromodal association cortex and in connections between the hippocampus and thalamus, which is involved in emotion recognition and regulation, respectively. Disrupted WM tracts in the anterior parts of corpus callosum, OFC, and PFC explain modulated behaviors and emotions through impulse control and information processing in BPD individuals (240). Moreover, disrupted WM tracts in ILF, unicate, and occipitofrontal fascicule of BPD adolescents possibly can be regarded as a neural substrate for the disconnection in OFC–amygdala tract in adults with BPD and a biologic marker to identify those at risk (241). Specifically, disrupted integrity of the inferior frontal WM circuits was associated with heightened impulsivity and affect dysregulation 2058

(242). Functional Neuroimaging Consistently, a number of fMRI studies have found altered activation patterns of brain regions responsible for affect dysregulation, self-injurious behavior (SIB), and disrupted pain processing and, interpersonal disturbances observed in BPD individuals (Table 29.10). TABLE 29.10 Functional Magnetic Resonance Imaging Findings in Individuals with Borderline Personality Disorder

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Affective Dysregulation Dysfunction of the emotional system is a clinical hallmark of BPD, related to various affective symptoms including profound emotional vulnerability, strong emotional reactions, heightened sensitivity to negative emotional stimuli, and a slow return to baseline emotional state (325). Previous fMRI studies have suggested disturbed frontolimbic neural circuitry as an underlying neural substrate responsible for BPD pathology. Attenuated function of the PFC including the DLPFC and OFC to regulate limbic functions leads to greater emotional reactivity and improper regulation of negative emotions (243–245). Specifically, the modified network has been believed as enhanced activation of the amygdala and insula confronted with emotion-related stimuli, lower frontolimbic connectivity (amygdala–mid-cingulate cortex) in response to neutral stimuli, and depressed ACC, vmPFC, and medial orbitofrontal cortex (mOFC) (252–255). This neural mechanism illustrates why BPD individuals are hypersensitive to social threats without proper inhibition of negative emotion and impulsive with decreased constraint. Self-Injurious Behavior and Disrupted Pain Processing SIBs such as cutting or burning occur in between 70% and 80% of BPD individuals (256). They experience an immediate emotional relief, elevated moods, and reduced dissociative symptoms by performing SIB (257). Increased activation of the mPFC and DLPFC regulates hyperresponsive subcortical limbic network, abnormally enhanced activation of the amygdala and insula (256). SIB can be regarded as an inappropriate strategy to control negative emotions related to psychological and social pain by increasing top-down regulation of the limbic regions through anterior brain regions. BPDs as compared to controls express reduced pain sensitivity with higher pain thresholds. Increased activation of the PFC along with deactivation of the ACC and limbic system was observed among the BPDs in response to pain (258). Interestingly, significant alterations in DMN (attenuated signal of DMN and weak connectivity between PCC and left DLPFC in response to pain) were suggested as a neural 2060

mechanism underlying difficulty to control emotions, concentrate one task at a time, and shift attention between tasks among BPD individuals (259). During pain perception, BPD individuals compared to controls had attenuated activation of the ACC and OFC during pain perception and while listening to personal situations of childhood abuse, implying dysfunctional ability to inhibit the elicited emotions and suppress irrelevant sensory information (256). Interpersonal Disturbances BPD individuals, who are known to be afraid of social and interpersonal rejection, express intense emotional arousal, and this dysfunctional behavior which causes reactions in interpersonal situations reinforces the apprehensions. Several fMRI studies have found the tendency of BPD individuals to interpret neutral situations more negatively and to exhibit impairment in basic emotional regulation (260–262). During exclusion, inclusion, and control conditions in a virtual ball-tossing game, BPD individuals had a stronger activation of the dorsolateral anterior cingulated cortex (dlACG) and mPFC, indicating a bias to interpret ambiguous situations as intentionally negative (260). Enhanced ACC activation of BPD individuals when telling monadic (being alone) rather than dyadic stories (interaction) also implies that BPD individuals tend to be intolerant of being alone and hypersensitive to the social environment (261). In addition, the insula activation of BPD individuals only correlated with the input not the output in a trust game. In other words, BPD individuals did not engage in repair behaviors such as providing more money to regain trust and cooperation. This finding illustrates the disturbed perception of social gestures in BPD individuals (262). Neurochemistry Previous MRS studies have investigated the concentrations of NAA, Cr, and Glu in brain regions in order to relate neurochemistry and symptoms of BPD individuals (244,263). Diminished NAA and Cr concentrations in the left amygdala indicate disrupted affect regulation and emotional information processing of BPD individuals (263). Correlations between increased left amygdalar Cr and reduced amygdalar volume, diminished absolute NAA concentrations in the DLPFC, heightened glutamate concentration in the ACGs support hypometabolism, low neuronal density, and neurodegeneration of BPD individuals (244). Antisocial Personality Disorder Antisocial personality disorder (APD) is a heterogeneous personality disorder influenced by various genetic and environmental factors and is characterized by negative affectivity and detachment (5). High comorbidity with substance use disorders and mood disorders and relationships with criminal and delinquent behaviors illustrate why investigating the clear etiology of APD has faced difficulties (264). According to recent epidemiologic studies, APD affects between 2% and 3% of the general population (3% in men and 1% in women) and higher percentages of the prisoners (47% in male prisoners and 21% in female prisoners) (265). The focus of APD diagnostic criteria changed from observable behaviors in DSM-4 such as repeated lying, disregarding and mistreating others, assaults, and other criminal behaviors to pathologic personality traits in DSM-5 including callousness, hostility, deceitfulness, impulsivity, and irresponsibility (5). Structural Neuroimaging Unfortunately given the heterogeneity, studies on APD have shown inconsistent structural variations across diverse brain regions. First, both enlarged and reduced volume of the amygdala and its deformation all have been suggested by studies in APD. Individuals with APD showed smaller amygdala volume and deformation (primarily in basolateral, lateral, cortical, and central nuclei), which is related to worse affective and interpersonal problems among APD individuals (266,267). In contrast, Boccardi et al. (268) found smaller basolateral (a region connected to the OFC) but greater central and lateral nuclei of the amygdala (a threat circuit involved in fear conditioning). Although these findings might be confounded by comorbidity with substance abuse, these volumetric alteration patterns depending on amygdala subregions suggest dysfunctional frontal–limbic circuitry, implying disrupted bottom-up (emotional system) and top-down systems (control system) (268). Moreover, several studies have suggested compromised medial frontal system and association areas as biologic underpinnings responsible for aggressiveness and impulsivity observed in APD individuals. Significant differences in GM volumes of the OFC and PFC between men and women illustrate higher 2061

prevalence and increased vulnerability of APD pathology to males than those of females (269). GM atrophy, laminar abnormalities, and cortical thinning in the PFC, OFC, and surrounding association areas including Brodmann’s areas (BA) 10, 11, 12, and 32 were associated with more severe aggressiveness, callousness, and impulsivity of APD individuals (267,268,270,339,340). However, some suggest that substance disorders and duration of alcohol consumption better explain these GM reductions in the DLPFC, OFC, and mPFC rather than trait psychopathology such as impulsivity and callousness (341,342). Furthermore, some altered volumes of the CC and posterior brain regions have implied that APD is related to neurodevelopmental dysfunction, brought by disruptions of axonal pruning and brain maturation processes (343,344). Smaller posterior hippocampus, abnormal morphology of the hippocampus, and greater striatum indicate that APD is related to difficulty learning socially and morally appropriate behaviors such as respecting others and others’ rights (345,346). In addition, positive associations between the length of cavum septum pellucidum (CSP) and higher psychopathy scores support that CSP, indicating fetal maldevelopment of limbic and septal structures, can be regarded as a predisposed biologic marker for antisocial behaviors such as deception and hostility (346). Studies on WM integrity changes in APD have implied interhemispheric and frontolimbic disconnectivity as neural correlates responsible for impaired mental flexibility in APD individuals. DTI studies have shown dysfunctional structural connectivity and integrity of the right UF, IFOF, anterior corona radiate, and CC in APD individuals, implying WM microstructural irregularities in the frontal regions (347). Reduced structural OFC/UF–amygdala connectivity illustrates that imbalance between cognitive and instinctive systems leads to mental inflexibility and disinhibition in APD individuals (348). Functional Neuroimaging Abnormal activity patterns throughout the whole brain regions including all four lobes of the cortex and numerous subcortical structures in APD individuals, in fact, can be seen as context dependent. The selection of task and stimuli in each study influences functional activation pattern, which can be either deactivation or hyperactivation even in the same brain region (Table 29.11) (345). Disrupted Amygdala-Dependent Learning Greater fluctuations in amygdala activation patterns depending on each type of stimuli in APD individuals compared to controls reveal dysregulated amygdala-dependent learning. Specifically, exaggerated amygdala responses while viewing emotionally salient scenes such as fearful faces and socially threatening situations were related to higher psychopathy scores, lower negative emotionality, and delayed responses in a picture–memory task regardless of working memory load in APD individuals (253,349). In contrast, the amygdala reactivity was attenuated during memorizing emotionality salient words, moral decision-making tasks, fear conditioning, and social cooperation tasks in APD individuals (353–356). The interpretation that memory interference was facilitated not by extensive memory load but by highly emotional stimuli implies that fluctuating amgydala sensitivity disrupts amygdala-related stimulus reinforcement learning. APD individuals cannot correctly interpret emotional stimuli and remember their reactions from the previous encountered social situations. APD individuals not only exhibit imbalanced emotional system, which represented as deceitfulness, callousness, and antagonism, but also cannot remember and learn the socially and morally appropriate situations from the previous experiences. In other words, APD individuals have difficulty understanding others with empathy and intimacy, and hardly differentiate morally and socially right situations from the wrong one. TABLE 29.11 Functional Magnetic Resonance Imaging Findings in Individuals with Antisocial Personality Disorder

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Impaired Prefrontal Cortex-Related Representation It has been consistently suggested that APD individuals have different neural mechanisms underlying cognitive control (264). Typically, the inhibitory frontal systems—the OFC and PFC—need more activation when violating moral standards and being antagonistic to others (357). However, APD individuals with high psychopathy scores showed diminished low-frequency fluctuations in the right OFC (in the DMN), reduced OFC activation (when choosing to cooperate in a prisoner’s dilemma game), and reduced DLPFC and rACC activation (when choosing to defect in the game), indicating antagonism —a bias toward defection in APD individuals (350,354). In addition, APD individuals showed weaker activation of the mPFC in response pictures describing moral violations and retaliation and of the DPFC and ACC when lying compared to truth-telling (293,294). Schiffer et al. (341) revealed that offenders with APD had decreased time interference and different activity patterns in the ACC, DLPFC, temporal cortices, putamen, amygdala, and thalamus when asked to perform nonverbal Stroop task requiring inhibition. These different activation patterns in the regions participating in emotional processing, cognitive control, language, and attention were associated with attentional impulsivity in APD individuals (341). Likewise normally, Stroop task, lying, selecting not to cooperate, and revenge activate the ACC, OFC, DLPFC, and mPFC because these situations violating moral and social norms, require more inhibitory control. Weakened activation of these regions even in the situations necessary for stronger cognitive control implies either differently set moral standards or dysfunctions of conflict management, emotional control, and mental flexibility in APD individuals. Neurochemistry Even though MRS studies in APD have not been active, one study has investigated the NAA/Cr concentrations in the ACC among Turkish individuals with APD (295). As male participants with APD have higher psychopathy overall scores especially in the affective and interpersonal domains, greater rates of violent crimes and conviction and lower NAA/Cr ratio in the ACC were noticed (295). Neurochemistry imbalance in the ACC observed in APD individuals infers that impaired neural integrity disrupts emotional information processing and decision-making processes, worsening interpersonal and affective problems among APD individuals (295). Substance-Related Disorders ALCOHOL-RELATED DISORDERS. Alcohol use disorder (AUD) affects approximately 13% of the general population with a lifetime incidence of 18% (296). Alcohol-related disorder, incorporating AUD, alcohol abuse, and alcohol dependence, is expected to have higher prevalence than AUD. According to 2063

the 2005 National Youth Risk Behavior Survey in the United States, 43.3% of the alcohol use was closely associated with the causal factors of the death for those aged 10 to 24 years (297). It is also considered as one of the most influential risk factors for other psychopathology including the ADHD, bipolar disorder, and other substance-related disorders (296). It is characterized by alcohol tolerance (reduced sensitivity due to chronic excessive intake) and withdrawal symptoms (dysfunctional symptoms at the termination of chronic intake), and accompanies neurodegenerative findings such as ventricular enlargement and widespread GM and WM atrophies (5,298). Cravings of alcohol intake for larger amounts over longer period and impairments in social and occupational functioning brought by chronic alcohol intake are the diagnostic criteria to fulfill alcohol-related disorder (5). Structural Neuroimaging Gray Matter Structural MRI studies have revealed reduced GM and WM volumes and enlarged CSF volumes in alcohol-dependent individuals (299). GM loss in the hippocampus and temporal cortex was found in late-onset (type 1) and early-onset alcoholics (type 2), suggesting impaired memory due to cumulative effects of alcohol intake for type 1 and an underlying unknown neurobiologic marker of psychopathology for type 2 (300). Widespread cortical atrophy and enlarged CSF and ventricles noticed in alcohol dependents indicate disturbed GM in the regions, which are essentially involved in emotion, cognition, visuospatial processing, memory, and inhibitory control (301). For instance, chronic alcoholism contributed to speed up age-related ventricular enlargement and GM reductions in the anterior hippocampus and temporal cortex, associated with their cognitive impairments mainly in memory and visual–spatial–motor processing (358,359). Hommer et al. (360) interestingly found the greater magnitude of differences in the brain volumes between alcoholic and nonalcoholic women than those between alcoholic and nonalcoholic men, implying increased sensitivity and vulnerability to alcohol neurotoxicity in females. In other words, smaller gray and white matter and enlarged sulcal and ventricular CSF were more prominent in alcoholdependent women than men along with faster atrophy rate in females (360). White Matter DTI studies combined with structural MRI studies have revealed disrupted WM structure throughout the whole brain regions. Alcohol dependents showed lower WM integrity in the right ACC and left motor cortex associated with lower psychomotor and executive performances measured on a Trail-Making Test (361) and in the thinner CC indicating weakened interhemispheric connections in alcohol dependents (298,361). In addition, abnormal WM integrity in the frontotemporal regions implies dysregulation of impulsivity, attention, and memory. Damaging the FOF bundle tracts (linking the frontal with the occipital lobe) illustrate problematic visual processing in alcohol dependents (362,363). Studies on recent alcohol-dependent abstainers (for 1 or 2 months) have demonstrated their partial recovery but still unrecovered WM damages in the parietal regions (implying disrupted visuospatial processing and self-awareness) and increased spaces between WM in the frontal, temporal, and parietal regions (suggesting demyelination) (362,364). Those with 27.8 months of alcohol abstinence were not problematic in decision-makings although they did not shift their choices flexibly from the disadvantageous to the advantageous decks in the Iowa Gambling Task (IGT) (364). In addition, posterior WM increase was associated with recovery of memory function after several months of abstinence (301). Functional Neuroimaging Numerous fMRI studies have indicated that alcohol-related problems are resulted by dysfunctional inhibitory systems for alcohol craving and exaggerated expectations of alcohol as potential reward (Table 29.12). Impaired Cognitive Control The dysfunctions of the regions which are implicated in posterror behavioral adjustment and conflict management have been suggested as neural correlates responsible for alcohol dependence. Impaired cognitive control (brain atrophy in the OFC, right mPFC, and ACC) and overreliance of habit learning over goal-directed behaviors (hyperactivation of the putamen, deactivation of the vmPFC and anterior putamen) illustrate dysregulated cognitive inhibition and habitual craving behaviors of subsequent 2064

relapsers and alcohol dependents, respectively (366,367). Subsequent relapsers showed enhanced left mPFC activation when confronted with alcohol-associated cues compared to neutral cues, implying their attentional bias toward habit learning and alcohol-associated cues (366,367). In addition, additional activation of the right frontoparietal regions and more time to complete the abstract reasoning problems in alcohol dependents indicate inefficient neural mechanisms for abstract reasoning problems, which involves goal-directed behaviors and cognitive control (365). In contrast, studies on recently detoxified alcohol dependents have indicated that enhanced activations of the PFC, ACC, and striatum during cognitive tasks represent recovered cognitive control and decision-making after short-term abstinence. They exhibited increased activity of the VLPFC and premotor cortex which are involved in executive behavioral control during n-back working memory tasks and hyperactivations of the ACC and medial frontal gyrus during aversive face cue-comparisons tasks (371,372). The finding that this ACC activation is correlated with longer abstinence and less lifetime alcohol intake confirms the neurotoxic effect of chronic alcohol intake by deactivating reward anticipating ACC (372). Additionally, alcohol abstainers showed strengthened functional connectivity (midbrain–left amygdala, midbrain–left OFC) and enhanced midbrain and subthalamic nucleus activation in response to alcohol cues, indicating their successful uncoupling of alcohol as reward (367). Dysfunctional Reward Reinforcement Numerous fMRI studies have interpreted the underlying neurobiologic mechanisms of alcohol dependence in which diminished activations to neutral and naturally reward-indicating stimuli disturb alcohol dependents’ motivations to feel pleasure in situations other than alcohol-related rewarding stimuli, shaping the reward system accordingly and maintaining alcohol dependence. Specifically, some studies demonstrated hyperactive frontostriatal regions (the ventral striatum) in response to reward (monetary cues) and alcohol-related cues and reduced reactivity to alcohol-unrelated stimuli (373,374). Negative correlation between the ventral striatum activation and alcohol craving implies that the ventral striatum is involved in cognitive control, promoting alcohol abstinence (374). Moreover, heightened responses of the ACC, mPFC, and striatum, induced by alcohol-related cues, predicted following alcohol intake in abstinent alcohol dependents (375). Likewise, dysfunctional functional coupling between the striatum and PFC is related to uncontrolled drug craving and abnormal rewardguided decision-making in alcohol dependents (368). Neurochemistry MRS studies have found brain metabolite alterations in alcohol dependents: reduced NAA (in the cerebellar WM, frontal GM and WM, thalamus, and temporal lobe), decreased Cho (in the parietal gray matter and thalamus), and increased Cr (in the parietal GM), and increased mI (in the ACC, parietal GM, and thalamus) (Fig. 29.1) (171,376–379). Lower NAA and Cho concentrations suggest disrupted neuronal viability and myelination due to neurotoxicity of chronic alcohol intake (379,380). Increased CR and mI represent abnormal energy and glucose storage and glial density (379). Together, these metabolite changes brought by alcoholism are most sensitive to the neocortex, limbic system, and cerebellum, related with behavioral and cognitive dysfunctions in alcoholics (disruptions in memory, emotion, personality, and executive functions) (381). TABLE 29.12 Functional Magnetic Resonance Imaging Findings in Individuals with Alcohol-Related Disorder

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Moreover, the first few weeks of abstinence could temporally reverse these alterations in brain metabolites brought by alcohol abuse and dependence, but this reversibility did not last in the long term. For instance, previous reduced cerebellar Cho/NAA in the frontal lobe and cerebellum increased during the first 3 to 4 weeks of abstinence, and lower NAA and Cho in the frontal and parietal regions partially recovered after 1 month of abstinence (379,382). Heightened glutamate concentrations in the PFC regions of the alcoholics developed acute withdrawal symptoms during abstinence, but normalized afterwards, increasing the likelihood of long-term abstinence (383). Substance-Related Disorders Other than Alcoholism Substance-related disorder, accompanying other psychopathology (BD and ADHD) and neurovascular damages (strokes and ischemia), has been a critical health problem worldwide, especially in the United States (384). According to the 2001–2003 national survey on 9,282 English speakers, 24.8% of the general population and 14.6% of those aged 18 and older had a lifetime prevalence of substance use disorders (385). Commonly abused substances include alcohol, amphetamines, opiate, cannabis, nicotine, methamphetamine (MA), and cocaine. The diagnostic criteria of substance-related disorders include tolerance due to chronic excessive substance intake (diminished sensitivity to the same dose), withdrawal symptoms (dysfunctional symptoms at the cessation of substance intake), disrupted social and occupational functioning, and craving of larger amount for longer time (5). Structural Neuroimaging 2066

Surprisingly, structural MRI studies have studied morphologic alterations for each substance type and found distinctive structural changes for each (Table 29.13). Methamphetamine GM atrophy and WMHs have been consistently reported findings in individuals with MA-related disorders. Specifically, increased WHM in MA abusers indicate cerebral perfusion deficits brought by chronic MA use (392). Bae and colleagues (294) also found that the greater magnitude differences of WMH severity in male MA abusers, rather than in female MA abusers, imply estrogen’s protective role against neurotoxic or ischemic effects of MA. In addition, ventricular enlargement mainly in areas close to the PFC–ventral striatal–thalamic circuits implies dysregulated top-down control system, which contributes to disrupted inhibitory control and prolonged compulsive MA administration. In addition, reduced GM density of the right frontal cortex in MA abusers was related to more errors in Wisconsin Card Sorting Test (WCST), a task which requires mental flexibility and cognitive switching (395). Chronic 3,4-methylenedioxymethamphetamine (MDMA) administration was associated with GM atrophy in the BA 18, 21, and 45, bilateral cerebellum, and midline brainstem, responsible for heightened impulsivity, dysfunctional memory, and impaired executive functions in MDMA users (394,396). TABLE 29.13 Structural Magnetic Resonance Imaging Findings in Individuals with StimulantRelated Disorder

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Opiate Enlarged CSP in opiate dependents and the longest CSP particularly in adolescent-onset opiate dependents compared to those started later indicate limbic abnormalities, a marker for neurodevelopmental dysfunctions responsible for opiate dependence (388). Interestingly, longer length rather than enlarged volume of the CSP was associated with more severe limbic disruptions, leading to earlier onset of dependence (388). In addition, GM reductions in the prefrontal, insular, and temporal regions found in opiate dependents were associated with disrupted executive behavior functions (the PFC), impaired visual memory, visuospatial motor functions, and sensory information processing (the temporal cortex), and biased responses to opiate-related cues, addiction (insular regions) (106). Cocaine The frontal cortex, temporal cortex, and cerebellum were the most sensitive brain regions to cocainerelated disorders. Those with insight cocaine use disorder had smaller GM volume in the error-induced rACC, related with more frequent cocaine use and impaired emotional insight (387). Cocaine dependents also showed reduced GM in the bilateral premotor and temporal cortices, right OFC, left thalamus, and bilateral cerebellum, and smaller right cerebellar WM volume compared to controls (391). Bilateral cerebellar GM volume was negatively associated with duration of cocaine use, confirming the dose-responsive neurotoxicity of cocaine use on cerebellar GM (391). Lower cerebellar GM and WM volumes reflect dysfunctions in executive and motor function induced by cocaine administration (391). In addition, more severe deep and insular WHM was found in cocaine dependents compared to opiate dependents and controls, showing cocaine’s powerful vasoconstrictive effect on ischemia and WMH (Fig. 29.8) (397). Nictoine Constant cigarette smokers compared to controls showed reduced bilateral PFC, left ventrolateral prefrontal cortex (VLPFC), and right medial cerebellum, indicating altered cognitive and motor control. GM atrophy in the frontal regions (the OFC, pars orbitalis, pars triangularis, frontal pole, and rostal middle frontal gyrus) can be seen as neurobiologic underpinnings for modified reward system and disrupted executive oversight system in substance dependents including nicotine (389).

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FIGURE 29.8 White matter hyperintensity in individuals with cocaine dependence.

DTI DTI studies have found disrupted frontal WM integrity near the anterior commissure–posterior commissure plane (AC–PC plane) in those with substance-related disorders. Lower right frontal WM integrity was associated poorer frontal executive function measured on the WCST. Disrupted WM integrity at the AC–PC plane indicated altered orbitofrontal connectivity, leading to poor decisionmaking in cocaine dependents (398). Heroin dependents also exhibited disruptions in right frontal WM: right precentral and left cingulated gyrus (399). Functional Neuroimaging Dysregulated Reward System Four modified networks of substance addiction are involved in reward or salience (hypothalamus, nucleus accumbens, and ventral pallidum), motivation (OFC), learning and memory (amygdala and hippocampus), and cognitive control (PFC, ACC) (400). The mechanisms and function of the neurotransmitters and brain regions involved in drug-seeking behaviors are summarized in Figure 29.9 (401). Consistently increased activation to drug-related stimuli and reduced sensitivity to drug-unrelated stimuli in those with substance-related disorders have been reported (402). The regions of the dopaminergic reward system—the striatum, the amygdala, and the frontal parts (the OFC, ACC, and DLPFC)—show enhanced activation in response to drug-related cues particularly during the acute withdrawal and craving states (402). Nevertheless, these regions exhibited decreased activation in response to neutral and substance-unrelated stimuli such as verbal feedback, reward evaluation, and decision-making (403). Specifically, long-term heroin users compared to controls exhibited weaker physiologic arousal responses in response to positive pictures (pictures of food) rather than substancerelated stimuli (pictures of drug injection and preparation) (404).

FIGURE 29.9 Magnetic resonance imaging findings in individuals with substance abuse disorders. β-END, βendorphin; CRF, corticotropin-releasing factor; DA, dopamine; ENK, enkephalin; NE, norepinephrine; VTA, ventral tegmental area. (From Koob GF, Le Moal M. Neurobiology of addiction. London: Academic Press, 2006, with permission.) (401)

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FIGURE 29.10 A schematic presentation of MRS regional brain findings in individuals with substance-related disorder. A, alcohol; CB, cannabis; CC, cocaine; Cho, choline; Cr, creatine; M, methamphetamine; mI, myo-inositol; N, nicotine; NAA, N-acetylaspartate; O, opiates.

Therefore, continued substance administration sensitizes the drug effect, and drug addicts show a motivational bias toward drug-related cues, represented by the abnormally high activation of the OFC (403). Hyperactivations of the ACC and nucleus accumbens imply modified reinforcement of drug as reward, and activations of the other dopaminergic reward system regions including the amygdala disturb learning this modified conditioning as abnormal, and persist cravings for substance administration (403). Dysfunctional Cognitive Control Cognitive control in the PFC and ACC was affected in the domains of spatial working memory, inhibition, and decision-making in those with substance-related disorders. Cannabis- using adolescents in comparison with controls revealed enhanced DLPFC activation and weakened IFC activation in spatial working memory tasks, implying either greater working memory load or inefficient working memory processes (405). Paulus et al. (406) found negative correlations between the PFC activation and risks for relapses in MA dependents. Enhanced PFC activation in response to substance-related stimuli and decreased activation during a decision-making task implies disrupted behavioral and executive function including decision-making (406). Moreover, cannabis-using adults when performing Stroop tasks showed diffuse inhibitory DLPFC activation and decreased error-induced ACC (407). The finding that adolescent substance users compared to controls showed enhanced activation of the bilateral parahippocampus and SFG during a Stroop task-requiring inhibition also supports conflict management problems in those with substance disorders (408). Neurochemistry Decreased NAA and higher Cr concentrations were found in cigarette smokers and cocaine dependents, representing disrupted neuronal viability and abnormal energy metabolism, respectively (409,410). Additionally, chronic intake of MA, opiate, and cannabis reduced NAA concentrations in the basal ganglia and frontal GM (Fig. 29.1) (171,411). Increased Cr particularly in the parietal regions and thalamus, indicating high-energy phosphate stores, was found in cocaine and cannabis dependents (376,409). Figure 29.10 shows detailed metabolic changes in specific brain regions brought by each substance abuse (376). In addition, Sung and colleagues (380) also found that frontal GM NAA concentrations were associated positively with abstinence duration and negatively with the overall cumulative MA dose. This dose-dependent effect was more prominent in the GM rather than in WM regions and in males than in females due to estrogen’s protective effect.

ACKNOWLEDGMENTS This work was supported by grant DA031247 (Dr. Renshaw) from the National Institute on Drug Abuse, grant A121080 (Dr. Lyoo) from the Korean Ministry of Health and Welfare, and grant A112009 (Dr. Kim) from the Korean Ministry of Health and Welfare.

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cocaine addiction. JAMA Psychiatry 2014;71:61–70. 388. Hwang J, Kim JE, Kaufman MJ, et al. Enlarged cavum septum pellucidum as a neurodevelopmental marker in adolescent-onset opiate dependence. PLoS One 2013;8:e78590. 389. Durazzo TC, Insel PS, Weiner MW, Alzheimer Disease Neuroimaging I. Greater regional brain atrophy rate in healthy elderly subjects with a history of cigarette smoking. Alzheimers Dement 2012;8:513–519. 390. Anderson CM, Rabi K, Lukas SE, et al. Cerebellar lingula size and experiential risk factors associated with high levels of alcohol and drug use in young adults. Cerebellum 2010;9:198–209. 391. Sim ME, Lyoo IK, Streeter CC, et al. Cerebellar gray matter volume correlates with duration of cocaine use in cocaine-dependent subjects. Neuropsychopharmacology 2007;32:2229–2237. 392. Bae SC, Lyoo IK, Sung YH, et al. Increased white matter hyperintensities in male methamphetamine abusers. Drug Alcohol Depend 2006;81:83–88. 393. Lyoo IK, Sung YH, Dager SR, et al. Regional cerebral cortical thinning in bipolar disorder. Bipolar Disord 2006;8:65–74. 394. Cowan RL, Lyoo IK, Sung SM, et al. Reduced cortical gray matter density in human MDMA (ecstasy) users: a voxel-based morphometry study. Drug Alcohol Depend 2003;72:225–235. 395. Kim SJ, Lyoo IK, Hwang J, et al. Prefrontal grey-matter changes in short-term and long-term abstinent methamphetamine abusers. Int J Neuropsychopharmacol 2006;9:221–228. 396. Parrott AC, Sisk E, Turner JJ. Psychobiological problems in heavy ‘ecstasy’ (MDMA) polydrug users. Drug Alcohol Depend 2000;60:105–110. 397. Lyoo IK, Streeter CC, Ahn KH, et al. White matter hyperintensities in subjects with cocaine and opiate dependence and healthy comparison subjects. Psychiatry Res 2004;131:135–145. 398. Lim KO, Choi SJ, Pomara N, et al. Reduced frontal white matter integrity in cocaine dependence: a controlled diffusion tensor imaging study. Biol Psychiatry 2002;51:890–895. 399. Liu H, Li L, Hao Y, et al. Disrupted white matter integrity in heroin dependence: a controlled study utilizing diffusion tensor imaging. Am J Drug Alcohol Abuse 2008;34:562–575. 400. Schnur P, Shurtleff D. Social neuroscience: applications to addiction. Drug Alcohol Depend 2008;94:285–290. 401. Koob GF. The neurobiology of addiction: a neuroadaptational view relevant for diagnosis. Addiction 2006;101(suppl 1):23–30. 402. Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 2002;159:1642–1652. 403. Diekhof EK, Falkai P, Gruber O. Functional neuroimaging of reward processing and decision-making: a review of aberrant motivational and affective processing in addiction and mood disorders. Brain Res Rev 2008;59:164–184. 404. Lubman DI, Yucel M, Kettle JW, et al. Responsiveness to drug cues and natural rewards in opiate addiction: associations with later heroin use. Arch Gen Psychiatry 2009;66:205–212. 405. Schweinsburg AD, Nagel BJ, Schweinsburg BC, et al. Abstinent adolescent marijuana users show altered fMRI response during spatial working memory. Psychiatry Res 2008;163:40–51. 406. Paulus MP, Tapert SF, Schuckit MA. Neural activation patterns of methamphetamine-dependent subjects during decision making predict relapse. Arch Gen Psychiatry 2005;62:761–768. 407. Gruber SA, Yurgelun-Todd DA. Neuroimaging of marijuana smokers during inhibitory processing: a pilot investigation. Brain Res Cogn Brain Res 2005;23:107–118. 408. Banich MT, Crowley TJ, Thompson LL, et al. Brain activation during the Stroop task in adolescents with severe substance and conduct problems: a pilot study. Drug Alcohol Depend 2007;90:175–182. 409. Magalhaes AC. Functional magnetic resonance and spectroscopy in drug and substance abuse. Top Magn Reson Imaging 2005;16:247–251. 410. Wang JJ, Durazzo TC, Gazdzinski S, et al. MRSI and DTI: a multimodal approach for improved detection of white matter abnormalities in alcohol and nicotine dependence. NMR Biomed 2009;22:516–522. 411. Ernst T, Chang L, Leonido-Yee M, et al. Evidence for long-term neurotoxicity associated with methamphetamine abuse: a 1H MRS study. Neurology 2000;54:1344–1349.

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30 MR Spectroscopy and the Biochemical Basis of Neurologic Disease Eva-Maria Ratai and R. Gilberto González

INTRODUCTION The purpose of this chapter is to provide practical guidance in the clinical application of proton MR spectroscopy (MRS) of the brain. It must be understood at this point in the maturation of clinical MR that MRS is only an adjunctive tool in the diagnostic neuroradiology armamentarium. Despite the initial excitement about the specificity and added value of metabolic information, the reality is that MRS has value, but that value is complementary and only rarely trumps other imaging findings. The radiologist employing this tool in the clinical setting must certainly keep foremost in mind that the information provided by MRS is properly interpreted only when all of the imaging and clinical information is incorporated. Key Concept: Always interpret the MR spectrum in light of other imaging data. This chapter is designed to be self-contained although some topics are covered in more detail elsewhere in this book. The focus is on 1H MRS because it is the method that is widely available clinically. The chapter covers the physics of MRS, the chemistry of the MR spectrum, technical aspects of in vivo brain MRS, and the biologic basis of the normal and abnormal brain spectrum. The chapter concludes with current clinical applications which we have divided into three classes based on practical considerations. This classification arises from the major limiting factor in using this technique: the low signal-to-noise ratio (SNR) of the brain proton MR spectrum. The concentrations of the metabolites measured by 1H MRS are some 10,000 times lower in concentration than water, and explains the three to four orders magnitude difference in SNR between MRS and MRI. The low SNR results in low spatial resolution and significant error in the measurement of peak heights or areas. Key Concept: The low SNR of in vivo MRS results in low spatial resolution and significant error in the measurement of peak heights or areas. The clinical applications of MRS are divided into three classes: Class A MRS applications are those circumstances in which the interpretation of the MR spectrum is of value in individual patients. Because of the SNR, an abnormal MR spectrum is usually only obvious in the case of a qualitative or large quantitative change. An example of the former would be the presence of a prominent lactate resonance in the case inborn errors of metabolism, and an example of the latter would be the high increase in the choline resonance in a high-grade glioma. Indeed, it is in the evaluation of brain masses and inborn errors of metabolism that MRS is most useful in individual patients and is the major subset of Class A applications. There are neurologic diseases where the changes in the MRS spectrum are occasionally large enough that they may be useful for clinical management in some individual patients; these have been designated as Class B MRS applications, such as ischemia and epilepsy. Class C MRS applications are those in which MRS is most meaningful in assessing groups of patients or possibly individual patients who have serial MRS studies. The MR spectrum is abnormal in these situations, but the change is more subtle, and may not be reliably appreciated by the radiologist because the change may fall within the range of normal variation between individuals. Examples of brain disorders in Class C comprise some neurodegenerative diseases and psychiatric diseases.

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Nuclear Magnetisms MRS has been known as nuclear magnetic resonance (NMR) since its development in the 1940s. NMR in the liquid state and solid state is based on the nuclei’s quantum mechanical properties and was first described in 1946 independently by Felix Bloch and Edward Mills Purcell, who shared the Nobel Prize in physics in 1952 for their discovery. Subatomic particles (electrons, protons, and neutrons) can be imagined as spinning on their axes. In most atoms (such as 1H and 13C), the nucleus possesses this overall angular momentum called “spin.” The rules for determining the net spin of a nucleus are as follows: If the number of neutrons and the number of protons are both even, then the nucleus has no spin (e.g., 12C, 16O). If either the number of neutrons or the number of protons is odd, then the nucleus has a half-integer spin (i.e., 1/2, 3/2, 5/2; e.g., 1H, 19F, 23Na, 31P). If the number of neutrons and the number of protons are both odd, then the nucleus has an integer spin (i.e., 1, 2, 3; e.g., 2H). Particles with an angular momentum or spin, , possess a magnetic dipole moment, , just as a rotating electrically charged body in classical electrodynamics generates a magnetic dipole moment. The strength and direction of the magnetic dipole moment is determined by the gyromagnetic ratio, γ, which is characteristic for each nucleus: TABLE 30.1 Properties of the Nuclei Routinely Used in NMR

Resonance When placed into a strong magnetic field, B0, quantum mechanics predict that the energy levels of the nucleus will degenerate (“split”) into those in which the spin is aligned with the applied magnetic field (lower energy level) and those in which the spin is in the opposite direction to the applied magnetic field (higher energy level). The initial populations of the energy levels are determined by thermodynamics, as described by the Boltzmann distribution. The lower energy level will contain slightly more nuclei than the higher level. The spins of the parallel and antiparallel protons cancel each other out; only the small number of low-energy protons left aligned with the magnetic field creates the overall net magnetization. It is possible to excite these nuclei into the higher level with electromagnetic radiation in the range of radio frequencies, RF. The frequency of radiation, ωL (L: Larmor), needed is determined by the difference in energy between the energy levels, which depends on B0 and γ, and can be described by the following Larmor equation: Table 30.1 summarizes the properties of some of the nuclei routinely used in NMR. Fourier Transformation and Free Induction Decay The development of NMR was revolutionized when a technique known as Fourier transform nuclear magnetic resonance (FT-NMR) spectroscopy was introduced. FT-NMR decreases the time required for a scan by allowing a range of frequencies to be explored at once. FT-NMR operates by irradiating the sample in the magnet with a short pulse containing all the frequencies in the range of interest via a coil 2085

in which the sample is placed. When exposed to the RF pulse, the magnetic moments of the nuclei begin to precess together, creating an oscillation in the surrounding magnetic field. This oscillation induces a current which can then be observed. RF coils are used to transmit the RF magnetic induction field (B1) and to detect the resulting signal. When the RF energy is removed, the magnetization will relax back to the equilibrium state over time. This decay is known as the free induction decay (FID). A mathematical function known as a Fourier transformation converts this time-dependent pattern into a frequencydependent pattern, revealing the NMR spectrum. In 1991, Richard R. Ernst, was awarded the Nobel Prize in Chemistry for his contributions toward the development of multidimensional FT-NMR spectroscopy. Relaxation How do nuclei in the higher energy state return to the lower state? There are two major relaxation processes: (1) spin–lattice (longitudinal) relaxation and (2) spin–spin (transverse) relaxation. Spin–Lattice Relaxation or T1 Relaxation Nuclei in an NMR experiment are in a bulk sample surrounded by magnetic spins and fluctuations of magnetic field sources, collectively referred to as lattices which are in vibrational and rotational motions, causing a magnetic field including many frequency components. Spin–lattice relaxation depends on the dissipation of absorbed energy into the surrounding molecular lattice, which varies with the characteristics of the molecule and the surrounding environment. Energy transfer is most efficient when the precessional frequency of the excited nuclei overlaps with the vibrational and rotational frequencies of the molecular lattice. The energy that a nucleus loses increases the amount of vibration and rotation within the lattice, resulting in a minuscule rise in the temperature of the sample. The relaxation time, T1, defined as the time when 63% of the original magnetization has recovered, is dependent on the gyromagnetic ratio and the mobility of the lattice. At three times T1, the magnetization has returned to 95% of its original values. Spin–Spin Relaxation or T2 Relaxation Spin–spin relaxation describes the interaction between neighboring nuclei. The net magnetization starts to dephase because each of the spin packets (a group of spins experiencing the same magnetic field strength) is experiencing a slightly different magnetic field and rotates at its own Larmor frequency. With increasing time, the phase difference becomes greater and the net magnetization vector dephases to zero. The time constant that describes the return to equilibrium of the transverse magnetization is called the spin–spin relaxation time, T2. This is the time it takes to reduce the transverse magnetization to 37%. There is no net change in the populations of the energy states, but the average lifetime of a nucleus in the excited state will decrease which results in a broadening of the spectral line width. T2 is always less than or equal to T1. There are two factors that contribute to the decay of transverse magnetization: (1) molecular interactions (pure T2 effect) and (2) variations in B0 (inhomogeneous T2 effect). The combination of these two factors is what results in the decay of transverse magnetization, the FID. The combined time constant is called T2 star (T2*). Chemical Shift The resonance frequency of the nucleus not only depends on the gyromagnetic ratio and the applied magnetic field B0, but also on the electronic environment of the nucleus in a molecule. This phenomenon is called the chemical shift and results from the magnetic shielding by the electrons around the nucleus. All nuclei in a given molecule are surrounded by an “electron cloud.” When placed inside the static external magnetic field, B0, a circulation in the electron cloud surrounding the nucleus is induced such that the induced magnetic field, Bind, is opposite to B0. The opposing magnetic field, Bind, reduces the field experienced by the nucleus, thus resulting in a “shielding” of the nucleus from the full strength of the external magnetic field. The effective magnetic field, Beff, felt by the nucleus is, therefore, smaller than the applied magnetic field, consequently resulting in a lower resonance frequency of the nucleus: The higher the electron density around a nucleus the more effective the nucleus is shielded. This 2086

effect is very small compared to the effect of the external magnetic field; the change in resonance frequency is on the order of 1 Hz per million Hz. The strength of the induced magnetic moment depends on the applied magnetic field and the shielding constant, σ: This relationship makes it difficult to compare NMR spectra taken on spectrometers operating at different field strengths. To avoid this problem, the term chemical shift was introduced. The chemical shift of a nucleus is the difference between the resonance frequencies of the nucleus and a standard, relative to the standard frequency. This quantity is measured in parts per million (ppm) and given the symbol delta, δ. In NMR spectroscopy, this standard is often the resonance of tetramethylsilane (TMS), which was arbitrarily defined as 0 ppm: Note by designating the shift as a fraction of B0, it becomes field independent. For in vivo MRS, the water resonance is typically used as an internal standard, at 4.7 ppm with respect to TMS. Figure 30.1 illustrates the chemical shift phenomena via the methanol molecule, which consists of protons in different chemical environments: three hydrogen atoms bind to the carbon in the methyl group (CH3 group) and one binds to the oxygen in the hydroxyl group (OH group), resulting in an uneven electron density within the molecule. The electron density of the hydroxyl proton is less because oxygen is more electronegative than the carbon, and thus it pulls electrons away from the hydrogen nucleus to a greater extent than does the carbon. Therefore, the OH hydrogens are less shielded than the CH3 hydrogens and experience a higher magnetic field (Beff) than the methyl hydrogens. Because the resonance frequency scales with Beff, the resonance frequency of the hydrogen atoms in the methyl group is lower than that of the OH group and the methyl peak is shifted toward lower frequencies with respect to the OH peak.

FIGURE 30.1 Representation of a proton spectrum of methanol (CH3OH). The OH hydrogens are less shielded because the oxygen is more electronegative resulting in a higher effective magnetic field (Beff) on the proton and thus has a higher resonance frequency.

Also note that the ratio of the areas under the two peaks is 3:1 because there are three protons in the CH3 group and one proton in the OH group. The intensity of absorption (the area under the peak) is proportional to the concentration of the nucleus, which is still valid for comparisons between different molecules. This makes NMR spectroscopy a quantitative tool (see Section on “Spectral Quantification”). J Coupling Another molecular interaction which modifies the resonance frequency of a spin is known as J coupling (also called indirect dipole–dipole coupling or spin–spin coupling). J coupling results from the interaction between adjacent nuclear spins and is transmitted via the bonding electrons within a molecule. Figure 30.2 illustrates the phenomenon. When spin A of a nucleus is coupled to a spin B, it can “sense” the orientation of that spin in the B0 field. If spin B is aligned with the field, spin A resonates at a frequency different from when spin B is aligned against the field. The population of A spins is, therefore, split into two. Since the probability of finding spin B in a spin-up orientation is the same as the probability of finding it spin down, we observe a doublet for spin A’s resonances with equal intensities. Spin–spin coupling can occur between similar nuclei (homonuclear coupling) or dissimilar nuclei (heteronuclear coupling). 2087

The splitting, J, reflects the strength of local field due to coupling, in Hz, and is independent of the external magnetic field, B0. In addition, when subjected to spin-echo sequences, coupled spins cannot be refocused by a 180-degree pulse if the refocusing pulse acts on both spins, because they always maintain their frequency differences. The result is a phase modulation of the signal that depends on the time delay between the pulses in which the modulation frequency is proportional to 1/J.

FIGURE 30.2 J coupling between two protons. Proton A and B are coupling partners within the same molecule resonating at different frequencies. When spin B is aligned with the magnetic field, spin A resonates at a frequency different from when spin B is aligned against the field. The population of A spins is, therefore, split into two. Since the probability of finding spin B in a spin-up orientation is the same as the probability of finding it spin down, we observe a doublet for spin A’s resonances with equal intensities.

CHEMICAL BASIS OF THE IN VIVO BRAIN MR SPECTRUM Major Resonances and Corresponding Metabolites N-Acetylaspartate (NAA) In the normal brain, the most prominent spectral peak originates from the trimethylamine group of NAA assigned at 2.02 ppm. NAA is a free amino acid synthesized in neuronal mitochondria by N-acetyl-Laspartate transferase (1) and it is localized primarily in the central and peripheral nervous systems (2,3), typically at a concentration of 10 to 16 mmol/kg (4–6). It has the highest concentration of any water-soluble molecule in the brain and is extremely metabolically active, with 100% turnover in approximately 16 hours (7). The high concentration and rapid turnover rate indicates that this molecule is very important in normal brain metabolism. ROLE OF NAA IN THE NERVOUS SYSTEM. The function of NAA is not fully understood, but accumulating evidence suggests multiple roles. It is believed to act as a storage form of aspartate and as a precursor of the neurotransmitter N-acetylaspartylglutamate (NAAG), as well as having a variety of other functions (3,8). Additionally, NAA may have a role as a messenger molecule between neurons, astrocytes, oligodendrocytes, and possibly microglia, and has been shown to be an osmoregulator (3,7,9,10). Baslow (9) has proposed that NAA is a key component of a water pump mechanism within the central nervous system (CNS). Having such a mechanism is important, as Baslow has pointed out, because the high metabolic rate of glucose metabolism that occurs in the brain produces a large quantity of water. Without an active mechanism to actively pump water against its gradient, the water production would be deleterious to cellular function. Through the synthesis and degradation of NAA, Baslow has proposed how NAA can serve as a means to enhance the efflux of water from intracellular compartments within the CNS into the blood stream. NEUROPATHOLOGY OF NAA CHANGE. NAA within the adult brain is found almost exclusively in neurons, and serves as a marker of neuronal density and viability (11–15). However, other studies suggested that NAA may be found in mast cells or oligodendrocyte (13,16). Overall, NAA does appear to be a good surrogate marker of neuronal health, but it may sometimes change independent of neuron cell density or function (17): Several quantitative studies of comparing NAA with pathologic measures in human brain tissues have been reported. Cheng et al. (18) found that NAA concentration correlated linearly with neuronal number in a brain from a patient with Pick’s disease. In addition, the same group reported that neuronal counts determined by stereology correlated linearly with the concentration of NAA measured in brain tissue from both Alzheimer’s disease (AD) and control subjects (19). The ratio of NAA to creatine (NAA/Cr) was compared with to a marker of astrogliosis in resected temporal lobe tissues from patients with temporal lobe epilepsy (TLE) by Cohen-Gadol and his coworkers (20). They found a significant inverse relationship of NAA/Cr to the glial fibrillary acidic protein (GFAP) immunoreactivity. This association is not surprising because in this and many other neurologic diseases, neuronal injury occurs along with a gliotic reaction in response to the neurologic insult. 2088

Animal models have been employed to explore the relationship between changes in NAA and corresponding changes revealed by histopathology. In a mouse model Huntington’s disease, Jenkins et al. reported a large (>50%) exponential decrease in NAA with time in both striatum and cortex in mice with trinucleotide (150 CAG, cytosine - adenine guanine) repeats (R6/2 strain). They also reported a linear decrease restricted to striatum in N171–82Q mice with 82 CAG repeats. Both the exponential and linear decreases of NAA were paralleled in time by decreases in neuronal area measured histologically (21,22). In the macaque model of neuroAIDS, Lentz et al. (23) compared levels NAA/Cr with quantitative levels of synaptophysin, microtubule-associated protein 2 (MAP2), and neuron number. They reported that shortly after infection with SIV, the macaque brain had a transient decrease in NAA/Cr. The best correlate of this change was the level of synaptophysin, a measure of synaptic density and synaptodendritic integrity. REVERSIBLE NAA CHANGE. Reversible changes of NAA have been observed, indicating that NAA levels also reflect neuronal dysfunction rather than just neuronal loss. For example, recovery of NAA levels has been observed with reversible ischemia (24) and brain injury (25). Reversal of reduced NAA levels have also been observed with multiple sclerosis (MS) (8), transient ischemia (26,27), and in a macaque model of neuroAIDS (23) in the absence of neuronal loss. It was discovered that during acute infection with SIV, the macaque brain exhibited significant changes in NAA. NAA/Cr best correlated with synaptophysin, a marker of synaptodendritic function. Synaptophysin is a key protein in the formation of synapses and has been shown to decline in a variety of diseases including AD. The best interpretation of this correlation between NAA and synaptophysin suggests that when a neuron experiences a sublethal insult (e.g., ischemia), it responds by reducing the number of synapses, and in parallel, a reduction in the steady-state levels of NAA. Because of this relationship between the synaptic marker and NAA, it is possible that in vivo MRS measurements of NAA not only reflect neuronal number but also the density of viable synapses in the CNS. Interestingly, increased NAA levels have been observed with Canavan’s disease, an inherited disorder in which the enzyme aspartoacylase, involved in the process of degrading NAA to aspartate and acetate, is not being produced, resulting in the accumulation of NAA to toxic levels (8,28). NAA and NAAG. On clinical MR scanners operating at 1.5 or 3.0 T, the NAA resonance at 2.02 ppm has additional contribution to the signal from NAAG. Using a fully relaxed, short echo time (TE) stimulated echo acquisition mode (STEAM) localization sequence at 2.0 T, separate concentrations for NAA and NAAG were obtained by spectral analysis (LCModel) (29,30). For details on STEAM and pointresolved spectroscopy (PRESS), see Section “Localization Techniques.” With the development of higher magnetic field strength magnets, the separation of NAA and NAAG becomes more feasible. Total Creatine (Cr) Another important peak in the proton spectrum is that of creatine, which is assigned at 3.03 ppm. This peak is composed of resonances from creatine (Cr) and phosphocreatine (PCr), and is referred to as total Cr (tCr) or just Cr. Phosphocreatine acts as a high-energy phosphate reservoir for the generation of ATP. Creatine is present in brain, muscle, and blood, and the synthesis of creatine takes place in the kidney and the liver. In vitro, glial cells contain a twofold to fourfold higher concentration of creatine than do neurons (14). Since Cr and PCr are in equilibrium, the tCr peak is commonly assumed to remain stable in size despite bioenergetic abnormalities that occur with many pathologies or with age (31). Consequently, the tCr resonance is often used as an internal standard and is commonly referred to as simply creatine (Cr). However, changes in creatine have been reported. Since Cr serves as a marker for energy-dependent systems in cells, it tends to be low in processes that have low metabolism, such as in necrosis and infarctions. Furthermore, Cr is typically decreased in brain tumors (32–34). However, elevated Cr levels have been reported in patients’ AIDS dementia (35). Choline-Containing Compounds (Cho) The choline resonance arises from signals of several soluble components that resonate at 3.2 ppm. This resonance contains contributions primarily from glycerophosphocholine (GPC), phosphocholine (PCho), and choline (Cho). Changes in this resonance are commonly seen with diseases that have alterations in membrane turnover. In diseases such as neoplasms, leukodystrophies, and MS, there is a substantial increase in MRS-visible Cho (36–38). The elevated Cho peak reflects a high steady-state level of these molecules that result from increased cellular membrane turnover. Thus, it is increased in most processes 2089

that are accompanied by hypercellularity (39–41). It is increased in primary and secondary brain tumors with higher Cho/Cr ratios found in malignant tumors (42). Elevated Cho has also been seen in developing brain (43,44) and is also observed in inflammatory and gliotic processes (45–49). Myo-Inositol (mI) Myo-inositol is a cyclic sugar alcohol and its most prominent peak is assigned at 3.56 ppm. mI can only be visualized at short TE (e.g., 30 ms). The function of mI is not fully understood, although it is believed to be an essential requirement for cell growth, an osmolyte, and a storage form for glucose (50). mI is primarily located in glia and an increase in mI is commonly thought to be a marker of gliosis (51). The identification of mI can be important in the evaluation of brain tumors (32,52). This metabolite is usually decreased in high-grade primary brain tumors, but visible in low-grade neoplasms (53). Elevated mI levels have been associated with AD (54–56), AIDS dementia, other neurodegenerative diseases, and brain injury (57). In addition, elevated mI has been reported in newborns (43). Reduced mI is observed in hepatic encephalopathy (58). Glutamate (Glu) and Glutamine (Gln) Glutamate (Glu) is the major excitatory neurotransmitter of the brain, although it has other important metabolic functions (4,50,59). Excess of glutamate surrounding neural cells can be toxic and can cause neuronal death. Cerebral glutamate concentration is reported to be increased in cerebral ischemia (60), hepatic encephalopathy (61), and Reye’s syndrome (62). The amino acid glutamine is a precursor and storage form of glutamate and is primarily located in astrocytes. Glutamate and glutamine have strongly coupled spin systems that give rise to complex spectra (63,64). Since glutamine and glutamate are structurally very similar, it is very difficult to separate their resonances at low field strength, and therefore, the sum of Glu and Gln is commonly referred to as Glx. The peaks of interest resonate between 2.1 and 2.5 ppm (left shoulder of NAA). While it is possible to quantify Glu and Gln independently at lower field strengths, e.g., 3 T (65), these overlapping peaks might be more reliably resolved at higher field strengths (66,67). Lactate (Lac) Under normal conditions, the lactate concentration is very low in the adult brain. This resonance (observed as a doublet) occurs at 1.32 ppm. Confirmation of the presence of lactate can be achieved by obtaining MRS with a TE of 144 ms, which results in the inversion of the lactate doublet below the baseline or with a TE of 288 ms resulting in MR spectra in which the lipid peaks have typically decayed due to T2 effects. Lactate is produced by anaerobic metabolism and has been detected in stroke patients (68–70). It has been reported that lactate levels after acute stroke correlate strongly with apparent diffusion coefficient (ADC) values (27). Increased lactate has been found during hypoxia (71), mitochondrial diseases (72–74), seizures (75), and in the first hours after birth (76). The presence of lactate in brain tumors has received a great deal of attention. This situation occurs in highly cellular and metabolic lesions that outgrow their blood supply. The presence of lactate indirectly measures glucose utilization. Increased energy demands by highly cellular lesions lead to excessive oxygen utilization, and increased reliance on anaerobic glycolysis resulting in the production of lactate. Therefore, the presence of lactate often accompanies malignant neoplasms (77). It has been observed that regions containing lactate correspond to areas of increased cerebral blood volume (CBV) in brain perfusion studies and thus may serve as an indicator of angiogenesis, another feature typical of highly malignant brain tumors (78). Lipids (Lip) MRS obtained with short TE offers the possibility of visualizing additional resonances, particularly those produced by compounds having short relaxation times such as lipids. Lipids resonate between 0.8 and 1.5 ppm and may obscure the presence of lactate. Mobile lipids are generally found in necrosis and, as such, are indicators of high-grade malignancies, both primary brain tumors and metastases (79,80). Alternatively, elevated lipids are an indicator for radiation necrosis. Radiologists reading MR spectra should use caution when interpreting lipid signals as lipids may also be present in the spectra due to contamination by subcutaneous fat and fat from marrow of the skull. Minor Resonances and Corresponding Biochemicals 2090

γ-Aminobutyric Acid (GABA) γ-aminobutyric acid (GABA) is an amino acid and an inhibitory neurotransmitter. GABA concentrations in the brain are close to the detection limits of in vivo MRS. In addition, the GABA resonances overlap considerably with contributions from other more abundant metabolites, in particular, creatine. However, the invention of specialized MRS techniques, such as selective editing techniques (81,82), localized two-dimensional (2D) chemical shift methods (83), or multi-quantum filtering methods (84), has enhanced the ability to detect and measure GABA. Proton MRS studies have found reduced or abnormal GABA concentrations in several neuropsychiatric disorders, including epilepsy, anxiety disorders, major depression, drug addiction (85), and autism (86). Glutathione (GSH) Glutathione is a tripeptide made up of glycine, cysteine, and glutamate; it exists in a reduced (GSH) and oxidized (GSSH) form in which GSH is an antioxidant. GSH is primarily located in astrocytes at a concentration of 2 to 3 mmol/kg and essential for maintaining normal red-cell structure, keeping hemoglobin in the ferrous state, serves in an amino acid transport system, and is a storage form of cysteine. The resonances of GSH overlap with those of Glu, Gln, GABA, Cr, and NAA; however, double quantum coherence filtering technique enables the selective observation of the resonances at 2.9 ppm from the overlapping resonances of GABA, creatine, and aspartate. Decreased GSH levels have been observed in patients with ALS (87), bipolar disorder (88), and major depression (89). Glycine (Gly) Glycine is an amino acid that acts as an inhibitory neurotransmitter and antioxidant, and is distributed throughout the CNS. Elevated glycine has been reported in tumors (90) and in patients with hyperglycinemia (91). For in vivo MRS measurements, the glycine resonance overlaps with those of mI (at 3.55 ppm), making definite observation of glycine not possible at shorter TEs, although its presence may be verified at longer TEs due to the reduction of the inositol multiplet. Alanine (Ala) Another metabolite that may be of interest when performing MRS of intracranial tumors is alanine. It is a nonessential amino acid that resonates between 1.3 and 1.4 ppm, and may be overshadowed by the presence of lactate and lipids. Alanine has been found to be elevated in some meningiomas (32). Valine (Val) Valine is an essential amino acid necessary for protein synthesis. The spectrum consists of two doublets from the two methyl protons that overlap with resonances of leucine and isoleucine in the range of 0.95 to 1.05 ppm. Hypervalinemia and branched-chain ketonuria are some of the diseases in which valine levels become elevated (92). Increased concentrations have also been observed in brain abscesses (93). Furthermore, accumulation of the branched-chain amino acids including valine, leucine, and isoleucine can be detected neonates with maple syrup urine disease (MSUD), a disorder caused by a deficiency of the branched-chain α-ketoacid dehydrogenase enzyme complex (Table 30.2) (94). Other Amino Acids Some compounds are only detected under disease or other abnormal conditions. Examples include compounds such as phenylalanine in patients with phenylketonurea (122), galactitol, ribitol, and arabitol in leukoencephalopathy associated with a disturbance in the metabolism of polyols (123). Macromolecules Like lipids, macromolecules can only be visualized at short TEs (124). The presence of pathologically altered macromolecules or mobile lipids may provide useful additional diagnostic information in various pathologies, such as brain tumors and MS (125,126). Table 30.3 summarizes the key metabolites, including their major resonance and the associated changes with brain disease. TABLE 30.2 Variations of Major 1H MRS Metabolites in Selected Inborn Errors of Metabolism

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TABLE 30.3 Summary of the Key Metabolites, Including Their Major Resonance and the Associated Changes with Brain Disease

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In Vivo Magnetic Resonance Spectroscopy The basic principles described in the previous section were primarily based on ex vivo samples using an NMR spectrometer. Figure 30.3A shows a typical NMR spectrum of human brain extract measured with a 14 T (600 MHz) NMR spectrometer. However, to be clinically relevant, MRS needs to be performed in vivo. Unfortunately, the spectral quality is compromised by magnetic field inhomogeneity and usually low field strengths. In vivo spectra are further broadened by chemical shift anisotropy, dipolar coupling from motionally constrained species, as well as magnetic susceptibility variations in the tissue, resulting in a loss of biochemical information. However, in many cases the spectral quality is still sufficient to diagnose diseases, monitor treatments, or to help understand the pathogenesis of diseases. Figure 30.3B shows a typical proton MR spectrum from the white matter (WM) of the centrum semiovale of a human brain acquired at a short TE of 35 ms at 3.0 T. The most prominent peak arises from NAA at 2.0 ppm. The other major peaks include creatine (Cr) and choline-containing compounds (Cho) and are observed at 3.0 and 3.2 ppm, respectively. Cr and Cho both have approximately half the height of NAA in the centrum semiovale of normal controls. The next section discusses metabolites and their significance for diagnosis.

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FIGURE 30.3 Comparison between ex vivo NMR and in vivo MRS. A: Typical ex vivo NMR spectrum of human white matter brain extracts measured with a 14 T (600 MHz) NMR spectrometer using a single pulse sequence with TR 20 s and 64 acquisitions. B: Typical proton MR spectrum from the white matter semiovale of a healthy male subject acquired with a single voxel PRESS sequence (TR/TE = 2,300/30, NS = 160) at a 3.0-T MRI scanner.

Localization Techniques For diagnostic purposes one is interested in directly comparing spectra from pathologic or abnormal tissue with normal tissue. Thus, to measure MR spectra in vivo, one has to be able to define the spatial origin of the detected signal. (A) Single-voxel spectroscopy (SVS) uses selective excitation pulses to localize a voxel of typically 3 to 8 cm3. SVS has the advantage of higher SNR and typically shorter acquisition times. However, the additional scan time typically permits acquisition of only a few locations. (B) Magnetic resonance spectroscopic imaging (MRSI) can be obtained in two or three dimensions. MRSI allows one to collect the spectral information from a volume consisting of many voxels with individual voxel sizes of typically 0.5 to 3 cm3 and makes it possible to cover large brain areas. However, spectra typically have a lower SNR compared to SVS. Single-Voxel Spectroscopy Localization of protons in a 3D volume requires the application of three distinct magnetic gradients during the pulse sequence. The two most commonly used localization methods include STEAM (127) and PRESS (128). In both sequences, three selective pulses along with three orthogonal gradients generate a stimulated-echo or a spin-echo within the volume of interest or voxel: (i) STEAM uses three consecutive slice selective 90-degree pulses that create a stimulated echo from the VOI; (ii) PRESS uses a selective 90-degree pulse followed by two slice-selective 180-degree pulses that create a spin echo. Both sequences have been compared in detail by Moonen et al. (129). STEAM provides excellent slice selection profiles because frequency selective 90-degree pulses generally have a good slice profile, and thus allows for sampling of smaller VOIs. In addition, signal losses due to T2 relaxation remain minor as the magnetization is stored on the z-axis between the second and third selection pulses. Therefore, STEAM is able to utilize very short TEs and it permits visualization of metabolites with shorter TEs such as mI, glutamate, and glutamine. Excellent water suppression can be achieved because additional water suppression pulses can be applied during the mixing time when the magnetization is stored in the z-axis. However, the stimulated echo has an intrinsically lower (50%) signal compared to MRS exams obtained with PRESS sequence, which leads to a lower SNR or longer scan times. PRESS typically requires a longer TE and consequently the signal from most metabolites in the brain would decay, except those of Cho, Cr, NAA, and Lac. In recent years, however, PRESS can be performed using short TEs, for example, 30 ms, which has made it the most commonly used technique in clinical MRS. In vivo MRS at higher field strengths is associated with (i) chemical shift displacement errors, (ii) spatial nonuniformity of RF excitation, and (iii) contamination with subcutaneous lipid signal. To address these problems, adiabatic pulses have been implemented in techniques such as LASER (130,131) and semi-LASER (132,133). The most commonly used adiabatic pulse is the hyperbolic secant adiabatic full passage (AFP) inversion pulse and the hyperbolic secant adiabatic half passage (AHP) pulse to archive a 90-degree pulse (134). Figure 30.4 compares spectra acquired with a PRESS and a LASER sequence in a tumor patient. 2094

Magnetic Resonance Spectroscopic Imaging MRSI, or chemical shift imaging (CSI), allows one to collect the spectral information from a volume consisting of many voxels. Like MRI, it produces an image of an object, but now each pixel also contains the spectral information. MRSI is superior for many clinical studies when it is necessary to obtain metabolic information of a large or heterogeneous lesion—possibly revealing new tumor growth that is not yet visible on a regular MRI. Additionally, spectral information from control regions may be obtained simultaneously.

FIGURE 30.4 Comparison between spectra in a tumor patient acquired with a PRESS (left) and a LASER sequence (right). (Red arrows) are pointing to the magnified voxels below. The PRESS sequence has been acquired with outer volume suppression (OVS), yet one can detect large lipid artifacts from skull inside the VOI. Using a LASER sequence (w/o OVS) these artifacts are mitigated. (Courtesy: Ovidiu Androresi and Greg Sorensen.)

The MRSI sequence is similar to an imaging sequence; however, the major difference is that no readout or frequency-encoding gradient is applied during data collection, because high magnetic field homogeneity is necessary during data acquisition to obtain the narrow line widths essential in MRS. Localization in spectroscopy is implemented with slab excitation followed by phase encoding (PE) gradients. The data can then either be displayed as a grid of many voxels, as individual voxels, or as metabolite maps in which the intensities displayed in the image are proportional to a particular metabolite signal strength (Fig. 30 5). Fast MRSI Techniques The main limitation of MRSI is the lengthy acquisition times, especially with 3D data acquisition. A number of fast CSI experiments have been presented, that promise to significantly reduce data acquisition duration. Some improvement may be achieved by acquiring data by reduced k-space sampling. Circular k-space sampling reduces the encoding time by 22% as compared to traditional square or rectangular sampling (135). When multiple averages are acquired, weighted k-space sampling reduces signal averaging of higher k-space. Comparison of k-space sampling schemes for multidimensional MRSI can be found at Hugg et al. (136). Fast CSI concepts have evolved from concepts related to spatial encoding using gradient switching during acquisition (137,138). These techniques were further developed by others (139–141). They work based on the fact that the dwell time to encode spectral information is long due to the relatively small spectral window—approximately 1 ms while the time to encode the spatial information is usually much faster—tens of microseconds. Therefore, it is possible to encode spectral and spatial information in an interleaved fashion using a series of inverted readout gradients that generates a series of echoes. Those interleaved spatial–spectral encoding methods can be either echo-planar imaging (EPI) (137) or spiral based.

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FIGURE 30.5 MRSI data can either be displayed as a grid of many voxels or as metabolite maps in which the intensities displayed in the image are proportional to a particular metabolite signal strength. In this example, the red indicates high concentration of choline that co-localizes with the contrast-enhancing mass lesion.

The proton echo-planar spectroscopic imaging (PEPSI) sequence can be based on either STEAM or PRESS; it uses standard phase encoding (PE) in the x-direction, while PE in the y-direction is replaced by bipolar gradients, switching during data acquisition (141). Spiral trajectories in k-space allow even faster encoding of spatial information due to faster gradient duty cycle (142,143). In spiral imaging, k-space is filled by spiral readouts that are produced by sinusoidally varying gradients in both the x- and y-axes. Recently, Andronesi et al. (144) implemented a 3D volumetric in vivo MRSI sequence using spiral trajectories and compared spectra acquired with a conventional PE sequence (1 cm3 voxels) with spectra acquired with the spiral encoding at similar and higher spatial resolution (0.39 cm3 voxels) and with shorter imaging time. 3D MR spectroscopic images were acquired 4x faster with spiral protocols than with the elliptical PE protocol at low spatial resolution (1 cm3). Higher–spatial resolution images (0.39 cm3) were acquired twice as fast with spiral protocols compared with the low–spatial resolution elliptical PE protocol. These improvements in image quality and imaging time allow more routine acquisition of spectroscopic data in the clinical setting (Fig. 30.6).

FIGURE 30.6 3D laser spiral MRSI. The fast spiral readout allows full 3D tumor sampling in approximately 7 minutes while maintaining high resolution (0.7 × 0.7 × 0.7 cm3 = 0.34 cm3) and an acceptable signal-to-noise ratio (SNR) (144).

Sensitivity encoding (SENSE) or simultaneous acquisition of spatial harmonics (SMASH) offers a new, highly effective approach to reducing the acquisition time in spectroscopic imaging. Phased array RF coils increase sensitivity especially in the cortical areas compared to conventional head coils. Compared to conventional fast CSI techniques, this method permits a reduction in the number of PE steps in each PE dimension. Fourfold reduction of scan time is achieved at preserved spectral and spatial resolution, maintaining a reasonable SNR (145,146). Another more time-efficient way to sample the third spatial dimension can be achieved with a 3D hybrid of 2D CSI and 1D fourth-order Hadamard spectroscopic imaging (HSI) sequence (147,148). CSI using PE with Fourier transformation methods suffers from two disadvantages: the field of view (FOV) 2096

needs to be larger than object to prevent aliasing extraneous signal and the spectral contamination from outside the voxel. The effect of the localization error or “voxel bleed” is reduced with increasing resolution. Thus, in a case where there are only a few partitions, for example, four in z-direction, Hadamard encoding is superior to CSI in the accuracy of localization. Water and Fat Suppression Brain metabolite concentrations are on the order of 10 millimolar (mM) or less compared with the ∼80 M concentration of water protons (149). Additionally, the extremely large lipids within skull, marrow, and extra cranial fat are also present in high concentrations (150). Therefore, it is essential to suppress the water and the lipid peaks to reliably measure the metabolite contractions. Water suppression can be accomplished by chemical selective saturation (CHESS) pulse on the water signal at 4.7 ppm (151), thereby suppressing the water signal 1,000- to 10,000-fold. The residual water may then be used as internal reference for phasing and frequency correction. The suppression efficiency in CHESS is affected by T1 relaxation and RF-pulse flip angles (which depend on B1) and sequence timing. Ogg et al. (152) introduced a water suppression scheme that is independent of B1 and T1, called WET (water suppression enhanced through T1 effects). This method uses four frequency-selective RF pulses with different numerically optimized flip angles and thus producing better water suppression without time-consuming optimization prior to each measurement.

FIGURE 30.7 MRSI data recorded using multi-slice MRSI pulse sequence with CHESS water suppression and outer volume saturation band lipid suppression. Metabolite images of Cho, Cr, and NAA from one slide of the level of the lateral ventricles in a normal volunteer (52-year-old white male). Scan parameters were TR 2,300 TE 280, 32 × 32 matrix, 4 slices (only 1 shown), 15 mm thick, nominal voxel size 0.8 cc. NAA is fairly evenly distributed at this level while choline shows an increase from posterior to anterior brain regions. (Courtesy of Dr. Peter Barker, Johns Hopkins University School of Medicine, Baltimore, MD.)

Lipids may be avoided by placing the VOI completely inside the brain excluding skull to avoid signal from marrow and subcutaneous fat. Additionally, or as an alternative, outer volume suppression (OVS) pulses are used for further lipid suppression (153). An inversion pulse scan can also be used for lipid suppression (154), taking advantage of the fact that T1 relaxation times of most metabolites vary between 1,000 and 2,000 ms while spin–lattice relaxation time of lipids are much shorter (approximately 300 ms). Figure 30.7 illustrates typical MRSI data recorded using eight OVS pulses arranged in an octagon on axial slides in order to saturate as much pericranial lipids as possible while the signal from the brain is unperturbed (153).

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FIGURE 30.8 Effect of TE. Top: Proton MR spectrum obtained at short echo time (TE = 35 ms). Middle: MR spectrum obtained at intermediate echo time (TE = 144 ms). Bottom: MR spectrum obtained at long echo time (TE/TR = 288 ms). All spectra were acquired at 3 T with a single-voxel PRESS sequence from the parietal gray matter with 128 acquisitions, TR 1,500 ms.

Acquisition Parameters As with MRI, the choice of TE and repetition time (TR) can have an enormous effect on the appearance of the information obtained in a proton MRS study. MR spectra obtained with shorter TEs (∼30 ms) allow the detection of more metabolites including glutamate, glutamine, and mI. However, the baseline is typically more complicated due to increased lipid and macromolecular background signals. Spectra obtained with longer TEs (144 or 288 ms) depict reduced number of metabolites. But, spectra are easier to process and analyze due to the relatively flat baseline (Fig. 30.8). In addition, lactate (1.3 ppm) and alanine (1.5 ppm) doublets are inverted, thereby allowing better differentiation between these metabolites and lipids/macromolecules. Spin–lattice relaxation times for selected resonances at 1.5 T vary between 1,100 and 1,700 ms (155). Ideally, one has to wait three times T1 (3 × 1,500 ms = 4,500 seconds) to gain approximately 95% of the original magnetization. With longer TR (>3 seconds), the SNR and the quantification improve. However, a long TR results in a long exam time. Therefore, typical TRs for clinical MRS experiments lie between 1 and 3 seconds. Field Strength Unfortunately, MRS suffers from inherently low SNR resulting in MRSI with low spatial resolution because the targeted metabolites are dilute. MRS SNR can be improved significantly by using higher magnetic field strengths since the SNR is proportional to B0, according to Equation (6): with Nv being the number of spins and T the temperature. Figure 30.9A shows the spectra from the parietal cortex obtained at three different field strengths, 1.5, 3.0, and 7 T of a healthy nonhuman primate. The SNR becomes higher at higher fields. The increased chemical shift dispersion at 7 T results in greater separation of the resonance peaks, and as a consequence, allows for better quantification of those metabolites that generally overlap with others such as glutamate and glutamine (collectively called Glx) and mI. Figure 30.9B shows a 7-T spectrum of the parietal cortex obtained using a STEAM (TE = 20 ms) sequence with a transverse electromagnetic (TEM) head coil optimized for macaque studies. Improvements in spectral resolutions are evident. Excellent resolution in in vivo 1H NMR spectroscopy of human brain at 7 T has been reported using ultra-short echo-time STEAM sequences (67).

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FIGURE 30.9 Effect of FIELD STRENGTH. A: Single-voxel 1H MRS spectra from the parietal cortex of rhesus macaques obtained at three different field strengths, 1.5 T (left), 3.0 T (middle), and 7 T (right). Increasing magnet field strength produces an approximately linear increase in the signal-to-noise ratio. B: Single-voxel 1H MRS STEAM spectrum from the parietal cortex obtained of a rhesus macaque at 7 T. High field strength also improves spectral dispersion. For example, the glutamate and glutamine resonances at 2.35 and 2.45 ppm were clearly separated. In addition, we could detect J coupling between the CH2 protons of myo-inositol. Acquisition parameters include TE = 15 ms, TR = 3000 ms, VOI 1.2 × 1.2 × 1.2 cm3, 196 acquisitions. (Adapted from Ratai EM, Pilkenton S, He J, et al. CD8 +lymphocyte depletion without SIV infection does not produce metabolic changes or pathological abnormalities in the rhesus macaque brain. J Med Primatol 2011;40(5):300–309.)

Editing Techniques Splitting of resonance lines into multiplets due to J-modulation results in signal loss and cancellation, and can make the quantification of an MR spectrum more challenging (157,158). In addition, many resonances of similar frequencies in the proton MR spectrum overlap. To overcome overlap, there are two major strategies for spectral editing in vivo. One method is based on difference spectroscopy and editing the other one on multiple quantum filtering. In difference editing, a selective and nonselective spin-echo spectra are acquired; the difference spectrum contains the target metabolite signal while all other contributors will be nulled (159,160). For the detection of GABA, the MEGA-PRESS (MEshcher–GArwood Point RESolved Spectroscopy) sequence (82) is currently the most widely used MRS technique (161). The sequence involves the collection of two interleaved datasets: In one dataset, an editing pulse is applied to GABA spins at 1.9 ppm in order to selectively refocus the evolution of J-coupling to the GABA spins at 3 ppm (often referred to as ‘ON’). In the other, the inversion pulse is applied at 7.5 ppm so that the J-coupling evolves freely throughout the TE (often referred to as ‘OFF’). Subtraction of the nonrefocused OFF spectrum from the refocused ON spectrum retains only those peaks that are affected by the editing pulses. Thus, in vivo, the edited spectrum contains signals close to 1.9 ppm (those directly affected by the pulses), the GABA signal at 3 ppm (coupled to GABA spins at 1.9 ppm), the combined glutamate/ glutamine (Glx) peaks at 3.75 ppm (coupled to the Glx resonances at approximately 2.1 ppm), and Jcoupled macromolecular (MM) peaks. Figure 30.10 shows two GABA-edited spectra acquired from the parietal lobe of a healthy 9-year-old boy. Multiple quantum filtering can be done in just one sequence, exploiting the difference between coupled and uncoupled metabolites (162).

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FIGURE 30.10 GABA edited spectrum acquired from a 3 × 3 × 3 cm3 ROI centered in the precuneus region in a healthy 9-year-old boy. For the detection of GABA, the MEGA-PRESS (MEshcher–GArwood Point RESolved Spectroscopy) sequence (82) has been used. Data were acquired at 3 T using a 32-channel receiver coil. Data parameters: TE/TR = 68 ms/1,500 ms, spectral width = 2 kHz and 160 acquisitions (8 minutes).

Regional Variations Regional differences in metabolite concentrations occur throughout the brain. There are differences between white and gray matter (GM), as well as between cerebrum, cerebellum, brainstem, and deep gray structures (Fig. 30.11). Moreover, there are differences between individuals. To properly evaluate a disease process in the brain, it is best to compare spectra from the voxel of interest to one from a similar location in a normal brain. In the case of the cerebrum, comparison with a voxel localized to a similar location within the contralateral hemisphere is appropriate. Spectral Quantification There are longstanding discussions and disputes on the best way to quantify MRS signals, specifically relative versus absolute quantification. The total area under the metabolite resonance peak is proportional to the concentration of that specific metabolite and the integration of this area is primary task needed for quantification. The easiest method is to employ metabolite ratios such as NAA/Cr or Cho/NAA. Ratios reported using creatine as an internal standard is often based on the assumption that the Cr concentration does not change during the disease process which is sometimes, but not always true. Alternatives include ratios of each metabolite of interest to the sum of metabolites, or using the spectral information from normal brain as a reference. Ratios are relatively easy to determine and are more reproducible than absolute concentration determination. However, when a change is detected, it may not be possible to determine whether it is due to a change in the numerator, denominator, or both. Absolute quantification of brain metabolites by MRS is more difficult, and they are generally expressed in units of mmol/kg.

FIGURE 30.11 MRS regional variations in normal adult brain. 1H MRS spectra are shown of a 30-year-old female adult brain from white matter (WM), gray matter (GM), basal ganglia (BG), and cerebellum (CB) using an 8-cc voxel, TR/TE = 2,300/30 and 160 averages at 1.5 T.

Methods used for absolute quantification include (a) phantom replacement techniques in which the in vivo metabolite concentrations will be estimated from the ratio of the in vivo and phantom signals, with corrections for differences in T1 and T2 relaxation times, RF coil loading, and receiver gain (163–166), (b) the use of unsuppressed water signal as a reference (167–169); (c) the use of an external reference 2100

(170,171), and (d) reciprocity (172). To date automated parametric spectral analysis methods have been implemented to quantify metabolite concentrations. These methods seek to determine the optimum parameters that enable some functions (so-called model functions) to best describe the MRS data. These model functions are based on prior information. Fortunately, considerable information on the observable metabolites and their spectral characteristics are available (4). Parametric modeling based on a priori spectral information has been made reasonably robust (30,173–177). Spectral fitting can be done in the time (178) or frequency domain (179). Currently, the most commonly used MRS analysis programs are LCModel (30,180,181) and jMRUI (182,183). Limitations of Clinical MRS A major limitation associated with in vivo MRS is due to the low SNR resulting in coarse spatial resolution; however, there are others. We will identify a few of the more important. B0 Inhomogeneities MRS is very sensitive to magnetic field (B0) inhomogeneities that cause broad line widths. This can result in peak overlap and poor quantification. Therefore, shimming to optimize B0 homogeneity at the beginning of each spectral acquisition is mandatory, in order to obtain narrow line widths in the MR spectrum. To minimize B0 inhomogeneities, a shimming procedure is used for both MRS and MRI. The MR instrument uses several additional coils that produce static magnetic field gradients designed to correct the existing field inhomogeneity. Voxel Location Proximity of the VOI to the paranasal sinuses and mastoids can result in line broadening and susceptibility artifacts. Additionally, iron and minerals that accumulate in the basal ganglia cause susceptibility broadening, resulting typically in lower-quality spectra. As previously stated, proximity of the VOI to scalp can result in contaminating lipid signals. However, techniques to suppress lipid signals can minimize this problem. There are limitations to the spatial selectivity of the MR spectrum. The spectrum for any given voxel contains contribution from neighboring voxels because the point-spread function is not an ideal cube (184). B1 Inhomogeneities MRI, MRS is also subject to chemical shift artifacts. The chemical shift between NAA and choline nuclei is about 1.3 ppm (∼85 Hz at 1.5 T, ∼250 Hz at 3 T, and 450 Hz at 7 T). Because of this difference in resonance frequency between NAA and Cho protons, spatial misregistration takes place when converting the MR signals from the frequency to the spatial domain by the Fourier transformation. To minimize these, saturation bands positioned outside the visible VOI have been employed. In addition, there is a focus to using adiabatic pulses to compensate for RF inhomogeneity and reduce the chemical shift displacement error (131,185).

FIGURE 30.12 Reproducible high MR spectral quality from multiple sites. 1H MR spectra were acquired at three different sites from cerebellar volume of interest (10 × 25 × 25 mm3, as shown on T1-weighted midsagittal image) in three healthy individuals. Spectra were obtained with 3.0-T MR units with same acquisition protocol (fast automatic shimming technique by mapping along projections, or FASTMAP, semi-LASER [localization by adiabatic selective refocusing] (203), 5,000/28, 64 repetitions). (Spectra from the Center for Magnetic Resonance Research, University of Minnesota; courtesy of Gülin Öz, MGH = Massachusetts General Hospital and Hôpital de la Salpêtrière courtesy of Fanny Mochel, MD, PhD) (Adapted from Oz G, Alger JR, Barker PB, et al. Clinical proton MR spectroscopy in central nervous system disorders. Radiology 2013;270(3):658–679, with permission.)

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Poor patient cooperation resulting in motion artifacts often limits the feasibility of MRI and MRS. Anesthesia is not always feasible and, in addition, carries risks to the patients (102). Thus motioncorrected sequences have been employed that may allow for the reduction in the need for sedation. Using new techniques such as propeller MRI, it has become possible to oversample k-space and thereby compensate for motion and allow follow-up MRI without sedation (186,187). As alternative to retrospective motion-corrected techniques, it is also possible to prospectively correct motion. Using image-based navigators, it is possible to correct motion in structural imaging, single-voxel and multivoxel spectroscopy prospectively (188–194). Reproducibility In clinical studies, reproducible measurements of metabolite concentrations are of paramount importance for detecting the effect of the disease or treatment in an individual or in a group. Several studies have been performed on the reproducibility of quantitative MRS of the human brain using SVS (195–199) and spectroscopic imaging methods (200–202). While intra-individual CVs for single-voxel MRS were reported to vary between 3.3% and 8.1% for absolute quantification (196), reproducibility of metabolite ratios obtained with MRSI was somewhat poorer. Importantly, standard clinical hardware generates reproducible MRS data from the human brain in a multicenter setting provided that identical and optimized acquisition protocols and calibration schemes are used (Fig. 30.12). The following summarizes the technical factors necessary for a clinically interpretable MR spectrum of the brain: Spectrum SNR >3 for major resonances Spectral resolution: full width at half maximum (FWHM) of metabolites 98% No lipid contamination from the scalp Artifacts such as chemical shift artifact, ghosting, patient motion, eddy currents, and volume averaging are absent or minor. Details on these technical criteria can be found in the following paragraphs and in a comprehensive review by Kreis et al. (204): Nonproton MRS MRS can be performed using nuclei other than 1H such as 13C, 19F, 31P, etc. 1H is most commonly used because it has the highest sensitivity compared to the other nuclei, and 1H MRS is easy to perform as we can use the same RF coils that are also used for standard MRI.

FIGURE 30.13 2D 31P CSI spectra of the brain of a healthy 10-year-old boy. Data were acquired with a 3.0-T MR unit using an 8-channel receive 31P coil and 31P birdcage transmit coil. Localization was confirmed using the 1H body coil. MRS data were acquired using a CSI-FID sequence with TR 1,500 ms, 32 averages, and 8 × 8 phaseencoding steps. 31P MRS is informative on cellular bioenergetics because it can measure adenosine triphosphate

(ATP) and phosphocreatine (PCr). It may also be used to measure phosphodiester compounds (PDEs), inorganic phosphate (Pi), and phosphomonoester compounds (PMEs). The chemical shift of the Pi peak is pH dependent and is commonly used for in vivo measurement of intracellular pH. Phosphorus has a larger chemical shift range (approximately 25 ppm) than protons (approximately 10 ppm). Solvent, for 2102

example, water suppression schemes are not required for 31P MRS; however, the strength of the MR signal is approximately an order of magnitude lower than those from protons. Thus, lower spatial resolution and/or longer exam times are required in 31P MRS to achieve adequate SNR. Despite these limitations, 31P has successfully been employed in brain (184,205–213), muscle (214–216), liver (217,218), heart (219–222), kidney (223,224), and prostate (225), as well as other regions (Fig. 30.13). The chemical shift range of 13C (∼200 ppm) is even greater than 31P; however, its natural abundance is only 1.1%, thus only metabolites with high intracellular concentrations such as liver and muscle glycogen can be detected. Infusion of 13C labeled glucose has revealed details of important metabolic pathways (226,227). Fluorine-19 has a natural abundance of 100% and has a high intrinsic sensitivity making it an excellent candidate for in vivo monitoring of fluorine-containing drugs (228). Other nuclei that have been used for clinical applications are 23Na, 39K, 7Li, and 17O.

BIOLOGIC BASIS OF THE NORMAL AND ABNORMAL IN VIVO BRAIN MR SPECTRUM 1H MRS Changes in Neurologic Disease Other than Neoplasia Within a 1H MRS voxel localized to the brain, there exists a complex arrangement of different cell types. The most important cell is the neuron, which is responsible for the function of the brain. However, there are a large number of supporting cells that are required for normal neuronal function. These include astrocytes, oligodendrocytes, microglial cells, immune cells, as well as cells related to the vasculature and blood. Each cell type has its unique MR spectrum as was demonstrated by Urenjak et al. (13,14). With neurologic disease, there are qualitative and quantitative changes in the complicated cellular milieu of the brain. These alterations are the basis for the abnormal MR spectrum that is observed with neurologic disease. In a landmark study, Urenjak et al. isolated pure collections of each of the major cell types of the brain. Using high-field NMR spectroscopy, they demonstrated that each cell type had a distinct 1H MR spectrum. This observation is reasonable because that it is expected that each cell type has a unique function that is reflected by a unique pattern of gene activation, protein synthesis, and ultimately metabolism. Thus the proton MR spectrum of a specific cell is a fingerprint that depicts the steady-state levels of the major biochemical components of that cell’s metabolic condition. When considering the spectrum derived from a voxel from the brain, it is best to consider the spectrum as a sum of individual spectra derived from each of the cells that make up the contents of the voxel that was sampled. The abnormal MR spectrum reflects a response of the brain to a stimulus or injury of some type. Depending on the stimulus, the cell population that is affected can respond in a global fashion or in a multifaceted manner by the constituent cells. An example of a global effect is the case of ischemia or hypoxia. In this case all the cells respond nearly at the same time by shifting to anaerobic metabolism. The result is increased lactate production and the appearance of the lactate resonance in the spectrum. In this situation all the cells are contributing in a similar fashion. In other disease states, the response is more complex. Other responses to brain injury can be separated into two categories. One type is an intracellular response. Examples of this are cell activation such as astrogliosis and microgliosis. The 1H MR spectrum that accompanies gliosis is thought to be an elevation of Cho and mI, but the relationship is complex and not well understood (229). Another example of intracellular response is the decline in NAA in neurons when they are injured (23). There can also be changes in the cell population within the voxel that is being probed. This can occur with an inflammatory process with an influx in the number of immune cells. Here elevated Cho is observed because of the normally high level of the cholinecontaining metabolites that normally occur in leukocytes. The other cell population change that can occur is cellular loss. The most common is the loss of neurons that occurs, for example, in neurodegenerative diseases, will be reflected in a decline of NAA. Of course, some or even all of these changes can occur simultaneously. 1H MRS Changes in Neoplasia In the 1H MR spectrum, the hallmark of neoplasia is an elevation of the Cho resonance which is observed in cancers arising from all parts of the body including the brain. As stated before, the Cho resonance is complex and the signal arises primarily from lipid precursor and degradation products 2103

including GPC and PCho. The increase in the Cho resonance is thought to arise from increased membrane turnover that occurs in rapidly dividing cells. In general, more rapidly dividing cells have increased membrane turnover and a higher steady-state level of the Cho resonance. Thus, a higher Cho resonance is more commonly seen in higher-grade tumors that are usually dividing at a higher rate than other lower-grade tumors. Just like each brain cell type exhibits a unique MR spectrum, each neoplastic cell type also has a unique spectrum (230). The occurrence of a brain mass represents a change in cell population at that location and the MR spectrum of a voxel containing a brain tumor may reflect this new cell type that is partially or completely displacing normal cells of the brain. The specific spectral pattern depends on the percentage of the voxel that is occupied by tumor cells, the amount of normal brain cells, and responses of normal brain cells to neoplasm. The simplest pattern to interpret occurs when brain tumor occupies nearly the entire voxel of the MR spectrum. In this situation virtually the entire signal arises from neoplastic cells and evaluation of the Cho level most closely reflects the grade of the tumor. But even within a pure tumor sample, complexity can arise because many tumors are heterogeneous, especially glioblastoma multiforme (GBM). In this type of tumor there may be regions of necrosis, hemorrhage, and inflammatory response. It has been demonstrated that distinct regions of the same GBM has discrete spectral pattern (231). Tumor heterogeneity is one source of complexity in interpreting the spectrum from a brain tumor. The other is volume averaging which is common in the case of infiltrating tumors such as gliomas. In malignant infiltrative tumor, neoplastic cells may only occupy a relatively small volume of the MRS voxel. For these reasons, a simplistic interpretation of the Cho resonance height can lead to an erroneous conclusion. For example, consider a situation where the malignant tumor cell has a Cho-to-Cr ratio of 5 to 1. If this tumor is infiltrative, and only comprises 25% of an MRS voxel, the apparent elevation of Cho to creatine would only be less than 2 to 1. A simplistic interpretation would suggest that this is a low-grade tumor. However, the reality is that it is an infiltrating high-grade tumor comprising a small fraction of the voxel that is being sampled. This conundrum may be partially solved by taking the NAA resonance into consideration. By focusing on the NAA one can estimate how much of the voxel being sampled contains normal cells. One can then qualitatively interpret how much of the voxel is normal tissue and attempt to assign a true Cho level of the neoplastic cells.

CLINICAL APPLICATIONS OF MR SPECTROSCOPY OF THE BRAIN Class A MRS Applications: Useful in Individual Patients Brain tumors Pediatric disorders Focal infections Class B MRS applications: occasionally useful in individual patients Ischemia, cardiac arrest, hypoxia and related cerebral insults Epilepsy Class C MRS applications: primarily of relevance to groups of patients Neurodegenerative diseases Traumatic head injury Hepatic encephalopathy Psychiatric disorders MRS changes with age in the normal brain The brain 1H MR spectrum has been shown to be altered in practically all neurologic diseases. The changes may be profound or subtle; the greater the change, the higher the likelihood that it can be reliably demonstrated by clinical MRS instrumentation. This hierarchy of MRS change defines to a large extent its clinical utility. In certain diseases, notably brain tumors, the brain spectrum may be so altered that it is readily and reliably observed, and thus it may be clinically useful in individual patients. In other diseases, the changes may be so subtle that statistical comparisons between groups of patients are required for the changes to be detected. 1H MRS in these diseases has very limited clinical utility for individual patients, but may be very informative in clinical research including drug studies. In this section, the clinical applications of 1H MRS are organized by this hierarchy of clinical utility. Class A MRS Applications: Useful in Individual Patients MRS of Brain Tumors 2104

The evaluation of brain masses, most importantly intra-axial masses, is the most common clinical application of MRS (232). It plays an important role in helping to differentiate a neoplasm from mimics such as MS and subacute ischemic infarction. MRS can also help to grade tumors, and to distinguish primary CNS neoplasms from metastasis. Another major application in this clinical arena is in the assessment of enhancing masses that arise at sites of previous resection of high-grade neoplasm followed by high-dosage radiation. In this circumstance, MRS helps in the clinically critical question of differentiating radiation change from recurrent tumor. Finally, with the advent of anti-angiogenic treatments, for example, bevacizumab, distinguishing actual tumor response from “pseudo-response” (due to blood–tumor barrier improvement that results in decreased contrast leakage on conventional MRI) has become challenging. However, recent studies suggest that MRS is able to distinguish tumor response to anti-angiogenic therapy from “pseudo-response.” DIFFERENTIATING BRAIN NEOPLASMS FROM NONNEOPLASTIC BRAIN MASSES. The biochemical information provided by MRS must always be interpreted within the context of the other available imaging information including structural (T1, T2, postcontrast imaging, etc.) and functional (diffusion, perfusion) data when available. The typical 1H MR spectrum of a neoplasm depicts a substantial elevation of Cho and a reduction of NAA, and little or minor changes in Cr (Fig. 30.14). The degree of Cho elevation depends on the metabolic activity of the neoplastic cell and the proportion of neoplastic to normal cells within the voxel of interest. The infiltrative nature of CNS gliomas results in variable neoplastic cell densities that produce variable Cho elevations and NAA deficits. Thus a high Cho-to-NAA ratio is a strong indicator of a higher-grade neoplasm, but a low Cho-to-NAA ratio could arise from a low-grade neoplasm, low neoplastic cellular density or nonneoplastic processes such as MS. Cr is typically decreased in astrocytomas and meningiomas (32) as well as schwanomas and metastases (33,34). mI levels may help in suggesting the grade of cerebral astrocytomas, as its concentration is typically high in low-grade gliomas and low in high-grade gliomas (Fig. 30.15) (32,53). Under normal conditions Lac is present in very low concentrations ( 6 months) and nonprogression-free survivors at 6 months (PFS ≤ 6 months). Error bars represent standard error of the mean. The number of patients is noted on the bottom. A decrease in NAA/Cho levels in the tumor at 8 weeks posttreatment was associated with failure of 6-month progression-free survival and overall survival. (Adapted from Ratai EM, Zhang Z, Snyder BS, et al. Magnetic resonance spectroscopy as an early indicator of response to anti-angiogenic therapy in patients with recurrent glioblastoma: RTOG 0625/ACRIN 6677. Neuro Oncol 2013;15(7):936–944.)

FIGURE 30.25 MRSI of a patient with GBM with IDH mutation. The spectra reveal elevated Cho (A–C). Spectral editing MRS reveals 2HG (D). After resection, the tumor was found to have a R132G IDH mutation (Courtesy of Ovidiu Andronesi. [Andronesi OC, Rapalino O, Gerstner E, et al. Detection of oncogenic IDH1 mutations using magnetic resonance spectroscopy of 2-hydroxyglutarate. J Clin Invest 2013;123(9):3659–3663]).

Most recently, MRS has been used to identify molecular subtypes of gliomas with enzyme isocitrate dehydrogenase (IDH) mutations (250). Patients with IDH1 gene mutation have a much greater survival rate compared to patients with wild-type IDH1 gliomas. Mutations in the IDH lead to the accumulation of the metabolite 2-hydroxyglutarate (2HG) which can be detected by spectral editing and 2D correlation magnetic resonance spectroscopy (COSY) (251). By detecting 2HG MRS may be useful in predicting patient outcomes (Fig. 30.25).

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EXTRA-AXIAL TUMORS. The contribution for MRS in the evaluation extra-axial brain tumors is limited. This is because such masses are rarely diagnostic dilemmas. Moreover, tumors such as meningiomas and choroid plexus papillomas can have very high levels of Cho even when these tumors are low grade by histologic criteria and clinical behavior. The reasons behind such an observation are unclear, but the radiologist must be aware of them (Fig. 30.26). MRS of Inborn Errors of Metabolism MRS is valuable in pediatric brain disorders that are due to inborn errors of metabolism. These include the leukodystrophies, mitochondrial disorders, and enzyme defects that cause an absence or accumulation of metabolites. For some of these diseases, MRS can be diagnostic. CANAVAN’S DISEASE. An example of such a disorder is Canavan’s disease, a childhood leukodystrophy caused by mutations in the gene for aspartoacylase whose role it is to break down of NAA to acetate. The abnormal accumulation of NAA in the brain can be detected by in vivo MRS (95). Figure 30.27 shows a 21-month-old boy suffering from Canavan’s disease. The lack of NAA’s further metabolism interferes with the growth of the myelin sheath of nerve fibers in the brain. Symptoms include intellectual disability, loss of previously acquired motor skills, feeding difficulties, abnormal muscle tone (i.e., floppiness or stiffness), poor head control, and megalocephaly.

FIGURE 30.26 Choroid plexus papilloma. Lobulated, intensely enhancing mass within the third ventricle. Biopsy resulted in a diagnosis of a choroid plexus papilloma. Single-voxel spectroscopy from the mass reveals a very high level of Cho, which is often seen in extra-axial tumors.

FIGURE 30.27 MRS of 6-month-old boy diagnosed with Canavan’s disease. The figure shows FLAIR image (left) and single-voxel MRS of the frontal white matter of a 21-month-old boy with Canavan’s disease. MR spectroscopy reveals abnormally increased NAA peak in the white matter characteristic for Canavan’s disease. FLAIR images show abnormally increased T2 signal intensity in the white matter.

PHENYLKETONURIA (PKU). Phenylketonuria (PKU) is caused by a deficiency of an enzyme called phenylalanine hydroxylase (PAH) that breaks down excess phenylalanine from food. The inability to break down phenylalanine results in an accumulation of phenylalanine which can be detected by proton MRS (96,97). GLYCINE ENCEPHALOPATHY (NONKETOTIC HYPERGLYCINEMIA). Glycine encephalopathy (nonketotic hyperglycinemia) is caused by a defect in the glycine cleavage system (GCS), an enzyme complex that normally breaks down glycine in the body. As a consequence, elevated glycine levels can be detected in the MR spectrum at intermediate TEs (Fig. 30.28). Symptoms of nonketotic hyperglycinemia include seizures and developmental delay (91,98–100). MAPLE SYRUP URINE DISEASE. MSUD is an inherited disorder in which the body is unable to process amino acids. The condition gets its name from the distinctive sweet odor of affected infants’ 2112

urine. If untreated, MSUD can lead to seizures, coma, and death. The accumulation of abnormal branched-chain amino acids and branched-chain alpha-keto acids peak at 0.9 ppm, accompanied by elevated lactate, are manifested in MSUD patients’ MR spectra (Fig. 30.29) (101,253). CREATINE DEFICIENCY. There are three cerebral creatine deficiency syndromes: two creatine biosynthesis defects, (1) guanidinoacetate methyltransferase (GAMT) deficiency and (2) Larginine:glycine amidinotransferase (AGAT or GATM) deficiency; and (3) a creatine transporter defect, creatine transporter (SLC6A8) deficiency (254). Epilepsy and developmental delay are common in all three types. Figure 30.30 shows a patient with creatine deficiency. 3 months of Cr monohydrate resulted in a normal-appearing spectrum (102,103).

FIGURE 30.28 MRI MRS exam of a patient with glycine encephalopathy (nonketotic hyperglycinemia). Axial T2 (A), short-echo MRS (B), and intermediate (144 ms) MRS (C) in a neonate. The short-echo spectrum demonstrates a composite mI and glycine resonance. The intermediate echo demonstrates glycine. (Courtesy: Otto Rapalino.)

FIGURE 30.29 MRS exam of a patient with maple syrup urine disease (MSUD). The accumulation of abnormal branched-chain amino acids and branched-chain alpha-keto acids peak at 0.9 ppm, accompanied by elevated lactate, are manifested in MSUD patients’ MR spectra. In addition, NAA levels are decreased in MSUD patients. (Reprinted with permission from Jan W, Zimmerman RA, Wang ZJ, et al. MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 2003;45(6):393–399.)

GALACTOSEMIA. In individuals with galactosemia, the enzyme which metabolizes galactose is either diminished or missing which leads to the accumulation of toxic levels of galactitol which can be detected by proton MRS as multiplet at ∼3.7 to 3.9 ppm (107). The only treatment for galactosemia is eliminating lactose and galactose from the diet. COMPLETE ABSENCE OF NAA. The complete absence of NAA has been reported once in the brain of a 3-year-old child with neurodevelopmental retardation and moderately delayed myelination (255). LEUKODYSTROPHIES. Although not specific, MRS does provide characteristic metabolic information in many other types of inborn errors of metabolism including leukodystrophies and mitochondrial disorders. Demyelinating leukodystrophies are generally characterized by increases in Cho and mI and a reduction in NAA. In severe cases lactate can be detected (Fig. 30.31). Follow-up studies are important to monitor disease progression characterized by gliosis, demyelination, and axonal damage to make a prognosis and subsequent choice of therapy. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder characterized by accumulation of very long chain fatty acids in the CNS, adrenal cortex, and 2113

testes. In children, X-ALD may manifest as rapidly progressive inflammatory demyelination (256). In adults, ALD manifests in axonal loss in the spinal cord, so-called adrenomyoloneuropathy (AMN); however, cerebral demyelinating lesions can also occur. Although it is not possible to predict phenotype by mutation analysis or biochemical assays, MRSI is able to identify impending or early stages of degeneration in WM that still appears normal on conventional MRI (108,109). Single-voxel MRS at high field has revealed extensive neurochemical changes in childhood ALD (110). Decreases in NAA/Cr in cortical GM have been reported in male patients with cerebral ALD (111).

FIGURE 30.30 MRI and MRS of a 2.5-year-old child with creatine deficiency. A: MRI and MRS of 2.5-year-old child with mental retardation, seizures, and speech delay. Conventional MRI showed two 3-mm nonspecific hyperintensities deep to the facial colliculi (not shown here) and was otherwise normal. 1H MRS at 1.5 T and TE 144 showed absence of the normal creatine resonance at 3.0 ppm. Serologic testing showed low levels of creatine and guanidinoacetate consistent with arginine:glycine amidinotransferase (AGAT) deficiency. B: 3 months of oral Cr monohydrate replacement therapy resulted in a normal-appearing spectrum.

MITOCHONDRIAL DISORDERS. Mitochondrial diseases such as MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) are characterized by increased lactate; however, increases in lactate are not specific, and are also found in high concentrations in hypoxia and inflammation. MRS of patients with MELAS show variable results in lactate levels depending on the stage of a strokelike episodes (Fig. 30.32) (115).

FIGURE 30.31 MRS of 6-year-old boy diagnosed with X-linked adrenoleukodystrophy. A: A 6-year-old boy presented with behavioral abnormalities, followed by gait and speech difficulties and hearing loss. Posterior periventricular lesions are seen on T2-weighted images. MRS spectra show increased Cho/NAA ratios in the peripheral, inflamed edge and the central area of the lesion. B: Follow-up scan 4 month later shows increased levels of lactate.

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FIGURE 30.32 Two cases of MELAS. Both cases show abnormal MRI on conventional and diffusion-weighted imaging. While the first case shows almost no lactate (A), case 2 shows significant elevation of lactate levels (B).

Complex I deficiency is one of the most common enzymatic defects of oxidative phosphorylation disorders and is also characterized by elevated lactate levels in the brain. Figure 30.33 shows the spectra of a 15-hour-old male baby whose initial manifestation at birth was that of hypoxic ischemic encephalopathy (HIE). MRS shows an elevated lactate peak consistent with ischemic injury. On follow up at 2 years, the child was found to have complex I ETC enzyme deficiency. This example emphasizes that the presence of a large lactate peak should raise suspicion of an underlying metabolic disorder even if clinical criteria for HIE are met.

FIGURE 30.33 MR spectrum of a 15-hour-old male baby, born with apnea and seizure activity. MR spectrum shows an elevated lactate peak consistent with hypoxic ischemic injury (HII). The second doublet at 1.1 ppm is most likely 1,2-propandiol, due to treatment with phenobarbitol, which metabolizes to 1,2-propandiol causing a detectable peak in the MR spectrum. On follow up at 2 years, this neonate was found to have a mitochondrial disorder (complex I ETC enzyme deficiency). Thus, the presence of a large lactate peak should raise suspicion of an underlying metabolic disorder even if clinical criteria for hypoxic ischemic injury are met.

Focal CNS Infections Brain infections are often life threatening and require prompt diagnosis. However, definitive laboratory diagnostic tests are often time consuming, thus delaying therapy (232). 1H MRS is able to distinguish abscesses from other cystic intracranial mass lesions and it can offer information about the type of infective agent (257,258). A single voxel should be placed at the center of the lesion thereby avoiding areas of calcifications, necrosis, or nonlesional tissue. An intermediate TE of 135 ms or 144 ms is ideal as it distinguishes Lac and amino acids from overlapping lipids between 0.9 and 1.3 ppm. MRS OF BACTERIAL INFECTIONS. It is not always possible to distinguish abscesses from other cystic intracranial mass lesions using conventional MRI. Abscesses and other cystic intracranial mass 2115

lesions may appear as ring-enhancing lesion on T1, postcontrast MR images. DWI may be helpful in distinguishing these types of lesion: High signal on DWI with low ADC is highly suggestive of brain abscesses indicating reduced diffusivity, while brain tumors usually have a low DWI signal and high ADC value (259,260). However, studies have shown that in the absence of restricted diffusion, MRS is useful to distinguish brain abscesses from cystic tumors (261). Spectra obtained from pyogenic abscesses are characterized by the elevation of cytosolic amino acids (leuine, ioleucine, and valine) which can be detected at 0.9 ppm, succinate at 2.4 ppm, acetate at 1.9 ppm, and alanine at 1.5 ppm, while NAA, Cho, and Cr are absent (260). Amino acids (AA) are the product by hydrolization of large amounts of neutrophils and proteins. Figure 30.34 shows an MRI/MRS study of a patient with a bacterial infection. Parasitic cysts contain succinate and acetate in the absence of amino acids, which helps differentiate them from pyogenic abscesses (258,262).

FIGURE 30.34 MRI/MRS exam of a 78-year-old male with a left frontal ring-enhancing cystic mass: pathologyconfirmed bacterial pyogenic abscess. The 78-year-old male has a history of known malignant pulmonary metastasis with recent right weakness paralysis and altered mental status. MRI shows an intra-axial, lobulated lesion in the left frontal lobe, showing smooth rim enhancement on T1 postcontrast images, and T2 hypointense center with extensive surrounding edema. In addition, there is mass effect on the left lateral ventricle with a midline shift to the right. The DWI is predominantly characterized by reduced diffusivity with a hypointense center of the lesion on ADC. Single voxel TE = 135 ms MRS shows presence of cytosolic AA, leuine, ioleucine, and valine at 0.9–1.0 ppm, Lac at 1.3 ppm and Ala at 1.5 ppm. Due to their characteristic J coupling, all these peaks are inverted at TE = 12 to 144 ms. Furthermore, a Gly peak can be seen at 3.6 ppm. Note the absence of Cho, Cr, and low NAA (attributed to minor contamination from suboptimal voxel placement over “normal” tissue). The lesion was resected and pathology confirmed a bacterial pyogenic abscess.

Furthermore, MRS is helpful in the differentiation of tuberculoma from other nontuberculous lesions such as metastasis, lymphomas, or other granulomas that have a similar appearance at conventional MRI. MRS from tuberculous abscess shows only Lac and lipid signals and no cytosolic amino acids (232). Figure 30.35 shows an MRI/MRS study of a patient with tuberculoma. MRS OF FUNGAL INFECTIONS. There is only limited literature on the spectral characteristics of fungal abscesses. In the majority of fungal abscesses, cytosolic AA and lactate are detected. In addition, peaks between 3.6 and 4 ppm were observed which have been assigned to represent trehalose, a component of the fungal wall (259,263). MRS OF VIRAL INFECTION. HIV infection can result in neurologic disease in two distinct manners. The immunodeficiency produced by the virus can result in opportunistic cerebral infections such as toxoplasmosis or CNS lymphoma. Second, the virus can directly affect the brain and can cause encephalitis that results in neurocognitive and motor abnormalities, commonly referred as HIVassociated neurocognitive disorders (HAND) which has been covered in CLASS C MRS Applications. Typical opportunistic infections include progressive multifocal leukoencephalopathy (PML), toxoplasmosis, neurosyphilis, and cytomegalovirus (CMV) encephalitis. One of the most common is toxoplasmosis which presents as enhancing masses or ring-enhancing lesions in the brain and can be difficult to differentiate from primary CNS lymphoma and pyogenic abscesses using structural imaging 2116

alone. Toxoplasmosis typically has a significantly lower level of Cho that is observed with lymphoma (264). Class B MRS Applications: Occasionally Useful in Individual Patients Ischemia, Hypoxia, and Related Brain Injuries A significant reduction of oxygen and nutrients such as glucose results in a rapid metabolic response by the brain. The intensity of the response depends on the severity of the deprivation and its duration. With a lack of oxygen, anaerobic metabolism ensues with the production of lactate that is visible on the MR spectrum (Fig. 30.36) (26,36,211,232,265–271). The absence of both oxygen and glucose that can occur in severe ischemia may result in some lactate production produced from stored levels of glycogen; typically, the levels of lactate in this circumstance are low. NAA is observed to decline shortly after the onset of hypoxic and/or ischemic injury. The rapidity of the decline, its extent, and duration also depends on the severity of the ischemia/hypoxia and its duration. ACUTE ISCHEMIC STROKE. The majority of acute ischemic strokes are caused by the occlusion of the cerebral artery by a thromboembolus. Depending on the size of the vessel occluded and the degree of collateral flow, a variety of changes can occur immediately after the event occurs in the brain regions adjacent to the occluded artery. If a major artery such as the middle cerebral artery is occluded, the nearby brain tissue typically will rapidly proceed to infarction; this region is the core of the infarction. With significant collateral flow there may be a large area of hypoperfused, symptomatic yet viable tissue. The latter region is often termed the ischemic penumbra. The most reliable clinical method for identifying the core is diffusion MRI. The penumbra can be estimated by several approaches. MRS can be useful in assessing the severity of ischemia within the region that is being perfused by collateral flow. With collateral flow adequate to maintain normal metabolism, the MR spectrum even in hypoperfused areas defined by MR perfusion imaging will appear normal. The further reduction of perfusion to frank ischemia will result in the elevation of lactate and the reduction of NAA in the 1H MR spectrum. If ischemia is reversed quickly or when only minor metabolic changes have occurred, then full recovery can be expected. However, if the ischemia has been severe, infarction will ensue and full metabolic recovery will not occur. The metabolic pattern of ischemic injury can be modulated using normobaric oxygen administration (Fig. 30.37) (270,272). The mechanism by which this modulation occurs is unclear. One possibility is that the diffusion of oxygen is sufficiently high that it can provide the return to a normal metabolic pattern within the penumbral zone. An alternative is that by some unknown mechanism normobaric oxygen administration results in an increase in perfusion.

FIGURE 30.35 MRI/MRS of a 31-year-old male with left occipital mass: pathology-confirmed tuberculoma. The subject had 3-year history of seizure disorder. A: The 3.5-cm mass centered within the left cuneus demonstrates T1 intrinsic hyperintensity. There is mild surrounding brain parenchymal volume loss and no significant intracranial mass effect. B: MR perfusion shows elevated CBV anteriorly within this mass. C–F: On MRS, mass demonstrates a prominent lipid peak, decreased NAA, and no evidence of elevated choline peak. Constellations of imaging findings favor a chronic infectious process, such as a tuberculoma. Subsequently, patient underwent surgical resection of the

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lesion for diagnostic and therapeutic purposes. Pathology confirmed tuberculoma.

CARDIAC ARREST AND GLOBAL HYPOXIA. Cardiac arrest results in complete cessation of blood flow to the brain. This of course can result in death if it is not reversed within a few minutes. With cardiopulmonary resuscitation, normal cardiac activity can resume blood flow to the brain. The injury sustained by the brain depends on the duration of lack of blood flow, and the MR spectrum can be variable in different regions of the brain. This reflects the variable susceptibility to severe hypoxic injury in different parts of the brain. A cardiac arrest of short duration may result in complete recovery of brain cell and the spectrum may appear normal. With more prolonged arrest, significant metabolic abnormalities can be observed by MRS despite the re-establishment of normal blood flow to the brain. The abnormalities include persistent elevation of lactate and reduction of NAA (Fig. 30.38) (273–279). NEAR DROWNING. In the case of near drowning, 1H MRS can provide valuable prognostic information as was demonstrated by Ross and colleagues (71,280). In studies of children who were rescued from near downing events, they showed that the spectra from those destined to recover fully were different from spectra of those who had a poor clinical outcome such as a persistent vegetative state. The most important parameter identified was the NAA/Cr level. If NAA/Cr is within normal limits or only mildly diminished, an excellent prognosis is highly likely. On the other hand, if NAA is well below normal, full recovery becomes much less likely. HYPOXIA/ISCHEMIA IN NEONATES. Hypoxic–ischemic injury (HII) continues to be a major cause of perinatal mortality and morbidity (281). Because the prognosis for any given baby is uncertain, reliable prognostic indicators are needed. The goal of MRI in HII lies in early detection, which could potentially influence therapy and predict outcomes. Diffusion MRI showing low ADC is very useful in identifying the extent of HII in these young patients (282). MRS can add additional information (43,283–285). The typical findings include a decline in NAA and an elevation of lactate (Fig. 30.33) (286). A persistent high level of lactate despite the restitution of normal oxygenated perfusion to the brain of neonates is an interesting observation that is not fully explained. Many investigators have shown that the presence of lactate is a reliable sign of a poor prognosis (285,287–291). A meta-analysis showed increased Lac and decreased NAA as the best predictors for adverse outcome (292). Most studies reported only metabolite ratios, however, Boichot et al. and others (286,293) showed that decreased absolute concentrations of NAA, Cr, and Cho are predictive of adverse outcome. Elevated glutamate/glutamine concentrations in patients with poor prognostic outcome are likely due to pathologic processes in which nerve cells are damaged (293,294). Epilepsy During seizure, the metabolic demands of brain cells can exceed the supply of oxygen and nutrients to the portion of the brain that is undergoing enhanced electrical activity. Under these circumstances, metabolic changes can be detected by MRS including the production of lactate (295,296), and if prolonged, the reduction of NAA. Abnormalities including the elevation of lactate can still be observed sometime after seizure activity ceases. It is uncommon to obtain MRS during seizure, and it is far more common for an MRS to be obtained interictally. The purpose is to help localize the source of the seizures. The most common clinical scenario for the use of 1H MRS is TLE. In this condition a large proportion of patients are refractory to medical management. It has been shown convincingly that surgical therapy is curative in most cases of TLE. However, identifying the correct side for resection is critical (Fig. 30.39).

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FIGURE 30.36 MRS of a patient with an acute stroke. The 65-year-old female with an acute stroke, scanned 3.5 hours after onset of aphasia and right-sided facial droop and visual neglect. An elevation of lactate and a mild reduction of NAA are seen in the left parietal lobe. (A) and (B) shows a spectrum from the contralateral side with normal metabolite ratios. Conventional FLAIR MRI at presentation only shows old lesions; however, at 1-week followup the region with elevated lactate (at presentation) has progressed to infarction. MRSI parameters include TR 1,700, TE 280 ms, 32 × 32 matrix, 3 slices (2 shown), 15 mm thick, nominal voxel size 0.8 cc. (Courtesy of Dr. Peter Barker, Johns Hopkins University School of Medicine, Baltimore, MD.)

FIGURE 30.37 Normobaric oxygen therapy in ischemic stroke. Patients with acute (0.9 for 8 hours. Serial MRI findings in a patient with cardioembolic right–MCA (middle cerebral artery) stroke treated with NBO for 8 hours. The baseline MRI, at the top, 7 hours postsymptom onset shows a large DWI lesion, a much larger MTT lesion, and occlusion of the MCA on the MRA. Right panel shows an elevation of lactate. The second MRI after 4 hours (during NBO) shows reduction in the DWI lesion, stable MTT deficit, persistent MCA–occlusion, and interestingly a reduction in lactate. A third MRI after 24 hours (post-NBO) shows reappearance of DWI abnormality in some areas of previous reversal; and increased lactate concentration (270,272).

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FIGURE 30.38 Resuscitation after cardiac arrest. A 72-year-old woman underwent MRI approximately 1.5 hours after being successfully resuscitated following cardiac arrest. MR angiography and perfusion MRI were normal. Diffusion MRI demonstrated multifocal regions of reduced diffusivity primarily involving cortical and deep gray matter (top left). MRS demonstrated large loss of NAA and very high lactate levels involving all parts of the brain including areas that had reduced diffusion and areas that were normal by diffusion MRI. Representative spectra (bottom) from spectroscopic imaging dataset delineated on FLAIR image (top image).

FIGURE 30.39 Temporal Lobe epilepsy. A 37-year-old male patient with a longstanding history of medically intractable and partial complex seizures. Single-voxel MRS shows a decrease in NAA in the left temporal compared to the right lobe—based on the MRI and MRS exam, the patient underwent temporal lobectomy and had a good outcome.

A variety of methods have been used in attempts to identify the abnormal side in patients with TLE, including electroencephalography, sometimes with the placement of intracranial electrodes. MRI can at times identify the abnormal side. The imaging findings on MRI include hyperintensity of the medial temporal lobe and/or shrinkage of the hippocampal formation. Imaging with SPECT or PET has also been used with varying success. Also employed in a minority of cases is Wada testing, which is selective cerebral artery catheterization for the administration of short-acting barbiturates coupled with psychological testing. Because of the variable accuracy of all these methods they are often used together for surgical planning. Proton MRS can be another contributor to the decision-making process (20,102,136,297–306). The typical MRS abnormalities when present include the reduction of NAA and an increase in the Cho in the abnormal side when compared to the contralateral side. It has been demonstrated that both medial temporal regions are abnormal in patients with TLE. After resection of the abnormal side, the metabolic abnormalities in the contralateral temporal lobe have been observed to revert to normal after a few months. Other diseases that produce seizures are neoplasms, cortical dysplasia, and inborn errors of metabolism. In the initial imaging phase, MRS is indicated for (1) screening for metabolic derangements that may occur from seizure or from certain metabolic disorders that may present with seizures such as mitochondrial disorders and creatine deficiencies and (2) the characterization of masses detected by conventional MRI as neoplasm or dysplasia. Metabolic derangements have been previously described in section “MRS of Inborn Errors of 2120

Metabolism”. Seizures alone and inborn errors of metabolism that cause seizures produce metabolic derangements that may be detectable by MRS and may be missed by conventional MRI (Fig. 30.40). Caruso (102) has recently reviewed the use of MRS in the evaluation of epilepsy. MRS may be useful in individual patients in the characterization of masses as well as in distinguishing dysplasia from neoplasm. When the clinical presentation, conventional MRI, and EEG suggest focal epilepsy, we have found MRS to be useful in confirming the lesion as a dysplasia (30-41A), or in raising concern for a neoplasm (30-41B). Kaminaga et al. (307) reported that NAA was significantly lower in the affected cortex in patients with cortical dysplasia, lissencephaly, and heterotopia compared to controls, indicating a decreased number, immaturity, or dysfunction of neuron in the affected cortex. Elevations in Cho/Cr ratios and decrease in NAA/Cr ratios are commonly observed in tumors (308,309). Although decreased NAA/Cr ratios are thus findings in both focal cortical dysplasias (FCDs) and some CNS neoplasms, the relatively normal Cho/Cr ratios in FCDs may help to distinguish FCDs from neoplasms when the conventional MRI findings are equivocal.

FIGURE 30.40 MRS raises concern for a metabolic derangement and seizure when conventional MR images appear normal. MRI/MRS exam of a 2-year-old boy with global developmental delay manifested clinically recognized seizures A: The conventional MRI was normal. B: 1H MRS obtained at TE 288 over the left centrum semiovale showed an abnormal lactate peak which prompted an EEG that was interpreted as diffusely abnormal.

A recent study showed that MRS provided additional information to the conventional MRI exam in ∼40% of pediatric patients with seizures (310). It added information more frequently for patients with a known diagnosis when compared to patients without a known diagnosis at the time of imaging. Adding MRS was particularly helpful in cases of HII with regard to prognosis (e.g., redirection of care), distinguishing dysplasia from neoplasm, and prompting additional clinical evaluation. Class C Applications: Useful Primarily in Groups of Patients (Research) Neurodegenerative Diseases The neurodegenerative diseases are characterized by injury to, and ultimately loss of neurons. The affected neurons may be of a certain type and possibly localized to specific regions of the brain. The causes for the neurodegeneration are unknown for many of these diseases and neuropathology often reveals a variable gliotic reaction in addition to neuronal injury and loss. MRS in patients with these diseases reflects the pathology. Early in the course of the disease no change may be detected. Later a decline of NAA may be detected in specific regions accompanied by an elevation of Cho and possibly mI. With progression to more severe neurodegeneration, a substantial decline of NAA may be observed. Currently, MRS has limited clinical utility in individual patients and is mostly used in research studies. MRS may become much more important clinically in the future when drugs are developed to treat these diseases. In such future scenarios, maintenance of NAA levels, or even reversal of NAA, may provide direct objective evidence of drug efficacy.

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FIGURE 30.41 MRS is able to distinguish between dysplasia from neoplasm. Top (A–D): MRS confirms a focal lesion as a dysplasia rather than a neoplasm. MRI/MRS exam of a 2-year-old boy with focal seizure semiology. EEG showed nearly continuous spikes with slow wave discharges in the left frontal region. Axial (A) and coronal (B) reformats from an MPRAGE show asymmetric sulcation and fullness of the left middle frontal gyrus (see white arrow). MRS (TE 35 ms) over the lesion (C) compared to MRS obtained over the contralateral normal right middle frontal gyrus (D) shows a reduced NAA/creatine ratio but no elevation in Cho/NAA. These findings favor dysplasia over neoplasia. The patient became medically refractory over the course of the next two years, underwent resection of the left middle frontal gyral lesion, and pathology confirmed a type IIB focal cortical dysplasia. Bottom (E–H): MRS raises concern for a neoplasm rather than a focal cortical dysplasia. MRI/MRS exam of a 7-year-old developmentally normal boy who presents with sudden onset of right face and arm twitching; EEG shows left parietal slowing and spikes. An axial T2 image (E) and a coronal MPRAGE (F) image show a lesion that appears largely isointense to gray matter and that expands the involved left parietal cortex (see white arrow). MRS (TE 288 ms) shows elevation in the choline and decrease in NAA (G) compared to adjacent normal cortex (H) that raised concern for neoplasia; a small lactate peak was also seen over the lesion. Based on the MRS findings, the lesion was followed closely during a trial of antiepileptics and was found to be increase in size on follow-up MRI several months later. The lesion was resected and pathology showed an angiocentric astrocytoma.

ALZHEIMER’S DISEASE. AD is the most common of the neurodegenerative diseases. As the population ages, this will become a more important problem in the United States. Its prevalence in the US population over 70 is estimated at ∼10% (311). The pathologic hallmark of AD is the presence of amyloid plaques and neurofibrillary tangles. While a definitive diagnosis of AD can only be made by examination of postmortem tissue, appropriate evaluations by experienced clinicians over a period of time can result in the diagnosis of probable AD with an accuracy exceeding 90%. Comprehensive evaluations include neurologic examination, neuropsychological evaluation, and standard anatomical imaging, typically MRI. The most reliable imaging finding for AD on a statistical basis is shrinkage of the hypocampal formation. Neurodegeneration and the pathologic process in AD typically initially involves the entorhinal cortex and proceeds to involve the hippocampal formation, and the temporal and parietal lobes. The posterior cingulate gyrus is often involved and later the frontal cortex is also involved. With severe AD virtually the entire brain is severely atrophied with relative sparing of the occipital lobes and the motor cortex. MRS of early AD demonstrates subtle changes which will become more prominent with progression of the disease. These changes include a decrease in NAA on global (312,313) and regional (314,315) levels. Whole-brain NAA is decreased in AD patients by ∼30% compared with healthy subjects (312,313). Regional changes were reported in the hippocampus and the posterior cingulate cortex (315,316), as well as other cortical and subcortical areas of the frontal, temporal, parietal, and occipital lobes (314,315,317)—brain areas known for their early involvement. Furthermore, increased mI or mI/Cr has been reported in patients with AD (54,318–322) suggesting inflammatory processes or glial proliferation. The increase in mI seems to precede decreasing NAA levels in AD (315). Studies involving Cho in AD yielded conflicting findings (315) and studies focusing on Glx indicated a decrease in that peak (314,315). Proton MRS may also be used to monitor treatment response in AD. For example, a transient increase in NAA concentration was associated with short-term functional response during treatment with acetylcholinesterase inhibitor donepezil (323). Other studies have shown a decreased mI/Cr ratio after donepezil treatment (324). PARKINSON’S DISEASE AND PARKINSONIAN SYNDROMES. In Parkinson’s disease the primary insult is to the substantia nigra. This structure is typically too small to be probed effectively by MRS. 2122

Several studies have not demonstrated significant changes in NAA of the striatum. However, in a multicenter trial, a decrease in the striatial NAA/Cho ratio was detected (325). More prominent changes on the MR spectrum have been observed in the other parkinsonian syndromes. Changes consistent with a decline in NAA in the striatum and the lentiform nucleus have been reported in progressive supranuclear palsy, multiple systems atrophy, cortical basal degeneration, (326–328) as well as in the lentiform nucleus of former boxers (329). HUNTINGTON’S DISEASE. The genetic defect for Huntington’s disease is an expanded CAG repeat region on chromosome 4. CAG encodes for glutamine in exon 1—this leads to expanded polyglutamine peptides which have a higher propensity to aggregate. Because of the genetic understanding of the cause in this disease, diagnosis is not difficult. MRS studies of patients with the disease have demonstrated decreased NAA and increased Cho in the basal ganglia and in the cortex of patients that are symptomatic with the disease (330–332). There have been reports of increased lactate in certain regions of the brain. MRS has a limited role in the clinical management of this disease. As more effective therapies are developed, MRS may be useful in monitoring their efficacy, for example, MRS has been used to demonstrate increased cortical NAA/Cho, NAA/Cr ratios after successful bilateral subthalamic nucleus stimulation (333). AMYOTROPHIC LATERAL SCLEROSIS. Amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motor neurons including upper and lower motor neurons. Decreased cortical NAA has been shown in patients with ALS. As would be expected, the motor strip has maximal changes in NAA (334–336), but additional areas including the sensory strip also demonstrate a decrease in this metabolite. Also consistent with the degeneration that occurs with ALS, diminished NAA has been recorded in the brain stem (337,338). Other findings in ALS include an increase in mI and Cho ratios (339,340) and variable results in Glx levels. A recent study using 7-T MRS revealed a decrease in Glu with no change in Gln in the motor cortex in patients with ALS compared to age-matched controls (341). HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND). A significant number of HIV-infected patients develop neurologic symptoms ranging from minor cognitive impairment to severe dementia (known HIV-associated dementia, HAD). It is believed that HIV enters the CNS during the early stages of infection by infected immune cells which initiate an inflammatory cascade which results in neuronal injury and loss. Early in the epidemic, dementia became common in HIV-infected individuals. Strikingly, after the introduction of the first antiretroviral therapy, azidothymidine (AZT), the incidence of dementia dropped dramatically. This observation was interesting because AZT was known not to cross the blood–brain barrier. Moreover, it was reported that in many patients the use of antiretroviral therapy would reverse clinical cognitive abnormalities. While the mechanism of action by which antiretroviral therapy produced improved cognitive functions is not entirely clear, recent studies primarily done in primates, indicate that the most likely reason is that a modest reduction of monocyte viral load in the periphery is sufficient to reduce the rate of trafficking of infected monocytes into the brain (342,343). The first reports on the use of MRS in people with HAND were published in the early 1990s. These early studies demonstrated significant reduction levels of NAA in the brains of these patients (46,344,345). Subsequently it was shown that earlier in disease elevations of Cho (346), mI (347,348), and sometime Cr preceded a drop in NAA. These findings of elevated Cho and mI suggested that a cerebral inflammatory process occurred before neuronal injury, and that neuronal injury occurred later, after the inflammatory process had persisted for some time. 1H MRS has proved useful in studies on the effects of therapies and in studying their mechanism of action. With antiretroviral therapy, reversal of the metabolic abnormalities have been reported (349). MULTIPLE SCLEROSIS. MS is the most common demyelinating disease and numerous studies have been performed on patients with this disease. MRS changes that occur during the development of an acute MS plaque include elevation of Cho and a decline in NAA (350–362). This reflects the inflammatory process and the neuronal injury, respectively, which occur in MS. After the acute phase these metabolic changes can return to normal. However, MRS of a chronic plaque may reveal a permanent decline in NAA along with a persistent Cho elevation. Interestingly, in patients with longstanding MS NAA may also be reduced in normal-appearing WM (363–365). In addition, it has been reported that the Cho/Cr ratio is elevated in normal-appearing WM months before 2123

lesions become detectable at conventional MRI (366). MS has traditionally been viewed as a WM disease. However, recent pathology and MRI studies have shown lesions in the GM as well (367) MRS studies of whole-brain NAA demonstrated that the loss in NAA cannot be explained by WM involvement alone, leading to a conclusion of extensive GM involvement even in a relatively early stage of the disease (368). Traumatic Brain Injury It is estimated that more than 2 million traumatic brain injuries (TBIs) occur in the United States each year, making it the leading cause of death and disability in children and young adults (369). MRS is not routinely used in the acute setting of head injuries. On the other hand, when the patient has stabilized, MRS may helpful in assessing the degree of neuronal injury and to predict patient outcomes. Especially in the case of diffuse axonal injury, many patients with TBIs suffer severe neurocognitive deficits in the absence of gross structural changes. MRS can detect neural metabolic alterations noninvasively after TBI even in areas that appear normal. For effective clinical management, objective means to evaluate long-term outcome are required. During the recovery period following TBI, the NAA/Cr ratio can be used to predict clinical outcome (370–373). Cohan et al. (374) reported a significant global decline of the neuronal marker NAA using whole-brain NAA quantification. In addition, patients with poorer outcomes had elevated mean GM Cho postinjury compared to patients with better outcomes, suggesting active inflammation (371,375–377). Lactate may have predictive value in determining the outcome in pediatric closed head injury (76,290,372,378). However, in cases of adult TBI this predictive ability may be lacking. While some reports indicate changes in Lac in this group, others reported conflicting observations (379–381). Furthermore, mI levels from occipital GM were increased in children with TBI. Patients with poor outcomes had higher mI levels compared with patients with good outcomes (373,382). In addition, glutamate from occipital GM was found to be increased in children with TBI compared with controls, but authors found no difference between children with good compared with poor outcomes (373,383). According to the literature, glutamate levels peak early after injury and fall rapidly. Thus, timing after TBI is an important issue. Ashwal et al. (373) reported that the optimum time to measure glutamate is early (within days after injury) after injury whereas NAA should be measured after 7 days.

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Hepatic Encephalopathy Liver disease that causes encephalopathy may be accompanied by brain MRS changes that are distinct from most other neurologic diseases. Reported findings include declines in Cho and mI as well as an increase in the complex glutamate/glutamine resonance region. These changes become more profound as the severity of the hepatic encephalopathy progresses. However, these patients are not often a diagnostic dilemma and 1H MRS is not widely employed in this circumstance. But, there may be a role for this technology in studies of patients with subclinical hepatic encephalopathy. MRS may be of help identifying patients where the reversal of the metabolic abnormalities by medical intervention could be useful. People with metabolic changes attributed to liver failure undergo reversal of these abnormalities when appropriately treated (384–387). Psychiatric Disorders MRS has been in used in patients with psychiatric disorders. It has been successfully employed to noninvasively detect neurotransmitters whose levels may be of importance in this group of diseases such as glutamate, its precursor glutamine, and GABA (388–390). Moreover, it has been used to measure brain levels of psychotropic medications (e.g., lithium) (391) and some fluorinated drugs (392). Most of the studies using 1H MRS have focused on changes produced in the standard brain proton MR spectrum as reviewed below. SCHIZOPHRENIA. Schizophrenia is associated with abnormalities in glutamatergic and GABAergic systems. Studies at 1.5 T reported increased Glx in schizophrenic patients suggesting an increase in either glutamine or glutamate (393,394). Measurements at a magnetic field strength of 4 T revealed that the increase is due primarily to glutamine, without a concomitant change in glutamate (395). Alterations in the levels of glutamate or glutamine could indicate abnormal neurotransmission or altered glial function. In addition, increased levels of Cho in the caudate in drug-naïve patients have been reported (396). In children, the most prominent changes were increases in Cr and Cho (397). Higher NAA levels in dorsolateral prefrontal cortex were measured when patients were on antipsychotic treatments for more than 4 weeks (398,399). This observation supports the belief that reduction in NAA may represent not only neuronal damage and death, but neuronal injuries that could be reversed with treatment. Decreased phosphomonoesters and increased phosphodiesters were observed in the frontal lobe using 31P MRS (389,400). Those findings have been related to the neurodevelopmental process of “pruning,” in which many synapses are eliminated during late childhood and adolescence (401). MOOD DISORDERS. Studies employing 31P MRS and 1H MRS have indicated possible abnormalities in membrane phospholipid metabolism, high-energy phosphate metabolism, and intracellular pH in affective disorders (402). Studies employing 7Li MRS and 19F MRS have elucidated the pharmacokinetic properties of lithium, fluoxetine, and fluvoxamine in the brain in patients treated with these drugs (403). Proton MRS studies have documented both increases (404–406) and decreases (407,408) in the Cho resonance in major depressive disorder. Electroconvulsive therapy induces an increase in the Cho levels (407). Changes in Cho may reflect alternations in signal transduction, local glucose metabolism, or in endocrine status. GABA levels are significantly decreased in the depressed population, and provide a surrogate maker for effective antidepressant treatment. Studies suggest that selective serotonin reuptake inhibitor (SSRI) administration transiently elevates cortical GABA levels in depressed people and normalizes cortical GABA levels after course of SSRI treatment (409–411). Reduced glutamate levels in the anterior cingulate have been reported. The role of glutamate and N-methyl-d-aspartate receptors has been implicated in the pathophysiology of depression (412). 1H MRS studies revealed decreased NAA/Cr in bipolar subjects, implying decreased neuronal density or neuronal dysfunction (413,414). With treatment of lithium, an increase of NAA was observed supporting the potential neuroprotective effect of lithium treatment (415). Alterations in Cho and mI metabolism have been noted in bipolar disorder, and the therapeutic efficacy of lithium in mania may be related to these effects (416). ANXIETY DISORDERS. 1H MRSI studies of panic subjects were pioneered by Dager et al. (417–419), 2125

who utilized the fact that intravenous infusion of sodium lactate induces panic attacks in the majority of panic disorder patients. MRS was then used to measure brain lactate during an episode. 1H MRS findings also showed reductions in cortical NAA levels in adults, particularly in frontal cortex and hippocampus, which were related to cognitive impairment (409,420).

FIGURE 30.42 Age-dependent metabolic changes. A: 1H MRS spectra (STEAM, TE = 20 ms, TR = 3,000) obtained in the occipital gray matter in four developmentally normal patients. Spectral peaks are assigned to NAA (NA) (2.0 ppm), glutamate and glutamine (Glx, 2.10–2.45 ppm), Cr (3.0 ppm), Ch (3.2 ppm), and myo-inositol (ml, 3.5 ppm). B: Age-dependent metabolic changes in NAA/Cr (NA/Cr) NAA/Cho (NA/Cho) and Cho/Cr ratios in occipital gray matter in 24 healthy control subjects. (Reproduced by permission of RSNA Publications from Holshouser BA, Ashwal S, Luh GY, et al. Proton MR spectroscopy after acute central nervous system injury: outcome prediction in neonates, infants, and children. Radiology 1997;202(2):487–496.)

Patients with panic disorder showed a significant reduction in GABA concentration providing evidence that reduction in GABA levels might contribute to the pathophysiology of panic disorder (421). Using 31P MRS, a significant left–right asymmetry of PCr concentration in the frontal lobes in patients with panic disorders compared to healthy controls was observed (422). NAA levels are reported to be decreased in adults (veterans of war) (423) and children (424) with posttraumatic stress disorder. OBSESSIVE–COMPULSIVE DISORDER. Obsessive–compulsive disorder (OCD) is a common and often debilitating neuropsychiatric condition characterized by persistent intrusive thoughts (obsessions), repetitive ritualistic behaviors (compulsions), and excessive anxiety. While the neurobiology and etiology of OCD have not been fully elucidated, there is growing evidence that disrupted 2126

neurotransmission of glutamate within corticalstriatal–thalamocortical circuitry plays a role in OCD pathogenesis (425). Increased levels of glutamate or the sum of Glu and Gln/Glx levels have been reported in people suffering from OCD. Glx/Cr levels in the orbitofrontal WM correlated with OCD symptoms (426) and Glx concentrations decreased in the caudate after paroxetine treatment (a type SSRI) (427). Furthermore, increased Cho in medial thalamus in children with OCD have been reported (428). AUTISM SPECTRUM DISORDER. Autism spectrum disorders (ASD) are behaviorally defined syndromes considered to reflect complex interactions of genetic and environmental influences that alter normal brain development and function in childhood. A growing body of research in ASD suggests the presence of active pathophysiologic disturbances such as increased excitation/inhibition (E/I) ratio, immune abnormalities, mitochondrial dysfunction, and other bioenergetic disturbances (429,430). These combined disturbances may be pertinent to the substantial risk of seizures in ASD which have a bimodal pattern of onset, one in the first 2 years of life and a second as patients enter puberty. Epilepsy prevalence rates are estimated between 15% and 38% (431) with a higher prevalence of subclinical seizures (432). MRS provides a noninvasive method for characterizing biochemical and cellular metabolic states in these patients. Most ASD studies utilizing brain MRS report either no change or a decrease of NAA in both GM and WM, suggesting neuronal injury or mitochondrial dysfunction (433). There are conflicting findings on choline-containing compounds and mI levels in ASD. Some but not all showed increases in Cho and mI, markers of gliosis and inflammation (434). The same ambiguity was found for total creatine (Cr), a marker for energy metabolism, in ASD (435). Glx has been found to be often decreased in ASD children often increased in ASD adults (433). Increased Glu release or impaired clearance from interstitial space might contribute to an ongoing state of increased cerebral excitability/excitotoxicity and increased CNS irritability, giving rise to increased seizure risk (432). SUBSTANCE ABUSE DISORDERS. Reductions of NAA levels have been reported in alcohol dependence (409,436,437). Genetic factors, acute ethanol toxicity, and chronic tissue damage characterized by cortical shrinkage may all contribute to loss or shrinkage of neurons and, therefore, to reductions in NAA. Some have reported that the NAA level can increase following detoxification (438,439). Methamphetamine (440), heroin (441), and cocaine (442) are associated with reductions of NAA levels. Reductions observed with ecstasy (443) correlated with scores on working memory testing (444). MRS Changes with Age in the Normal Brain Several studies have been conducted on the age effect in the normal human brain, especially in the developing brain (43,44,205,445–451). In neonates, the mI resonance is typically the dominant in the H MR spectrum obtained at short TE (30 ms). As the infant progresses in age, Cho becomes the most dominant and then finally NAA becomes dominant (30-42A). During the first 6 months, these metabolic changes are most rapid and then begin to level off at about 30 months of age (30-42B) (43). Because of these rapid spectroscopic changes, the interpretation of neonatal spectra especially in the case of preterm neonates requires extra care (452–454). In adults, the spectral line width increases with age as a result of increase of local magnetic field inhomogeneity most likely due to deposition of minerals. This effect is the strongest in basal ganglia (455). Later in life, decreases in NAA/Cr and increases of MI/Cr and Cho/Cr have been reported with age in adult patients (58).

ACKNOWLEDGMENTS We thank Drs. Florian Eichler, Otto Rapalino, Paul Caruso, and Ellen Grant for providing clinical case data.

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31 Functional MRI Susie Y. Huang, Behroze Vachha, Steven M. Stufflebeam, Bruce R. Rosen, and Bradley R. Buchbinder

INTRODUCTION Since its inception, functional magnetic resonance imaging (fMRI) has attracted interest for its potential role in assisting the clinical diagnosis and management of patients who may have disruption of brain function due to pathologic conditions. Significant advancements have been made in applying fMRI to presurgical functional mapping in patients with structural brain lesions, including tumors, vascular malformations, epilepsy, and other lesions (1). The primary goal of presurgical planning using fMRI is to localize areas of eloquent cortex and associated white matter tracts in relation to lesions in order to avoid injury to critical functional areas during surgical resection. This chapter provides a summary of the physiologic basis and biophysical principles of fMRI using the blood oxygen level-dependent (BOLD) effect, the main contrast mechanism used in nearly all clinical fMRI studies. We also discuss the practical concerns in clinical fMRI, including patient preparation, study design, image acquisition and processing, and data analysis and interpretation. We illustrate the utility of fMRI in presurgical planning through clinical cases. Finally, we address the potential challenges of clinical fMRI under pathologic conditions and anticipate future developments, including the most recent advancements in resting state fMRI. Principles of BOLD fMRI Physiologic Basis of BOLD fMRI The interplay between neuronal activity, energy metabolism, and blood flow is central to understanding and interpreting fMRI. Although it was suggested more than a century ago that increased neural activity leads to increased regional cerebral blood flow (CBF) and cerebral blood volume (CBV) to meet metabolic demands, the complex biochemical and physiologic mechanisms underlying this process are still incompletely understood. For detailed discussion of the mechanisms involved, the reader is referred to the starred section “A basic model for the BOLD fMRI signal” (see later) as well as more complete texts on fMRI (2–4). The general premise of the underlying physiology is as follows: the brain requires a continuous supply of glucose and oxygen to function, which is provided by CBF. Activated areas of the brain show increased glucose and oxygen metabolism and in turn increased CBF and CBV, which deliver the glucose and oxygen needed to meet metabolic demands. The oxygenation state of blood depends on the flow of blood into and out of a given volume of brain tissue as well as the rate of oxygen metabolism. At rest, the rate of oxygen consumption is matched to CBF, such that the fraction of oxygen extracted from blood remains relatively constant at approximately 40% throughout the brain (5). With neuronal activation, local increases in CBF and CBV increase the oxygenation state of blood and facilitate increased diffusion of oxygen from vessels to mitochondria within metabolically active cells. The CBF response overwhelms the demand for oxygen in the activated state (6,7), such that as blood flow increases, the fraction of oxygen that leaves the blood and is consumed by cells paradoxically decreases. As the delivery of oxygen by blood flow markedly increases while less oxygen is removed from the blood, the net effect is increased blood oxygenation in areas of brain activation. The increase in blood oxygenation with activation is the key physiologic underpinning of fMRI, as changes in the oxygen 2143

saturation of hemoglobin are responsible for the small changes in MR signal that are measured in BOLD fMRI. Biophysical Principles of BOLD fMRI The first demonstrations of functional MRI used dynamic susceptibility contrast from injected gadolinium-based contrast agents to track changes in CBF as a function of neuronal activation (8). Soon after these initial experiments, subsequent fMRI experiments (9) replaced the use of exogenous contrast agents with two endogenous contrast mechanisms: arterial spin-labeled flow contrast (10) and the intrinsic contrast arising from the local magnetic susceptibility changes induced by changes in the deoxyhemoglobin content of blood, that is, blood oxygen level–dependent (BOLD) contrast (11,12). Arterial spin labeling (ASL) alters the longitudinal magnetization of inflowing blood and creates contrast between the tagged longitudinal magnetization of inflowing arterial blood and stationary protons within the imaged volume. Because the functional sensitivity of ASL is lower than that of the BOLD method, ASL has found more limited application for fMRI than BOLD contrast, which is now by far the most commonly used contrast mechanism for fMRI and will be the focus of the remainder of this chapter. The BOLD effect takes advantage of the intrinsic susceptibility contrast provided by blood in varying states of oxygenation. It was first observed in vitro by Thulborn et al. (12) and later demonstrated in vivo by Ogawa et al. (11,13), who applied BOLD contrast to the study of brain activation. BOLD imaging is based on the fact that deoxyhemoglobin, which is paramagnetic, changes the local magnetic field or susceptibility of capillaries and veins containing deoxygenated blood. Magnetic susceptibility represents the degree to which a material develops magnetization of its own when placed in an external magnetic field. Paramagnetic substances such as deoxyhemoglobin strengthen the local magnetic field while diamagnetic substances such as oxyhemoglobin weaken the local magnetic field. The difference in magnetic susceptibility between deoxyhemoglobin within red blood cells and surrounding oxygenated tissue results in local magnetic field nonuniformity and a net reduction in the local MR signal, which is described as a T2* effect or reduction in the apparent transverse relaxation time. Conversely, as blood oxygenation increases, the local MR signal also increases.

FIGURE 31.1 Schematic summary of key physiologic contributions to the T2*-weighted BOLD signal. Neural activity increases cerebral blood flow (CBF, red), cerebral metabolic rate of oxygen consumption (CMRO2, blue), and cerebral blood volume (CBV, green). Increased CBF delivers oxygen to the vessels, increasing the oxyhemoglobin to deoxyhemoglobin ratio (Oxy:Deoxy Hb). Increased CMRO2 extracts O2 from the vessels, decreasing the Oxy:Deoxy Hb ratio. Increased CBV augments the volume fraction of capillaries and venules more than arterioles, also decreasing the Oxy:Deoxy Hb ratio. On balance, the CBF increase is disproportionate to the CMRO2 and CBV increases, resulting in a net increased Oxy:Deoxy Hb ratio, decreased susceptibility-induced perivascular magnetic field perturbations, and increased T2*-weighted BOLD signal.

Deoxyhemoglobin acts as an endogenous paramagnetic contrast agent in blood, which is modulated by variations in oxygen supply delivered by blood flow and oxygen consumption by tissue metabolism. In this simplified picture, neuronal activity leads to increased tissue metabolism, which in turn causes an increase in CBF to increase the delivery of oxygen (Fig. 31.1). As CBF increases to a greater extent than oxygen consumption, the fraction of oxygen that is extracted from blood decreases, and the blood becomes more oxygenated. The decrease in deoxyhemoglobin concentration leads to a small, but measurable, MR signal increase, which is in essence the BOLD effect.

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FIGURE 31.2 Schematic time course of the BOLD hemodynamic/metabolic impulse response. Vertical arrow represents a brief impulse of neural activity at time 0. Red curve represents a model for the time course of the BOLD impulse response. The time course is divided into three phases. (1) Some studies have observed an initial decrease in BOLD signal lasting 1 to 2 seconds, called the “initial dip.” It is likely due to a burst of oxidative metabolism that precedes the rise in CBF and associated influx of oxygen (15–17). (2) CBF subsequently increases disproportionately to CMRO2 and CBV, [dHb] declines, and the BOLD signal rises to a peak at about 5 to 6 seconds. As CBF and CMRO2 responses dissipate, the BOLD signal declines toward baseline. Later, the signal typically falls below baseline, forming a poststimulus undershoot which peaks at about 15 seconds, the origin of which remains controversial (17). The entire BOLD impulse response may last longer than 20 seconds.

It is generally accepted that brain activation, metabolic processes, and the hemodynamic response are coupled closely in both space and time. The BOLD signal is spatially mapped to functional areas of the brain through spatial encoding by magnetic field gradients following the principles of MR image formation. The temporal evolution of the BOLD signal in relation to neuronal activation also needs to be considered (Fig. 31.2). The BOLD hemodynamic response is relatively slow, evolving on the order of seconds, compared to the timescale of electrical activity in the brain, which is in the order of milliseconds. Following the initial stimulus, some studies have shown a rapid initial decrease in signal intensity lasting 1 to 2 seconds called the “initial dip” (14–17), which is thought to reflect the initial increase in metabolic demand and increase in concentration of deoxyhemoglobin before the CBF response sets in. The early response is followed by a rise in the BOLD signal, peaking at about 5 to 6 seconds, due to the disproportionate rise in CBF and resulting decrease in concentration of deoxyhemoglobin. The BOLD signal gradually decreases and returns to baseline at about 10 seconds. A delayed undershoot of the signal below the baseline has been observed (17), reaching a minimum value at approximately 15 seconds. This “poststimulus undershoot” is hypothesized to result from hemodynamic and metabolic effects, including a slowly resolving CBV response (18,19), although the exact etiology remains unclear (17). The entire BOLD response can last longer than 20 seconds. The hemodynamic response is modeled as a mathematical function that can then be incorporated into the analysis of functional activation maps. *A Basic Model for the BOLD fMRI Signal A basic quantitative model helps to elucidate the physiologic and biophysical origins of the BOLD fMRI signal (2,17,20,21). Here, we outline a chain of reasoning that links activation-induced changes in blood flow, blood volume, and oxygen consumption to the magnitude of the T2*-weighted BOLD fMRI signal. While both gradient echo (GRE) and spin echo (SE) sequences can measure the BOLD effect, here we focus on the GRE sequence, which is preferred for most fMRI studies. Figures 31.3–31.9 illustrate the component principles. Numbered equations in the text link to the figures, and Figure 31.10 synthesizes the entire model.

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FIGURE 31.3 The balance between oxygen supply and demand modulates capillary–venous deoxyhemoglobin concentration (dHb). Oxygen supply is proportional to CBF (F). Oxygen demand is CMRO2 (M). The balance between oxygen supply and demand is reflected by the OEF (E) as the ratio M/F (Equation (1)). Assuming arterial blood is fully oxygenated, capillary-venous [dHb] is the total hemoglobin concentration ([Hb]) times the fractional deoxygenation (E) (Equation (2)). Cylinders represent a capillary or venule. Arrows schematically indicate different relative changes in CBF and CMRO2. Cylinder colors schematically indicate changes in [dHb] (inversely, O2 saturation). A: Baseline condition. Single arrows schematically indicate baseline CBF and CMRO2. Purple color indicates intermediate oxygen saturation. B: Outcome if neural activation were to cause equivalent relative increases in CBF and CMRO2 (%ΔF = %ΔM): OEF and [dHb] would be unchanged and there would be no BOLD effect. (Purple color indicates unchanged oxygen saturation.) C: Outcome when neural activation causes disproportionately greater increase in CBF than CMRO2 (%ΔF > %ΔM): OEF and [dHb] decrease, giving rise to the typical positive BOLD effect. Red color indicates increased oxygen saturation. D: Outcome if neural activation were to cause disproportionately greater increase in CMRO2 than CBF (%ΔF < %ΔM): OEF and [dHb] would increase, resulting in a negative BOLD effect. (Blue color indicates decreased oxygen saturation.) A negative BOLD effect can occur under some pathologic conditions, such as distal to a severe arterial stenosis (22–24) or in the presence of hemodynamic steal phenomenon associated with an arteriovenous malformation (25). The surprising fact that neural activation increases CBF disproportionately to CMRO2 undergirds the existence of BOLD fMRI.

The Balance Between Oxygen Supply and Demand Modulates Capillary Venous Deoxyhemoglobin Concentration The balance between oxygen supply and demand determines the degree of capillary venous oxygenation. The rate of oxygen supply increases in proportion to the rate of blood flow and the arterial oxygen concentration: CBF [O2]art. The rate of oxygen demand is the cerebral metabolic rate of oxygen consumption, CMRO2. The balance between oxygen supply and demand can be expressed by the oxygen extraction fraction (OEF), given by the ratio of the rate of consumption to the rate of delivery: OEF = CMRO2/(CBF [O2]art). Assuming that the arterial oxygen concentration is constant, and denoting OEF, CMRO2, and CBF by E, M, and F, respectively, for brevity, we can summarize the balance between oxygen supply and demand by

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FIGURE 31.4 Deoxyhemoglobin (dHb) concentration modulates perivascular field perturbations. Colored cylinders represent capillaries or venules at different levels of oxygenation. The difference between intravascular and extravascular magnetic susceptibility (Δχ) increases in proportion to the concentration of intravascular paramagnetic dHb (Equation (3)). The compartmentalized differences in magnetic susceptibility generate perivascular magnetic field perturbations. The magnitude and distribution of the perivascular field varies with distance from the vessel, angular position around the vessel, and orientation of the vessel with respect to B0. The maximum perturbation at the vessel surface is a characteristic measure of its perturbing effect, denoted by ΔB. For illustrative purposes, all vessels are oriented perpendicular to B0, and the field is computed assuming that the cylinders are infinitely long. The perivascular field is illustrated in a plane perpendicular to the vessel. Areas of higher and lower field strength relative to the background field are indicated by shades of red and blue, respectively. The background field strength is indicated by pale green. The perivascular field has a dipolelike shape. Perivascular field perturbations increase in proportion to Δχ, and hence [dHb]. Left: Full oxygenation, indicated by the red cylinder. Since [dHb] = 0, the background field is unperturbed. Middle: Moderate oxygenation, indicated by the purple cylinder. Moderate [dHb] causes a moderate perivascular field perturbation. Right: Strong deoxygenation, indicated by the blue cylinder. High [dHb] causes a strong perivascular field perturbation.

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FIGURE 31.5 T2′ relaxation in the absence of spin diffusion: static dephasing. After RF excitation, each fixed spin precesses at a constant frequency proportional to the field strength at its locus (Larmor equation). Within a voxel, the distribution of frequencies is a scaled version of the distribution of field strengths. The dispersion of precession frequencies causes loss of spin phase coherence and, consequently, signal decay. The decay envelope is the Fourier transform of the frequency distribution and is not necessarily exponential. The Rows A, B, and C illustrate different spatial distributions of magnetic field (left), the associated distribution of magnetic field offsets (δB) (middle), and the resulting time course of the free induction decay (FID) or GRE signal decay (right), neglecting intrinsic T2 relaxation. A: Uniform field. Since all spins share the same precession frequency, they remain in phase and there is no signal decay. B: Dipolelike field distribution surrounding a single infinitely long cylinder perpendicular to B0, as discussed in Figure 31.4. Distribution of field offsets for spins outside cylinder shows a central peak due to peripheral spins at the background field strength, and two symmetrical side peaks, due to nearby spins in the dipolelike zones of higher and lower field strength, indicated by strong red and blue colors on the field map. The Fourier transform of this frequency distribution yields a nonexponential signal decay. C: Field distribution due to 100 randomly distributed infinite cylinders perpendicular to B0, for spins outside the cylinders. This arrangement models the random positions of microvessels within a voxel. (Additional randomization of the cylinder orientations provides a more realistic model, and decreases the magnitude of the effects, but the overall findings are unchanged [26].) The large number and random positions of cylinders within the voxel smoothes the distribution of field offsets, which closely approximates a Lorentzian distribution. The signal (black), therefore, closely approximates an exponential decay (red) (the Fourier transform of a Lorentzian distribution). (The early signal deviates from exponential decay, but later it closely approximates an exponential.) Monte Carlo modeling and experiments in model systems show that under conditions of static dephasing, the transverse relaxation rate increases in proportion to the characteristic field offset and vascular volume fraction, that is, in proportion to the tissue dHb content (Equations (3) and (4)): ΔR2′ = k · ΔB · V (see also Fig. 31.8). The constant k depends on the vessel geometry but is independent of vessel size.

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FIGURE 31.6 Spin diffusion decreases the R2′ relaxation rate. A,B: The progressive extravascular spin phase dispersion after radiofrequency excitation, without and with spin diffusion, in a model system simulating susceptibilityinduced perivascular field perturbations. Results of Monte Carlo simulation using 10,000 spins randomly seeded within a plane perpendicular to 100 randomly positioned infinite cylinders perpendicular to B0, as shown in Figure 31.5C. Since motion parallel to the cylinders does not change the field, diffusion was modeled in the plane perpendicular to the cylinders. Spin phase distributions are shown at three discrete time points, t = 0, t = 0.1, t = 0.2 seconds. Histograms show probability per bin versus accumulated phase (Φ) resulting from the simulation. Superimposed smooth red curves represent the best fit to model distributions. A: Static dephasing. At t = 0, all spins are in phase, with Φ = 0. Over time, spin phases spread, always approximately conforming to a Lorentzian distribution, representing scaled versions of the Lorentzian magnetic field distribution shown in Figure 31.5 C. B: Dephasing in the presence of spin diffusion. Random diffusive spin displacements cause motional averaging of spin phases. As a result, (1) the spin phase distributions are approximately Gaussian (normal distribution) instead of Lorentzian; and (2) at any given moment in time, the spin phase distribution is narrower compared with static dephasing (motional narrowing). C: FID or GRE signal decay in the absence (solid line) and presence (dashed line) of spin diffusion. Signal decay is approximately exponential in both cases. However, diffusion-induced motional narrowing reduces the rate of T2′ relaxation. (In both cases, the early signal deviates from exponential decay, but later it closely approximates an exponential.) The dashed red lines demarcate the two time points illustrated in panels A and B directly above.

In turn, the capillary venous oxygenation determines the ratio of oxygenated to deoxygenated hemoglobin, while the concentration of deoxyhemoglobin [dHb] determines the magnetic susceptibility of the microvasculature. Assuming that the arterial blood is fully oxygenated, the fraction of hemoglobin that is deoxygenated is equal to the OEF. Therefore, the concentration of microvascular deoxyhemoglobin is

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FIGURE 31.7 Spin diffusion causes R2′ to vary with vessel size. A: Diffusive motion around a small infinite cylindrical perturber of radius r = 1 μ, simulating a capillary (though smaller than most for illustrative purposes). Sample trajectory of a single spin, starting at the top surface, and followed over 4 ms in time steps of 0.1 ms, with a typical diffusion coefficient for brain water of D = 1 μ2/ms. Since the perivascular field falls off as (r/s)2 with perpendicular distance s from the centerline of the cylinder, and the radius is small, the field varies widely over the spatial scale of the diffusion trajectory: The spin samples a wide range of fields along its course, resulting in motional averaging of its phase history. As a result, diffusion strongly attenuates R2′ around small perturbers. B: As in A, but with r = 20 μ. With a large radius, the field varies little over the spatial scale of the diffusion trajectory: the spin samples a nearly constant field along its course, approximating static dephasing. As a result, diffusion does not significantly attenuate R2′ around larger perturbers. C: Monte Carlo simulation of FID or GRE T2′ relaxation due to infinite cylindrical perturbers of varying size, following methods similar to (26). For each cylinder size, the phase histories of 10,000 spins were computed as they diffused around randomly distributed cylinders oriented perpendicular to B0, at a fixed cylindrical volume fraction of 2%, with D = 1 μ2/ms and Δχ = 1.0 × 10−7 (in dimensionless cgs units). In each case, R2′ was computed by fitting an exponential to the computed signal decay. A log-linear plot of R2′ versus radius shows: (1) At larger radii, R2′ plateaus to a constant value because the diffusion effect is negligible in comparison with static dephasing (static dephasing regime), as illustrated in panel B. This result is consistent with the analytical model of (27), which predicts that R2′ is independent of cylinder radius for static dephasing (dashed black line). At smaller radii, R2′ declines because motional averaging progressively dominates static dephasing (motional narrowing regime), as illustrated in panel A. Equation (5) summarizes the vessel size dependence: R2′ is proportional to a factor that depends on vessel radius. The factor also depends on vascular volume fraction (CBV) and Δχ, but panel C illustrates the general shape of the size dependence.

where [Hb] denotes the total blood hemoglobin concentration. Importantly, if neural activation were to increase CMRO2 and CBF by the same relative amount (i.e., percentage change), then the OEF, and hence deoxyhemoglobin concentration, would remain unchanged: there would be no consequent BOLD effect. Surprisingly, during neural activation, CBF increases disproportionately to CMRO2, so OEF, and hence the microvascular deoxyhemoglobin concentration, falls: this key physiologic fact drives the existence of BOLD fMRI. Conversely, if CMRO2 were to increase disproportionately to CBF, then the OEF, and hence the deoxyhemoglobin concentration, would rise, resulting in a negative BOLD effect. These physiologic principles are summarized in Figure 31.3.

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FIGURE 31.8 Dependence of R2′ on ΔB and CBV accounting for spin diffusion. Results of Monte Carlo simulations using the methods described in Figure 31.7C. Data points derive from simulations. Curves represent least-squares fit to power-law relationships, as indicated. A: R2′ versus Δχ, at a fixed vascular volume fraction of V = 2%. For large cylinders with r = 20 μ, where the static dephasing regime prevails, R2′ increases linearly withΔχ. For small cylinders with r = 1 μ, where the motional narrowing regime prevails, R2′ increases quadratically with Δχ. For intermediate cylinder sizes, R2′ ∝ Δχ β, where 1 < β < 2 (not illustrated). For a distribution of cylinder sizes that simulates cortical capillaries and venules, Monte Carlo simulations show a good fit with β = 1.5 (20,26) R2′ also depends on vessel size: at any given value of Δχ, R2′ is attenuated for r = 1 μ compared to r = 20 μ due to motional averaging, as illustrated in Figure 31.7. These results are summarized by Equation (5b). B: R2′ versus vascular volume fraction, V, at Δχ = 1.0 × 10−7 (cgs units). R2′increases linearly with V, independent of vessel size. Again, for any value of V, the vessel size dependence results in attenuation of R2′ for r = 1 μ (motional narrowing) compared with r = 20 μ (static dephasing). These results are summarized by Equation (5c). Noting that the strength of the field perturbation is proportional to Δχ · B0, the results in panel A would also apply by varying B0 instead of Δχ, so the Δχ dependence can be more generally replaced by a ΔB dependence. Finally, for a physiologic distribution of vessel sizes, the R2′dependence on V and ΔB can be summarized by Equation (5), where k depends on the vessel geometry and size distribution, and β ≈ 1.5.

Deoxyhemoglobin Concentration Modulates Perivascular Magnetic Field Perturbations Paramagnetic deoxyhemoglobin represents the interface between the physiologic and biophysical facets of BOLD signal formation. Specifically, the difference between intravascular and extravascular magnetic susceptibility, Δχ, is proportional to the concentration of intravascular deoxyhemoglobin: In turn, Δχ induces local magnetic field perturbations around the vessels. The field perturbations decrease with distance from the vessel, vary with angular position around the vessel, and depend on the orientation of the vessel with respect to the direction of B0. However, the maximum perturbation at the vessel surface represents a characteristic measure of its perturbing effect, denoted here by ΔB. The magnitude of the perturbations scales in proportion to Δχ and B0: Therefore, the magnetic field perturbations around capillaries and veins are stronger in proportion to their magnetic susceptibility, and hence deoxyhemoglobin concentration. These principles are summarized in Figure 31.4. Perivascular Magnetic Field Perturbations Induce T2′ Relaxation 2151

By the Larmor equation, perivascular magnetic field perturbations induce a proportional dispersion of precession frequencies. After radiofrequency (RF) excitation, the spins gradually lose phase coherence and the transverse magnetization decays approximately exponentially, characterized by the total transverse relaxation time T2*, or its reciprocal the total transverse relaxation rate R2*. R2* includes components due to intrinsic spin–spin interactions, R2, and to static field inhomogeneities, R2′, where R2* = R2 + R2′. Since changes in vascular susceptibility alter R2′ but not R2, activation-induced changes in R2* are reflected entirely by changes in R2′: ΔR2* = ΔR2′, so that henceforth, we focus on R2′.

FIGURE 31.9 GRE BOLD signal change. A: Maps of magnetic field perturbations around randomly placed cylinders perpendicular to the magnetic field and the plot plane, simulating microvascular susceptibility effects, using the same configuration illustrated in Figure 31.5C. In the baseline condition, [dHb] is relatively high and perivascular field perturbations are strong. During activation, a disproportionate rise in CBF relative to CMRO2 and CBV decreases [dHb], so perivascular field perturbations are attenuated. B: Exponential decay of FID or GRE signal in the baseline (blue) and activated (red) conditions. Strong field perturbations in the baseline condition result in a relatively large R2′, hence rapid decay. Weaker field perturbations in the activated condition result in a comparatively small R2′, hence slower decay. At any given TE, activation causes the T2*-weighted signal to increase, representing the end result of the BOLD effect. The fractional change in GRE T2*-weighted signal is given by Equation (6). The BOLD signal is approximately proportional to the change in susceptibility-induced transverse relaxation rate and TE.

T2′ Relaxation in the Absence of Spin Diffusion In the absence of spin diffusion, all spins are fixed in position. The phase of any particular spin increases over time in proportion to the field strength at its fixed position. Therefore, at any moment in time, the distribution of spin phases is a scaled version of the distribution of field offsets, ΔB, relative to the unperturbed extravascular background field, or equivalently, the distribution of resonance frequency offsets, Δω = γ · ΔB, where Δω is the frequency offset in radians/s and γ is the gyromagnetic ratio of the proton. As a result, the signal-decay envelope is the Fourier transform of the frequency distribution. The distribution of field/frequency offsets is determined by the geometry and spatial distribution of the vessels. In general, transverse relaxation due to static dephasing in the setting of susceptibility-induced field perturbations is not exponential. However, analytical modeling (27), Monte Carlo modeling (26,28,29), and experiments in model systems (26,29) show that when the perturbers occupy a physiologically low fractional volume (i.e., CBV), the distribution of field/frequency offsets is approximately Lorentzian. Consequently, the signal decay envelope is approximately exponential (the Fourier transform of a Lorentzian distribution), and is well characterized by an exponential rate constant R2′. Under conditions of static dephasing, and considering only the effect of the extravascular 2152

spins (the vast majority), R2′ increases in proportion to the magnitude of the vascular field perturbations, ΔB, and their density (the vascular volume fraction, CBV, here denoted by V for brevity): R2′ = k · ΔB · V, where the constant of proportionality, k, depends on the vascular geometry, but is independent of the vessel size. In conjunction with Equations (3) and (4), we see that for conditions of static dephasing, R2′ is simply proportional to the tissue deoxyhemoglobin content, that is, the amount of deoxyhemoglobin per unit volume of tissue. The principles of static dephasing by vascular susceptibility effects are illustrated in Figure 31.5. T2′ Relaxation in the Presence of Spin Diffusion Diffusion of spins through the extravascular magnetic field perturbations adds nuance to the BOLD physics. Diffusion modifies the simple dependencies of R2′ on vessel size (independent), ΔB (linear), and V (linear) that occur with static dephasing. SPIN DIFFUSION: MOTIONAL NARROWING. In the presence of spin diffusion, the phase of any particular spin does not simply increase over time in proportion to a fixed frequency. Rather, the frequency of precession varies as the spin moves randomly from place to place, experiencing slightly different fields at each moment in time. The net phase for any individual spin increases in proportion to the average of the phase shifts caused by the various fields that the spin encounters over the course of its random motion. This motional averaging has three consequences. First, in contrast to the static dephasing case, at any given moment in time, the distribution of spin phases is not a scaled version of the approximately Lorentzian distribution of magnetic field offsets, and the net signal is no longer the Fourier transform of the susceptibility-induced frequency distribution. Rather, as the spins randomly sample a large range of magnetic fields, the distribution of phases becomes approximately Gaussian, as with many other random processes (explained by the Central Limit Theorem in probability theory). Nevertheless, as in the static dephasing case, gradual spin dephasing still causes approximately exponential decay, which can be characterized by a relaxation rate R2′ (26,29). Second, different spins tend to experience similar average phase shifts because they sample a similar range of fields. At any moment in time, their net phase shifts are more alike than they would be in the static dephasing situation: that is, the distribution of spin phases throughout the sample (e.g., voxel) is narrower (motional narrowing). Finally, and most importantly for its effect on the BOLD signal, with less overall dephasing at any given time, the rate of relaxation induced by vascular susceptibility perturbations, R2′, is lower with diffusion than without it. The effects of motional narrowing on spin dephasing and T2′ relaxation are illustrated in Figure 31.6.

FIGURE 31.10 Synthesis of the Davis model for BOLD signal change, following (2,20,21). Six equations link activation-induced changes in CBF (F), CMRO2 (M), and CBV (V) to the fractional change in GRE T2*-weighted

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signal that constitutes the BOLD effect. The principles underlying these relationships are discussed in the text and illustrated in Figures 31.3–31.10, to which they are keyed. The magnetic susceptibility effect of paramagnetic deoxyhemoglobin (Equation (3)) is the interface between the physiologic (Equations (1) and (2)) and biophysical (Equations (4) to (6)) origins of the BOLD signal. Stepwise substitution of the model parameters, followed by algebraic rearrangement, leads to Equation (7), which expresses the BOLD signal as a function of dimensionless changes in CBF, CBV, and CMRO2. E = OEF. [Hb] = total intravascular hemoglobin concentration. F0, V0, and M 0 denote baseline values. Fa, Va, and M a denote activated values. The constant K has important implications for the BOLD signal. Its factors and significance are further discussed in the text. A typical value measured at 1.5 T is 8%.

SPIN DIFFUSION: DEPENDENCE OF R2′ ON VESSEL SIZE. The effect of diffusion on R2′ is not an all-or-nothing phenomenon. Its impact depends on the balance between the tendency for static field perturbations to spread the spin phases and the tendency for diffusion to motionally narrow them. This balance plays out in a dependence of the BOLD signal on the radius of the perturbing vessels. The balance between static dephasing and motional narrowing can be described by characteristic time constants for the two processes. Static dephasing is characterized by the time required for a spin at the characteristic frequency offset Δω to undergo a characteristic phase shift of 1 radian: Δω · τsd = 1. Diffusion is characterized by the time required for a spin to sample a relatively large range of magnetic fields around the perturbers. Since the magnetic field produced by a cylindrical perturber of radius r falls off as (r/s)2 with perpendicular distance s from its centerline, the vessel radius is often taken as a characteristic average displacement for significant motional narrowing to occur. The time necessary for spins to diffuse an average distance r perpendicular to the vessel, τdiff, is given by the Einstein relation r2 = 4Dτdiff. If τdiff >> τsd, then the spins have abundant time to statically dephase before any motional averaging can occur, and static dephasing prevails, called the static dephasing regime. Conversely, if τdiff > τsd, spins operate well within the static dephasing regime around 25μ venules. Conversely, the characteristic diffusion time for a capillary of radius 3μ is τdiff = 2.25 ms. In this case, since τdiff 6.5. The activation is centered on the central sulcus (dashed line). The top time course in panel A is taken from a voxel near-peak activation, showing a very high BOLD signal-to-noise ratio (SNR), and correspondingly very high tstatistic of 22.0. The middle time course is taken from a voxel 4 mm posterior to the site of peak activation, showing a much lower SNR, with t = 6.0, just at the edge of the activation, as rendered with a threshold of 6.5. The bottom time course is taken from a voxel in the anterior parietal lobe, remote from peak activation, showing essentially no activation signal in the model (the blue line is flat; ≈ 0), with a correspondingly very low t-statistic of 0.2. Several foci of nonprimary sensorimotor activation are also visualized within the bilateral frontal and left parietal lobes. Data was analyzed using FEAT (FMRI Expert Analysis Tool) and related tools in FSL (FMRIB’s Software Library, www.fmrib.ox.ac.uk/fsl) (Smith SM, Jenkinson M, Woolrich MW, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 2004;23(suppl 1):S208–S219).

Sensorimotor and Supplementary Motor Area Mapping Motor and somatosensory mapping is the most frequently used presurgical application of fMRI due to 2164

the relative ease with which it is performed and the relatively stable functional activation. Given that sensorimotor activation is the most robust fMRI task, most clinical fMRI protocols begin with a straightforward sensorimotor task, regardless of the location of the lesion being studied. This serves as a means of readily validating that the acquisition and processing system is functioning, and also that the patient can understand and cooperate with the fMRI study, that is, that the study should go forward. The surgical areas of interest usually include the primary sensorimotor cortex and associated corticospinal tracts, which can result in permanent hemiplegia or hemiparesis if disrupted (Figs. 31.16 and 31.17). The supplementary motor area (SMA) is also of interest from a surgical standpoint as disruptions in this area have been associated with transient motor and speech deficits, which may be immediate or delayed postsurgery and which typically resolve 4 to 8 weeks after surgery (50).

FIGURE 31.16 Sensorimotor fMRI for presurgical evaluation of a 39-year-old female presenting with new onset focal motor seizures involving the left arm as well as left-hand numbness. Axial, coronal, and sagittal T2 FLAIR images without contrast, overlaid with areas of left foot (turquoise), left hand (magenta), face (green), and tongue (yellow) sensorimotor activation. A T2 hyperintense mass expands the right precentral gyrus, effaces the central sulcus, and displaces it posteriorly. Left foot primary sensorimotor (M1/S1) and supplementary (SMA) activations abut the superomedial tumor margin (arrows). Left-hand M1/S1 activation is draped along the lateral and posterolateral tumor margins, and SMA activation is near the medial tumor margin. Face activation is in close proximity to the inferolateral tumor margin. Tongue activation partially overlaps the face activation, and is centered slightly further from the inferolateral tumor margin. Note expected foot, hand, face, tongue somatotopy along the cerebral convexity, and bilateral face and tongue activation. Intraoperative direct electrocortical stimulation confirmed that the hand motor area was within the middle of the tumor, and it was deemed unresectable. Biopsy revealed IDH1-mutant anaplastic astrocytoma WHO grade III/IV. See also Figures 31.17–31.19 for integration with DTI tractography. Data was as analyzed and visualized in the iPlan Cranial v. 3.0 neurosurgical planning system (Brainlab, Feldkirchen, Germany).

Typical sensorimotor task paradigms aim to localize cortical tongue, face, hand, and foot representations for lesions in the rolandic and perirolandic regions. The task paradigms usually employ a block design and the control condition is usually rest or visual fixation on a cross hair. During tongue movement, subjects are asked to sweep their tongue against the back of their teeth in a closed mouth to avoid head motion. Small movements of the tongue generate strong fMRI signals due to the large cortical representation of the tongue relative to other parts of the body within the homunculus. For hand motor tasks, subjects perform finger–thumb opposition movements avoiding arm or shoulder motion. Opening and closing the fist can produce similar fMRI results. More complex sequential motions 2165

of the fingers will capture activation in the premotor areas as well as in the primary motor cortex. Foot motor paradigms may include repetitive toe flexion–extension movements; however, a passive sensory stimulation (which would activate the sensory and not the motor gyrus) is often preferred to avoid head motion. Lee et al. (51) published one of the first studies evaluating the impact of fMRI sensorimotor mapping on neurosurgical planning. The authors retrospectively reviewed medical records of 46 patients with either brain tumors or epilepsy who had undergone preoperative sensorimotor fMRI to document how often and in what ways the imaging studies had influenced patient management. In patients with epilepsy, the functional MRI results were used to determine in part the feasibility of a proposed surgical resection in 70% of patients, to aid in surgical planning in 43%, and to select patients for invasive surgical functional mapping in 52%. In tumor surgical candidates, the fMRI results were used to determine in part the feasibility of surgical resection in 55%, to aid in surgical planning in 22%, and to select patients for invasive surgical functional mapping in 78%. Overall, fMRI studies were used in one or more of the three clinical decision-making categories in 91% of epilepsy surgery patients and in 89% of tumor patients (51). Ternovoi et al. (52) reported a similar range demonstrating that presurgical fMRI results had an influence on pretherapeutic decision-making in 69% of 16 patients with brain tumors.

FIGURE 31.17 DTI tractography for the patient presented in Figure 31.16. Models of the bilateral corticospinal tracts (CST) are displayed as colorized paths overlaid on T2 FLAIR images, extending between the paracentral regions and the posterior limbs of the internal capsules. Fibers of the putative right corticospinal tract are draped along the anterior, medial, and posterior tumor margins, extending from the vertex to the centrum semiovale. The standard color scheme indicates the principal fiber direction within each voxel on the fiber path: blue = superior–inferior; red = left–right; green = anterior–posterior. Data was analyzed and displayed using iPlan Cranial v. 3.0 (Brainlab, Feldkirchen, Germany).

Several studies have attempted to establish predictors for postoperative clinical outcomes based on presurgical fMRI findings (50,53–56). A retrospective analysis of 74 patients with primary or metastatic brain tumors who underwent presurgical fMRI-based motor mapping demonstrated that motor deficits increased linearly as the distance from the tumor margin to the sensorimotor cortex decreased (57). Moreover, survival analysis revealed that pre- and postoperative deficits, tumor grade, tumor location, and distance from the tumor margin to areas of eloquent cortex predicted mortality (57). Nelson et al. (58) provided further evidence supporting a relationship between tumor proximity to eloquent cortex (in this case SMA) as determined by fMRI by showing a 100% risk of postoperative speech or motor deficits when the distance between the SMA and the tumor margin was 5 mm or less and 0% when the distance was greater than 5 mm. In a larger retrospective study, Voss et al. (59) showed that in patients 2166

with preoperative motor deficits based on clinical examination, the likelihood of persistent postoperative motor deficits was greater (81%) when the lesions were less than 2 cm from the SMA activation area on fMRI. When used together, pre- and intraoperative fMRI mapping have successfully determined resection margins of low-grade infiltrative gliomas whose borders are difficult to establish based on morphologic imaging alone with resultant near total tumor resection and decreased postoperative neurologic deficits (60,61). The reference procedure for mapping human brain function intraoperatively is direct intraoperative electrocortical stimulation (ECS). Precise quantitative comparisons between fMRI and ECS localization can be confounded by several factors, including (1) ECS is always on the surface while fMRI activations are often deep to the surface; (2) intraoperative brain shifts introduce quantitative errors, and (3) the extent of fMRI and ECS activation can vary with statistical and electrical thresholds, respectively. Despite these limitations, several studies have reported high concordance between presurgical fMRI mapping of sensorimotor cortex and ECS with agreement between the two methods ranging from 83% (62) to 92% (63). In a quantitative assessment of fMRI accuracy relative to ECS in 22 patients with central tumors, Krings et al. (64) found that fMRI and ECS localizations were within 1 cm on the same gyrus in 15 patients, within 1 to 2 cm on the same gyrus in 5 patients, and further than 2 cm, or on a different gyrus in 1 patient. Intraoperative neuronavigation-guided electrocortical mapping of the motor cortex and correlation with fMRI motor foci showed 100% agreement within about 10 mm spatial resolution in 17 patients with glioma suggesting the reliability of fMRI as a preoperative and intraoperative adjunct in patients selected for surgery of gliomas within or adjacent to the motor cortex (65).

FIGURE 31.18 Integration of sensorimotor fMRI and DTI tractography for the patient presented in Figure 31.16. Axial and sagittal images demonstrate the close spatial relationships between the tumor, sites of functional activation, and the corticospinal tract. Left foot (turquoise), left hand (magenta), right hand (orange), face (green), tongue (yellow), CST (blue). Single white arrow, left foot M1/S1 activation; double white arrows, left- and right-hand M1/S1 activations; single black arrow, overlapping left foot and hand SMA activations; double black arrows, close somatotopic alignment and partial overlap of the left hand, face, and tongue activations along the inferolateral aspect of the central sulcus. Activation and tract results are superimposed on T2 FLAIR images. Data was analyzed and displayed using iPlan Cranial v. 3.0 (Brainlab, Feldkirchen, Germany).

Overall, sensorimotor areas are identified with high success rates using fMRI, particularly in patients with central lesions (Fig. 31.16). The use of combined presurgical fMRI and diffusion tensor tractography when integrated into an intraoperative neuronavigation system is likely to provide a better estimate of the proximity of tumor margins to eloquent sensorimotor cortex, map the corticospinal tract in relation to sensorimotor cortex activation, and overall improve surgical outcomes (Figs. 31.17–31.19) (1,66–69). Language Mapping 2167

The goals of presurgical language mapping include localizing language areas in relation to brain lesions or epileptogenic zones and identifying the language dominant hemisphere (i.e., language lateralization) (Figs. 31.20–31.23). It is generally accepted that every clinical fMRI report should include an assessment of speech and language localization. Language processing is complex, involving the interaction of various linguistic components (phonetic, phonologic, orthographic, lexical, semantic, and syntactic) and associated cognitive processes (auditory input, attention, memory, executive function, and motor planning) (70). Recent studies based on functional neuroimaging, intraoperative ECS, and lesion-deficit correlations suggest that the classical language model (71,72) comprising the left inferior frontal gyrus (Brodmann areas 44 and 45) and the left superior temporal gyrus (Brodmann area 22) is oversimplified (73–76). A more accurate representation of language processing likely involves networks along the perisylvian region including areas within the frontal, parietal, and temporal lobes (70,77,78). Given its complexity, models of language processing are continually evolving (79) and a standard language paradigm for presurgical mapping has not been universally adopted (70,80). These factors make implementation of language fMRI studies in clinical practice more problematic than sensorimotor mapping (80). Despite the complexity and attendant challenges of language fMRI, multiple studies have demonstrated the reliability of fMRI to localize and lateralize language preoperatively with language fMRI increasingly accepted as a noninvasive alternative to Wada testing for determining hemispheric language dominance (81). The majority of these language tasks involve covert (nonvoiced) responses to avoid motion and susceptibility-related artifacts associated with overt speaking. Common language paradigms used include a verb generation task in which the subject must generate verbs in response to either spoken or written nouns. This task results inactivation of the dominant inferior and dorsolateral frontal lobe (83). The resultant lateralization measures obtained from this task correlate well with WADA testing and are superior to lateralization measures obtained from phonologically based generation tasks such as covert repetition (84). Other commonly used language paradigms include verbal fluency tasks (subjects generate words starting with visually presented letters) and semantic decision–making tasks (e.g., determining if a presented word is abstract or concrete). The control condition is an important consideration in generating paradigms, since a resting or visual fixation baseline does not control for default mode processing (70).

FIGURE 31.19 Three-dimensional (3D) renderings of anatomic, functional, and tract data for the patient presented inFigure 31.16. Tumor, orange; left-hand activation, magenta; face activation, green; tongue activation, yellow; corticospinal tract, blue. A: Frontal view. Right corticospinal tract is splayed around the right paracentral tumor, but the tumor is obscured in this projection. B: Coronal section showing that CST courses along and probably through the medial aspect of the tumor. C: Right lateral oblique view. This view shows the fibers of the CST nearly surrounding the tumor. D: Right lateral oblique view. This rendering also superimposes the areas of activation, emphasizing the 3D relationships among tumor, sites of activation, and CST. Data was analyzed and displayed using

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iPlan Cranial v. 3.0 (Brainlab, Feldkirchen, Germany).

FIGURE 31.20 fMRI language lateralization in two left-handed patients. A: A 15-year-old left-handed female presenting with a generalized seizure. Axial and sagittal contrast-enhanced T1-weighted images overlaid with sites of mean language activation from two verb generation runs and one abstract versus concrete semantic decision run (vs. visual fixation). Axial and right sagittal images show a right temporal lobe cystic mass with an enhancing mural nodule. Language activation is strongly left lateralized. The left sagittal image shows a typical distribution of activations associated with these tasks, including 1) putative Broca’s region and adjacent prefrontal and premotor areas (white arrow); putative Wernicke’s region involving posterior temporal lobe and inferior parietal lobe (supramarginal gyrus) (black arrows). Language function was completely intact after patient underwent resection under general anesthesia without a Wada test; pathology revealed ganglioglioma. B: A 34-year-old left-handed male presenting with seizures. Axial and sagittal T2 FLAIR images overlaid with sites of mean language activation from two verb generations runs (dark orange) and two abstract versus concrete semantic decision runs (light orange). Axial image shows an expansile T2 hyperintense left frontal infiltrating glioma invading the corpus callosum. Language activation is strongly right lateralized. The right sagittal image shows a typical distribution of activations including (1) putative Broca’s region and its environs (white arrows); (2) putative Wernicke’s region, involving posterior temporal lobe and inferior parietal lobe (angular gyrus). Language function was completely intact after patient underwent partial resection under general anesthesia without a Wada test. Data was analyzed using FEAT (FMRI Expert Analysis Tool) and related tools in FSL (FMRIB’s Software Library, www.fmrib.ox.ac.uk/fsl) (82). (Reproduced with permission from Buchbinder BR. Functional magnetic resonance imaging. In: Masdeu JC, Gonzalez, RG, eds. Neuroimaging Part I. Amsterdam: Elsevier; 2016, in press.)

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FIGURE 31.21 Language fMRI for presurgical evaluation of a 28-year-old right-handed female presenting with focal seizures characterized by transient auditory hallucinations and aphasia (difficulty comprehending speech; producing nonsensical speech). Sagittal and axial noncontrast T1-weighted images are overlaid with sites of language activation from two verb generation runs (VG1, magenta; VG2, turquoise) and two abstract versus concrete semantic decision runs (AC1, green; AC2, yellow). A large mass expands the left superior temporal, middle temporal, and transverse temporal (Heschl’s) gyri, temporal stem, and insula. The lesion did not enhance after contrast administration. Language activation is strongly left lateralized. Activation sites show strong concordance across the different runs and tasks. Consistent activations are demonstrated in (1) putative Broca’s area (BA), including the left inferior frontal gyrus and adjacent premotor and prefrontal areas; (2) putative Wernicke’s area (WA), including the posterior aspect of the left superior temporal sulcus and supramarginal gyrus; (3) putative visual word form area (VWFA), along the posterior aspect of the lateral occipitotemporal sulcus; and (4) putative supplementary and presupplementary motor areas (SMA, pre-SMA), in the medial aspect of the superior frontal gyri. The putative WA activation is approximately 1 cm posterior to the tumor margin. The putative VWFA activation is more distant, approximately 2 cm posteroinferior to the tumor margin. Putative Broca’s area is in close proximity to the tumor, but separated by the sylvian fissure. Direct electrocortical stimulation during awake craniotomy confirmed speech disruption in Wernicke’s area immediately posterior to the tumor. Stimulation was negative along more anterior areas over the tumor, allowing near-total temporoinsular resection with no intraoperative or durable postoperative language deficit. See Figures 31.22 and 31.23 for correlation with DTI tractography. Data was analyzed and displayed using iPlan Cranial v. 3.0 (Brainlab, Feldkirchen, Germany).

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FIGURE 31.22 Integration of presurgical language fMRI and DTI tractography for the patient presented in Figure 31.21. Composite language activations (red) and DTI models for the left superior longitudinal and arcuate fasciculi (SLF/AF, green), left inferior occipitofrontal fasciculus (IFOF, yellow), and left corticospinal tract (CST) are overlaid on noncontrast T1-weighted images. The composite language map is the union of the two verb generation and two abstract versus concrete semantic decision runs shown in Figure 31.21. Fascicles of the SLF terminate near Broca’s, Wernicke’s, and visual word form areas. The SLF and AF are draped over the superior and posterior tumor margins. The IFOF is draped along the posteromedial tumor margin. The CST courses in close proximity to the medial tumor margin, and nearly abuts it at the junction of the internal capsule and corona radiata. These findings alerted the neurosurgeon that Wernicke’s area, the SLF/AF, the IOFF, and CST were potentially at risk along the posterior, superior, and medial tumor margins. Specific efforts were made during surgery to preserve these regions. Data was analyzed and displayed using iPlan Cranial v. 3.0 (Brainlab, Feldkirchen, Germany).

FIGURE 31.23 3D renderings of the tumor and tracts for the patient presented in Figure 31.21. Tumor (orange),

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superior longitudinal/arcuate fasciculus (SLF/AF) (green), inferior occipitofrontal fasciculus (IOFF, yellow), corticospinal tract (CST, blue). The SLF/AF courses along the superior posterior tumor margin. The IOFF and CST course along the medial tumor margin. All three tracts are distorted by tumor mass effect. A: Left lateral view. B: Right lateral view. C: Frontal view. D: Posterior view. Data was analyzed and displayed using iPlan Cranial v. 3.0 (Brainlab, Feldkirchen, Germany).

Word generation and semantic decision tasks have been used to determine hemispheric dominance in patients with brain tumors (60,85). In a large group of patients with lesions near language areas, activation of the Wernicke area was obtained in 91% and of the Broca area in77% patients applying a covert picture naming task (86). In the same study, fMRI language lateralization agreed with Wada testing in all 13 patients who underwent it (86). fMRI has also been used to determine language lateralization in patients with epilepsy (87). The relatively high prevalence of atypical language representation in epilepsy patients (87) suggests the importance of assessment of language lateralization prior to surgery. Correlations between language fMRI and ECS have been reported (88–91). However, these correlations are more heterogeneous, with false-positive and false-negative results noted. These findings may reflect the different methods by which language is tested in fMRI compared to ECS. For instance, fMRI activates language function while ECS disrupts it. Moreover, ECS is believed to predict essential language cortex while fMRI activates both essential and participating areas. Language paradigms in the operating room often differ from those used in fMRI. Memory Mapping Memory mapping has been the subject of extensive cognitive neuroscience research but has yet to gain acceptance in routine clinical use for presurgical mapping despite three validation studies that compared preoperative memory fMRI lateralization with preoperative Wada test results and/or postoperative memory outcome (1,70,92–94). Interestingly, Binder et al. (95) demonstrated that preoperative fMRI was useful for identifying patients with epilepsy at high risk for verbal memory decline prior to left anterior temporal lobectomy surgery. The authors found that lateralization of language was correlated with lateralization of verbal memory, whereas Wada memory testing was either insufficiently reliable or insufficiently material-specific to accurately localize verbal memory processes. This study suggests that language fMRI may play an important role in assessing both language and verbal memory deficits in patients with epilepsy who undergo left temporal lobectomy. Pitfalls Several challenges arise in interpreting clinical fMRI examinations. Many of the shortcomings of fMRI are technical, including sensitivity to motion and field inhomogeneity. Motion artifact can be voluntary or involuntary and may also relate to the tasks involved, such as word vocalization for language mapping. Rapid image acquisition with EPI reduces the impact of motion on fMRI studies, as does securing the head and providing guides for visual fixation. Susceptibility artifact at air–tissue interfaces and in the presence of surgical hardware can result in signal dropout and potentially decrease the expected BOLD response, leading to false-negative results. Interpretation of functional activation maps should take into account these technical factors. Additional pitfalls in clinical fMRI interpretation stem from the fact that fMRI does not measure neuronal activity directly but instead relies on assumptions about the coupling between neuronal activity and blood flow. The presence of pathology may disrupt the normal mechanisms of neurovascular coupling and alter interpretation of the BOLD fMRI signal. In areas where cerebral perfusion is compromised, such as in patients with cerebrovascular disease and proximal arterial stenosis (22–24), the BOLD response may be attenuated due to inadequate hemodynamic reserve, thereby resulting in false-negative results. False-negative results can be particularly problematic in fMRI performed for presurgical planning, as they may lead to unintentional resection of eloquent cortex in areas that would otherwise show a positive BOLD response. Hemodynamic alterations associated with arteriovenous malformations may blunt the BOLD response in eloquent areas, leading to false negatives and, for example, inaccurate language lateralization (25). Perfusion imaging using dynamic susceptibility contrast imaging can aid interpretation of BOLD activation maps in the presence of perfusion abnormalities. The effect of tumor angiogenesis on the BOLD signal is an area of ongoing research with clinical relevance to surgical resection of high-grade gliomas. The loss of autoregulation in abnormal tumor neovasculature is thought to result in decoupling of neuronal activity from the CBF response, such that 2172

an increase in neuronal activity may not lead to an increase in blood flow, thereby attenuating the BOLD response. Tumor hypoxia in glioblastomas can also contribute to false-negative results, as the vasculature may already by maximally dilated under such conditions and unable to further increase blood flow in response to neuronal activity (96). A number of approaches have been devised to assess cerebrovascular reactivity and detect uncoupling of the neurovascular response through exposing the patient to a hypercapnic environment (97). The standard technique for cerebrovascular reactivity mapping is administration of exogenous CO2 gas during MRI (98–100). The breath-hold technique is an alternative approach that is easier to implement in patients and can produce hypercapnia without the need for inhaling exogenous gases (97,101). The breath-hold technique involves short periods of breath-holding, usually lasting between 10 and 30 seconds, that alternate with periods of regular breathing. Such approaches ensure that the patient has intact neurovascular coupling and minimize the potential for false negatives due to hemodynamic compromise. Resting-State fMRI and Functional Connectivity Background on Resting-State fMRI Traditionally, studies of brain function have focused on using task-based motor, language, and memory paradigms; using relative changes in BOLD signal between a baseline “resting” condition and an activation condition in response to a task/stimulus, one infers certain areas of the brain are activated. However, more recently, attention has been focused on intrinsic brain activity occurring continuously during the so-called baseline “resting state” (102–105), and resting-state fMRI (rs-fMRI) has emerged as a novel new method of identifying regional interactions that occur when a subject is not performing an explicit task. A persuasive argument in support of intrinsic activity at rest playing as important a role as activation in response to tasks/stimuli comes from an understanding of brain energy consumption. In the average adult human brain, the baseline resting state accounts for the great amount of neural activity with activation resulting in energy expenditure only slightly over a high level of baseline brain energy metabolism (102,103). Furthermore, ongoing EEG activity even during sleep and anesthesia support the presence of resting-state activity. Finally, both PET and fMRI have demonstrated a consistently reproducible set of brain regions that are activated during rest conditions but show decreased activations in response to goal-directed behavior (106,107). These regions together form the default mode network (DMN) (discussed later) and provide additional proof of intrinsic activity accounting for the majority of all neural activities. rs-fMRI identifies networks of functionally connected brain regions based on temporal correlations in spontaneous low frequency (∼0.01–0.1 Hz) fluctuations of their resting-state BOLD signals. Of note, “rest” merely refers to a constant condition in which the subject is not exposed to tasks or stimuli. To date, the spatial signatures of several consistently reproducible resting-state networks have been elucidated, including motor, language, visual, attention, and DMNs (Fig. 31.24) (108,109). Of these networks, the DMN consisting of the posterior cingulate cortex, medial prefrontal cortex, and medial temporal lobe is considered the most fundamental resting-state network and has been extensively studied in a number of neurocognitive disorders (104,110). The DMN was first identified from PET data by Raichle et al. (106) as a consistent network of brain regions that were active at rest but decreased their activity when goal-directed tasks were performed. Two years after the Raichle et al. study, Grecius and colleagues (107) identified the DMN using fMRI; since then it has been confirmed in many studies using a variety of analysis methods (109,111–113). Changes in the DMN have been associated with many conditions, including reduced connectivity in patients with attention-deficit hyperactivity disorder (114), autism (115), Alzheimer’s disease (116), schizophrenia (117), depression (118), and epilepsy (119).

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FIGURE 31.24 Resting-state networks. Some consistently identified resting state networks are displayed here on partially inflated renderings of the brain surface. A: Default mode network. B: Somatomotor network. C: Visual network. D: Language network. E: Dorsal attention network. F: Ventral attention network. G: Frontoparietal network. (Reproduced from Lee MH, Smyser CD, Shimony JS. Resting-state fMRI: a review of methods and clinical applications. AJNR Am J Neuroradiol 2013;34(10):1866–1872, with permission.)

FIGURE 31.25 Seed-based analysis of resting-state fMRI. A seed voxel was placed in the posterior cingulated cortex/precuneus (PCC) (green disk) in a single subject. The time course of the seed voxel was correlated with all other brain voxels and maps of the correlation coefficients are displayed on partially inflated brain surfaces. Red–yellow areas indicate positive correlations, while blue–turquoise areas indicate negative correlations (anticorrelations). Correlated regions encompass the default mode network (DMN), including PCC, medial prefrontal cortex (MPF), and lateral parietal cortex. Anticorrelated regions include intraparietal sulcus (IPS), frontal eye fields, and middle temporal region. The time course for the seed voxel, shown in yellow, is clearly correlated with the time course of a voxel in the MPF (orange) and negatively correlated with a voxel in the IPS (turquoise). Anticorrelations in these two resting-state networks mirror their opposite behavior during task activation: Task-induced activations in regions outside the DMN, such as the blue regions here, routinely cause deactivation of the DMN. (Reproduced with permission from Fox MD, Snyder AZ, Vincent JL, et al. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A 2005;102(27):9673–9678.)

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T2*-weighted BOLD images are acquired while the subject lies in the scanner without falling asleep either with eyes open with visual fixation on a cross-hair or with eyes closed. The scanning period ranges from 5 to 10 minutes. Resting BOLD data are subjected to many of the preprocessing steps routinely applied to task-based fMRI data with a few important differences (see Cole et al. [120] for a more complete review). For example, high-pass temporal filtering applied to task-based data is usually not used for resting-state data as it may result in removing some of the relevant resting-state network frequency information. Beyond the regular preprocessing, there are two main approaches to the analysis of rs-fMRI data: seed-based correlation analysis (SbCA) and independent component analysis (ICA) (121). Additional methods of analysis such as graph theory and clustering algorithms have recently emerged as promising tools for analyzing rs-fMRI data but are beyond the scope of this review. SbCA extracts the BOLD time course from a region of interest (seed-region) and determines the temporal correlation between this extracted signal and the time course from all other brain voxels (Fig. 31.25). The primary advantage of this method is that it is easy to interpret by clearly demonstrating the network of regions most strongly functionally connected with the region of interest and has moderate– high test–retest reliability (120). The disadvantages of this method are that it is dependent on a priori definition of the seed region and requires subjective expertise in selecting seed regions. Moreover, unlike ICA (which is discussed below), SbCA only demonstrates the “seeded network” and all other networks are essentially ignored. ICA extracts multiple spatiotemporally coherent components that are maximally statistically independent (120). In contrast to SbCA, ICA is entirely data driven, does not depend on subjective expertise in selecting seed regions and generates multiple networks during one analysis (Fig. 31.26). A disadvantage of this method of analysis is that the interpreter must define the number of components before analyses; a low number of components would result in multiple networks being grouped into one map while a high number of components could potentially fragment a single network into multiple maps (104,120). Moreover, the interpreter has to determine which of the generated components reflect noise and which reflect actual neuroanatomical systems (104). Advantages and Disadvantages of rs-fMRI Over Traditional Task-Based fMRI There are several advantages of using rs-fMRI in place of, or, to supplement information obtained from, traditional task-based fMRI. First, by not placing task-based demands on the subject, rs-fMRI can be used to assess brain function in pediatric patients, developmentally challenged patients, patients with language barriers and patients under anesthesia who may not be able to perform the task adequately to elicit a reliable BOLD signal response. Second, rs-fMRI can be used to simultaneously study multiple cortical systems in contrast to task-based fMRI, which requires dedicated data acquisitions for each function that requires localization. Finally, rs-fMRI may be beneficial in longitudinal studies evaluating drug effects or disease progression, in which repeated task sessions can be confounded by practice effects or adaption to the task (122). Despite these obvious advantages, there are several barriers to the clinical application of rs-fMRI. First, while many current studies have described results of rs-fMRI based on group analyses, evaluation of rs-fMRI in individual subjects remains a challenge. Mueller et al. (123) demonstrated high intersubject variability in intrinsic brain networks generated from rs-fMRI, with the highest functional connectivity variability found in frontal, temporal, and parietal association cortex areas. Second, differences in acquisition parameters and processing as well as analysis pipelines across different rsfMRI studies yield vastly different results. Finally, related to the second disadvantage, standard guidelines for reliable rs-fMRI mapping of brain disease are yet to be established, precluding reproducibility of findings and preventing translation to everyday clinical practice.

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FIGURE 31.26 Probabilistic independent component analysis (ICA) of resting-state fMRI. Eight putative resting-state networks were identified in this group analysis of 10 subjects: (a) medial visual cortical areas; (b) lateral visual cortical areas; (c) auditory system; (d) sensory motor system; (e) visuospatial system; (f) executive control system; (g,h) dorsal visual stream. Distances refer to millimeter distances from the anterior commissure. (Reproduced with permission from Beckmann CF, DeLuca M, Devlin JT, et al. Investigations into resting-state connectivity using independent component analysis. Philos Trans R Soc Lond B Biol Sci 2005;360(1457):1001–1013.)

Applications of rs-fMRI Cognitive neuroscience research has provided many interesting insights on resting-state networks in both the healthy brain and in multiple neurocognitive disorders (104,124); however, the majority of these studies have focused on group-level analyses. Potential translational clinical applications at the single-subject level are beginning to emerge; however, more validation studies are required to establish the reliability and applicability of rs-fMRI to individual patients rather than groups (104,125). In this section, we describe studies that demonstrate the potential for single-subject applicability. rs-fMRI has been applied to identify specific brain resting-state motor networks for presurgical planning in patients with epilepsy (126) and brain tumors (Figs. 31.27 and 31.28) (104). Tie et al. (127) were able to extract language activations using rs-fMRI at the individual subject level suggesting the possibility of using a task-free method of evaluation of language networks as part of presurgical planning. Other studies have demonstrated proof of concept of the utility of rs-fMRI in identifying the epileptogenic zone in candidates for epilepsy surgery (128,129). Beyond epilepsy, several studies have demonstrated altered patterns of resting-state connectivity, particularly with respect to the DMN, in patients with mild cognitive impairment and Alzheimer’s disease (130–132). rs-fMRI has also been studied in a number of neuropsychiatric and neurocognitive disorders including schizophrenia (133), major depressive disorder (134), and autism spectrum disorder (135,136). Finally, rs-fMRI has been applied to study pediatric populations including evaluation of the development of resting-state networks in a cohort of preterm infants (137) and healthy term-born subjects (138). Conclusion Unlike the wide acceptance of fMRI by the neuroscience community (139), the clinical application of fMRI clinically has moved forward cautiously. The development of more sophisticated approaches to 2176

fMRI image acquisition and analysis, as well as the advent of rs-fMRI, has introduced more efficient approaches to obtaining reliable fMRI data. With continued investigation into the efficacy and impact of fMRI on clinical outcomes and with the proliferation of 3-T scanners in clinical settings, it is anticipated that fMRI will find greater acceptance and applications in the clinical realm.

FIGURE 31.27 Potential value of resting-state fMRI (rs-fMRI) in individual subjects for presurgical planning. A: Comparison between task-based fMRI (tb-fMRI) and rs-fMRI in four individual patients with tumors or epileptic foci near the motor cortex. fMRI maps are overlaid on each patient’s own T1-weighted structural images. Left column: Maps of sensorimotor activation with movement of the hand contralateral to the lesion or epileptic focus. Arrowheads indicate brain lesions in patients 1, 2, and 4. Patient 3 had no visible lesion. Center column: Maps of seed-based functional connectivity, using a seed in the anatomic “hand knob” of the contralesional hemisphere. Right column: Superimposition of tb-fMRI and rs-fMRI maps, showing overlap in red. Strong concordance was seen in each case. (Patient gender and age indicated in the upper right corner.) (Reproduced with permission from Liu H, Buckner RL, Talukdar T, et al. Task-free presurgical mapping using functional magnetic resonance imaging intrinsic activity. J Neurosurg 2009;111(4):746–754.) B: Comparison between tb-fMRI and rs-fMRI in a patient with epilepsy. Language areas show substantial overlap, especially in Broca’s area and surrounding prefrontal and premotor areas, with additional areas of activity in the inferior parietal lobule (supramarginal and angular gyri) on the rs-fMRI. (arrow)

FIGURE 31.28 Potential value of resting-state fMRI (rs-fMRI) for localization of focal epileptic discharges using functional connectivity analysis. Each row shows data for one patient. Left 3 columns: Results of functional

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connectivity analysis in representative coronal, axial, and sagittal slices. Areas of abnormal local (red) and remote (blue) functional connectivity area shown, derived from each patient’s rs-fMRI data, compared with a normative data sample of 300 healthy individuals. Right column: Combined areas of abnormal remote or local connectivity are displayed on the brain surface (red) and compared with intraoperative EEG (iEEG) findings. Blue circles: Electrode positions corresponding to seizure onset. Green circles: Electrode positions corresponding to frequent interictal discharges. In each case, areas of abnormal functional connectivity fell within 5 mm of the ictal onset zone, as determined by iEEG. The findings suggest that abnormal functional connectivity may help characterize and localize the pathologic substrate for epileptogenesis in surgical candidates for epilepsy surgery. (Reproduced with permission from Stufflebeam SM, Liu H, Sepulcre J, et al. Localization of focal epileptic discharges using functional connectivity magnetic resonance imaging. J Neurosurg 2011;114(6):1693–1697.)

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Index Note: Page number followed by f and t indicates figure and table respectively. A AAION. See Arteritic anterior ischemic optic neuropathy (AAION) ABCs. See Aneurysmal bone cysts (ABCs) Abducens nerve, 1030 Abscess, 759, 767 cerebritis and, 759 development of, 759–760 DTI of, 766 DWI of, 762–763, 762f, 763f, 764f, 766, 766f edema and, 760 with internal restricted diffusion, 764f meningitis and, 769 MR characteristics, 760, 760f, 761f MRS for, 764–765, 764f–765f pituitary, 1002–1003, 1003f pyogenic, 760, 760f, 761f, 764f, 765f ring enhancement with, 760, 762 spinal epidural, 1403–1408, 1404f–1407f, 1404t spinal subdural, 1408–1409 subperiosteal, 1066, 1067f therapy for, 765–766 tuberculous, 783 AC. See Arachnoid cyst (AC) ACC. See Adenoid cystic carcinoma (ACC) Acquired hepatocerebral syndromes, 858 neuroimaging and pathology, 858–860, 859f–860f Actinomycosis, 1430–1432, 1432f vertebral involvement of, 1431–1432 Active shimming, 9 Acute disseminated encephalomyelitis (ADEM), 1073, 1421–1423 causes of, 1423t clinical features, 228 MRI findings, 228–230, 228f, 229f pathologic features, 228 spinal cord involvement in, 1422, 1423f Acute hemorrhagic leukoencephalitis, 230, 230f, 231f Acute perivascular myelinoclasis. See Acute disseminated encephalomyelitis (ADEM) Acute transverse myelopathy (ATM), 1410, 1414, 1414t diagnostic criteria for, 1413t MRI for, 1414, 1414f–1415f and postvaricella spinal cord atrophy, 1416f and segmental atrophy of thoracic cord, 1416f AD. See Alzheimer disease (AD) Adamantinomatous craniopharyngioma, 975–976 Adamantinomatous tumors, 975 ADC. See Apparent diffusion coefficient (ADC) ADEM. See Acute disseminated encephalomyelitis (ADEM) Adenocarcinoma, 899 Adenoid cystic carcinoma (ACC), 904, 907, 1080, 1083, 1085f ADHD. See Attention deficit-hyperactivity disorder (ADHD) Adrenoleukodystrophy, 258 clinical features, 258 2183

MRI findings, 258, 259f–260f pathologic findings, 258 Adrenomyeloneuropathy. See Adrenoleukodystrophy Aging and cognitive impairment, 817 MRI brain changes with, 818 atrophy, 818, 818f foci of high signal intensity, 818–820, 819f, 821f, 822f frontal horns and, 819 iron deposition, 820, 822f–825f, 823, 825 posterior internal capsule and, 819, 819f terminal areas of myelination and, 819, 819f Virchow-Robin space and, 820, 821f, 822f Aicardi syndrome, 83, 86, 87f AIDS, 730–731. See also Human immunodeficiency virus (HIV) CMV infection in, 727–728 myelopathy associated with, 1458–1459 spinal cord inflammatory lesions in, 1458t VZV infection in, 726–727, 727f AIDS dementia complex (ADC), 731 Air-core magnets, 6 Alcohol use disorder (AUD), 1588–1589 fMRI of, 1589, 1590t MRI of, 1589 MRS of, 1589–1590 Alexander disease clinical features, 267–268 MRI findings, 268–269, 268f pathologic findings, 268 Aliasing, 28, 30f Alien-limb syndrome, 847 ALL. See Anterior longitudinal ligament (ALL), spine Alobar holoprosencephaly, 107, 109, 110f. See also Holoprosencephaly (HPE) with monoventricle, 1511f Alper disease, 260, 262f ALS. See Amyotrophic lateral sclerosis (ALS) Alzheimer disease (AD), 825–826 amnestic MCI (aMCI) and, 826 and arterial spin labeling, 1559f biomarkers for, 828, 833, 833f dementia in, 825 diagnosis of, 825 diagnostic criteria for, 826 early onset, 825 genetics of, 826 imaging of, 828 diffusion tensor imaging for, 831 DWI for, 831 functional MRI for, 831 1H MRS for, 830, 830f longitudinal measures, 830 molecular imaging, 831–832, 832f MR perfusion for, 831 structural MRI for, 828–829, 828f, 829f voxel-based morphometry studies, 829–830, 830f incidence and prevalence of, 825 late onset, 825 2184

mild cognitive impairment (MCI) and, 826 MRS of, 1630 pathology/etiology of, 827–828, 827f neurofibrillary tangles, 827, 827f senile plaque, 827, 827f preclinical, 833, 833f risk factors for, 825 treatments for, 826–827 Amebiasis, 811–812, 811f, 812f Amino and organic acid disorders, 265, 267t maple syrup urine disease, 266f ornithine transcarbamylase deficiency, 266f propionic acidemia, 266f Amyloid angiopathy, 584, 585f Amyotrophic lateral sclerosis (ALS), 867–871, 867f–871f criteria for clinical diagnosis of, 867 DTI for, 870 familial, 867 intracellular inclusions in, 867, 868f MRS for, 870–871, 1630 neuroimaging and pathology, 867–871, 867f–871f sporadic, 867 symptoms, 867 Anaplastic astrocytoma, 327f, 337–339, 338f–341f contrast enhancement in, 338, 339f, 340f with hemorrhage, 339f with intratumoral hypervascularity, 338, 339f microscopic examination, 337, 338f Anaplastic oligodendroglioma, 322f–323f Andersson fractures, 1402 Aneurysmal bone cysts (ABCs), 1259 imaging, 1259, 1260f pathology, 1259 treatment, 1259 Aneurysms, 1008, 1011f, 1012f basilar tip, 1496f carotid cave, 1497 cavernous carotid, 906f cerebral, 158–160, 160f classification, 610 extradural, 1497 flow-related, 554f–555f giant, 618–622, 618f–625f intracranial, 610–628, 1494 diagnosis of, 1496 endovascular coiling, 610 false-negative MRA for follow-up of aneurysm coiling, 617, 617f formation of, risk factors for, 1494 giant aneurysms, 618–622, 618f–625f high-risk populations, screening of, 1495 imaging techniques, 1494–1495 incidental unruptured aneurysms (IUA), 1495–1496 MR angiography for, 622, 624, 625f–628f, 627–628, 1495, 1497f optic nerve and chiasm compression by, 614f–616f perianeurysmal hemorrhage and, 625f population at higher risk for, 627t risk of rupture, 1494 2185

Aneurysms (continued) ruptured, 611, 611f saccular aneurysms, 610–618, 611f–617f signal void of looping vessel masquerading as, 626f subarachnoid hemorrhage and, 610, 611, 612f, 613f, 625f symptomatic, 1495 treatment planning, 1496–1497 unruptured, 610, 611, 624, 626f–627f intratradural, 1497 mass lesions in parasellar area and, 904 mycotic, 767, 769f–770f NF1 and, 173, 174f nidal, and arteriovenous malformation, 556f partially thrombosed giant, 622, 622f, 627f–628f of petrous carotid artery, 909 ruptured intranidal, 557f saccular, 610–618, 611f–617f, 1008, 1011f third nerve palsy and, 611, 616f thrombosed giant, 509f, 509t Angiocentric glioma, 352, 354, 354f Angiofibroma, juvenile, 906, 906f Angiograpy, in Von Hippel–Lindau (VHL) disease, 198, 198f Angiomyolipomas, in kidney, 189 Ankylosing spondylitis, 1239, 1241f, 1333, 1333f, 1401–1402, 1402t Anorectal malformations, 1145 Anterior atlas axis subluxation (AAAS), 1398 Anterior cerebral artery, 654, 656f Anterior choroidal artery, 655 Anterior communicating artery (AComA), 157 Anterior cord syndrome, 1345, 1345f Anterior eye segment (AES), 1036 Anterior inferior cerebellar artery (AICA), 655, 656, 919f Anterior longitudinal ligament (ALL), spine, 1192, 1316–1317, 1317–1321f Anterior sacral meningoceles, 1152, 1153f Anterior spinal artery (ASA), 1367–1368, 1387 Anterior temporal lobectomy (ATL), 280t Antiferrimagnetism, 486 Antiferromagnetism, 486 Anti-neutrophil cytoplasmic antibody (ANCA), 1069 Antisocial personality disorder (APD) fMRI of, 1587–1588, 1588t MRI of, 1587 MRS of, 1588 Anxiety disorders fMRI of, 1575–1577, 1576t MRI of, 1575 MRS of, 1632–1633 Apparent diffusion coefficient (ADC), 330, 968, 1022, 1531 Arachnoid cyst (AC), 150–154, 313, 313f, 416–417, 418f, 999, 1000f and epidermoids, 152 imaging findings, 151–152, 152f–154f intraventricular, 152f and mega cisterna magna, 152 middle cerebral artery branches, displacement of, 153f posterior fossa, 122, 122f, 154f of quadrigeminal cistern, 418f retrovermian, 153f 2186

transtentorial, 152f Arachnoid granulations, 918, 920f–922f Arachnoiditis, 1224, 1224f, 1225f, 1409–1410 arachnoid cysts and, 1410 calcifications of meninges in, 1410 causes of, 1409t chemical, 1411f clinical signs, 1409 complications of, 1409–1410 and failed back surgery syndrome, 1409 inflammatory reaction of, 1409 lumbar spine adhesive, 1409 MRI for, 1409, 1410f–1413f, 1410t syringomyelia with, 1409, 1412f Argyll–Robertson pupil, 775 Arnold nerve, 913 Arterial anatomy, cerebrovascular, 654–655, 655f Arterial dissection, and large-artery infarction, 636, 637f Arterial dysplasia, NF1 and, 173 Arterial spin labeling (ASL), 330, 1552–1553, 1553f Alzheimer disease and, 1559f background suppression in, 1556, 1557, 1557f BOLD vs., 1641 brain tumors, 330 labeling strategies for, 1554–1555, 1554f, 1555f in left middle cerebral artery occlusion, 649f magnetization transfer and, 1558 modified Bloch equations and, 1553–1554, 1553f motion artifacts in, 1556, 1557f multislice, 1557–1558, 1558f perfusion quantification in, 1555–1556, 1556f vessel-selective labeling and, 1558 Arteriovenous malformations (AVMs), 161–162, 163f, 164f, 531–573, 1060, 1061f, 1497 advances in noninvasive modalities, 1501 aneurysms and, 535, 552, 554f–557f ARUBA trial, 534 cerebral proliferative angiopathy and, 574–575, 574f, 575f clinical features, 532–534, 532f–533f clinical presentation, 1497 corpus callosum, 551f, 552f cryptic, 558, 558f with deep venous drainage, 543f–544f diagnosis and characterization, 1497, 1500f–1502f differential diagnosis, 552, 557f–564f, 558, 560, 563 3D time-of-flight (TOF) MRA, 552 fMRI, 569, 571f–573f hemangioblastomas and, 558 hematoma with, 558f, 568f and hemorrhage, 532, 532f–533f, 534, 547f, 548f–550f, 552, 559f incidence of, 531–532 with intraventricular siderosis, 548f magnetic resonance imaging, 538, 539f–556f, 546–548, 552 mixed malformation, 558, 559f–561f MRA for, 568–569, 568f, 570f neurologic deficits from, 534 nidus and, 532, 532f, 552 pathologic findings, 534–535, 535f–537f 2187

postembolization magnetic resonance, 566f posttherapy MR, 563, 565f–568f, 1501 pretreatment grading of, 535, 537, 537t prior hemorrhage and, 535, 537 with radiation necrosis after treatment, 563, 566f radiosurgery, effects of, 563, 565f and seizures, 534 Spetzler–Martin grading system, 537t grade III, 542f–543f grade IV, 544f supratentorial, 534 therapy, 537–538 treatment, 1500–1501 vein of Galen malformation, 566f–567f Arteritic anterior ischemic optic neuropathy (AAION), 1073 Artery of Adamkiewicz, 1368, 1368f Artery of Percheron, 655, 659f Articular facets, anatomy of, 1193 Artifacts center-brightening, 14, 15f chemical shift, 31, 31f fat in tumors and, 319–320, 320f cystic lesion, 313 eye makeup, 1022f fat suppression, 1024 ghosting, 1021f TOF MRA and, 1472, 1472f venetian blind, 1473 ASD. See Autism spectrum disorder (ASD) Aspergillosis, 788, 789f–790f, 1442–1443 Aspergillus colonization, 896, 897 Asphyxia and infarction, 665, 666f in perinatal period, 677–678, 679f Astroblastoma, 354, 355f Astrocytic brain tumors, 333 classification of, 333t diffuse (infiltrative), 334–354, 334t histopathologic grading of, 334 localized (noninfiltrative), 354–358 Astrocytoma, 311, 334, 1288–1294 anaplastic, 337–339, 338f–341f cerebellar, 431–434, 432f–434f cervical, 1289f conus, 1290f versus ependymoma, 1297, 1297f fibrillary, 334–336, 335f–338f hemorrhagic, 514f imaging, 1289, 1289f–1297f pathology, 1289 pilocytic, 354, 356t, 362f pilomyxoid, 450, 453f protoplasmic, 338f subependymal giant cell, 182, 184f, 185f, 188–189, 355–356, 356f, 356t, 357f symptoms, 1288 thoracic, with cyst formation, 1290, 1290f, 1292 AT. See Ataxia telangiectasia (AT) 2188

Ataxia autosomal recessive inherited, 866–867 cerebellar degenerative, 860 (see also Cerebellar cortical atrophy (CCA); Multiple system atrophy (MSA)) with ocular motor apraxia type 1 (AOA1), 866–867 with ocular motor apraxia type 2 (AOA2), 867 with vitamin E deficiency, 866 Ataxia telangiectasia (AT), 199–200, 865–866 neuroimaging and pathology, 866, 866f neurologic signs, 866 Athabascan brainstem dysgenesis syndrome (ABDS), 134 Atherosclerotic infarction, 636 plaque formation and, 636 Athetosis, 851 Atlanto-occipital dislocation, 1334f ATM. See Acute transverse myelopathy (ATM) Atretic cephaloceles, 143–144, 143f Atrophy aging and, 818, 818f cerebellar cortical, 861, 861f, 861t Attention deficit-hyperactivity disorder (ADHD) fMRI of, 1568, 1569t MRI of, 1568 MRS of, 1569–1570 Autism spectrum disorder (ASD) MRI of, 1563, 1566t–1567t, 1567 MRS of, 1564t–1565t, 1565f, 1567–1568, 1633 Autoimmune-mediated encephalitis (AME), 297, 297f Autosomal dominant cerebellar ataxias. See Spinocerebellar ataxias (SCA) Autosomal recessive cerebellar ataxia type 1 (ARCA1), 867 AVMs. See Arteriovenous malformations (AVMs) Axonal guidance disorders, 116 Azygos anterior cerebral artery, 157–158, 158f, 159f B Back projection, 2 Bacterial infection cerebritis and abscess, 758–767 empyema, 772–774, 773f, 774f Lyme disease, 774–775, 774f meningitis, 767, 769–772, 771f mycobacterium tuberculosis, 776, 778–783, 779f–782f septic emboli, 767, 768f–769f syphilis, 775–776, 776f–778f Bacterial labyrinthitis, 931 Baggio–Yoshinari syndrome, 1433 Balanced fast field echo (B-FFE), 928 Balanced steady-state free precession (bSSFP), 45 Balloon cell proliferation, 290, 290f Balò concentric sclerosis, 223, 225f Basilar artery, 655 Basilar tip aneurysm, 1496f Basilary artery fenestration, 157, 157f BBB. See Blood-brain barrier (BBB) BD. See Brainstem disconnection (BD) Behçet’s disease (BD), 1426–1427, 1427f MR findings, 1427, 1427f neuro-BD (NBD), 1426 2189

Bell palsy, 922, 923, 923f Bevacizumab, 393, 413 B-FFE. See Balanced fast field echo (B-FFE) Bickerstaff encephalitis, 726 Bilharziasis. See Schistosomiasis Binswanger disease, 668, 834 Bipolar disorder (BD) fMRI of, 1573–1574 MRI of, 1573 MRS of, 1574–1575, 1574t, 1575f Birdcage resonator, 12–13, 12f Black blood angiography, 1477 Black-blood techniques, 1332 Blake’s pouch cyst (BPC), 121, 121f Blastic metastases, 908 Blood–brain barrier (BBB), 323, 326, 326f tumor enhancement and, 326–329, 327f–329f Blood–endolymph barrier, 930 Blood–nerve barrier, 1186 Blood–ocular barrier, 1032 Blood oxygenation level–dependent (BOLD) fMRI data preprocessing, 1653 experimental design, 1652–1653 image acquisition for, 1651–1652 principles of, 1641–1643, 1642f sensitivity of, 1652, 1652f signal basic quantitative model for, 1643–1651 Davis Model for, 1650–1651, 1651f statistical analysis in, 1653 Bone invasion, 1063 lesions, 891, 894, 894f–896f skull base and, 882–884, 884f, 885f Bone marrow transplantation, 241 Borderline personality disorder (BPD), 1584–1585 fMRI of, 1585–1587, 1585t–1586t MRI of, 1585 MRS of, 1587 Bosley–Salih–Alorainy syndrome (BSAS), 134 Bottom-of-sulcus dysplasia, 93, 291, 291f BPC. See Blake’s pouch cyst (BPC) Brain infections of bacterial, 758–783 fungal, 783–794 parasitic, 794–815 viral, 719–758 Sturge–Weber syndrome and, 194–195 tumors of, 303, 304f astrocytic (see Astrocytic brain tumors) cystic lesion, 311, 313, 313f–316f, 313t enhancement and blood–brain barrier, 323, 326–329, 326f–329f extra-axial mass lesions, 304–306, 304t, 305f–307f, 310 fat-containing neoplasms, 319–320, 320f hemorrhagic, 313, 313t, 315, 317f–319f, 317t identification and localization, 303–310 2190

intra-axial mass lesions, 304, 305, 307f–309f lesion characterization, 310–322, 311t, 312f–325f melanin in, 320, 321f, 321t metastases, 310, 385, 387–391, 388f–391f multicompartmental lesions, 310, 310f–311f neuronal and glial–neuronal composition, 358–369 pediatric, 430–481 (see also Pediatric brain tumors) radiation effects, 391–393 Brainstem disconnection (BD), 134, 135f Brainstem gliomas, pediatric, 443, 445–448, 445f–449f Brainstem injury (BSI), 706–708, 709f due to herniation from extensive contusions, 707f due to transtentorial uncal herniation, 706f primary, 706–707 secondary, 707 Breast carcinoma, 1035f, 1068 intramedullary cord metastasis from, 1302f–1303f Brown–Séquard syndrome, 1285, 1343, 1345, 1346f Brucellosis, 1429–1430, 1431f diagnosis of, 1430 differential diagnosis for, 1430 MRI for, 1430, 1431f BSI. See Brainstem injury (BSI) Buphthalmos, 1045, 1046t Sturge–Weber syndrome and, 194 C CADASIL (cerebral autosomal dominant arteriopathy leukoencephalopathy), 834 Calcification, 891, 899, 975 ependymoma, 518f ganglioglioma, pediatric, 453, 455f herniated discs, 1232 HIV-infected children, 738 hypoparathyroidism, 517f–518f intratumoral, 518f, 519f meningiomas, 362, 363f–364f pleomorphic xanthoastrocytoma, 519f Sturge–Weber syndrome, 189, 190f, 195 tuberous sclerosis, 182, 183f–184f Callosal agenesis, 1512–1516, 1515f Canavan disease, 269t clinical features, 265 MRI findings, 267, 267f, 268f MRS of, 1621–1622, 1622f pathologic findings, 265, 267 Canavan–van Bogaert–Bertrand disease. See Canavan disease Candida discitis, 1444, 1445f Candida meningoradiculitis, 1446f Candidiasis, 784–785, 784f, 1443–1444, 1445f disseminated, 784 radiologic presentation, 784–785 Capillary angiomas, 584. See also Capillary telangiectasia Capillary telangiectasia, 584–588, 586f–588f basal ganglia, 586f cavernous malformation, 585 developmental venous anomaly and, 588f necropsy specimen, 587f 2191

with

subcortical

infarcts

and

pontine, 587f Carbon monoxide intoxication, 240, 240f Cardioembolic stroke, causes of, 636 Carotid agenesis/hypogenesis, 154, 155f Carotid artery and atherosclerosis, 1482–1483 clinical evaluation, 1485–1486 screening for, 1483–1485, 1483f–1484f treatment, 1483 dissection, 1488–1490, 1489f injuries of, 715, 715f in skull base tumor, 886, 888, 889f–890f Carotid-cavernous fistulae (CCFs), 597–598, 599f–601f, 715f, 717, 1014, 1015f, 1016f, 1056 direct, 599f–600f indirect, 601f types of, 598 Carr–Purcell–Meiboom–Gill (CPMG) sequence, 49 Cauda equina neuritis, 1215 Cauda equina syndrome (CES), 1345, 1347f, 1402 Caudal cell mass and canalization, 1135–1137, 1136f Caudal regression, syndrome of, 1147–1150, 1149f–1151f, 1151t Caudal spinal anomalies, with anorectal and urogenital malformations, 1145 Cavernous angioma, 162–163, 165f, 507f, 509t. See also Cavernous malformations and developmental venous anomaly, 163–166, 165f, 166f of hypothalamus, 1014–1015, 1017f Cavernous carotid aneurysm, 906f Cavernous hemangiomas, 923 Cavernous malformations (CMs), 575–584, 1014–1015, 1017f, 1057–1058 in brain, 575 clinical features, 575–576 with developmental venous anomaly, 583f differential diagnosis, 584t enhancement characteristics on MR, 581f–583f extra-axial origin of, 577f familial, 575, 580f and hemorrhage, 576 imaging characteristics, 578–584, 579f–585f intraosseous, 577f–578f in left optic chiasm and tract, 576f microscopic examination, 577 multiple, 581f pathologic findings, 576–577, 576f–578f and seizures, 576 spine, 1384–1386, 1386f with surrounding hemosiderin, 578f Cavernous sinus, 886, 904, 906 Cavernous sinus dural arteriovenous malformations, 1014, 1015f, 1016f Cavernous sinus thrombosis, 1053, 1055f, 1056 CBS. See Corticobasal degeneration syndrome (CBS) CCFs. See Carotid-cavernous fistulae (CCFs) Center-brightening artifact, 14, 15f Central cord syndrome, 1345 Central nervous system (CNS) embryogenesis of, 80–81, 81f GM and WM of, 205 infections of, 719 bacterial, 758–783 2192

fungal, 783–794 parasitic, 794–815 viral, 719–758 malformations, classification of, 81–82 (see also specific malformations) myelination of, 205–206 primary lymphoma of, 379, 381–385, 382f–385f vasculitis, 246–247, 246f, 247f Central neurocytoma, 362–364, 363f Central pontine and extrapontine myelinolysis clinical features, 236–237 MRI findings, 237, 237f, 238f pathologic findings, 237 with restricted diffusion, 237, 238f Cephaloceles, 141, 143f, 960–961, 961f atretic, 143–144, 143f occipital, 144, 144f transalar, 145, 145f transsphenoidal, 144, 145f Cerebellar agenesis, 129, 129f Cerebellar astrocytoma CT findings of, 432–433, 432f, 433f cystic, 432–433, 432f MRI of, 433–434, 433f, 434f pilocytic astrocytoma, 431, 431t, 432f, 434 postoperative evaluation, 434 solid, 433f Cerebellar cortical atrophy (CCA), 861, 861f, 861t Cerebellar degeneration, acquired, 861, 862f Cerebellar dysplasia, 124, 125f Cerebellar hyperplasia, 125–126, 127f Cerebellar hypoplasia (CH), 117–118, 118f Cerebello-pontine angle (CPA), 910, 919f Cerebellopontine angle cistern epidermoid, 149, 150f Cerebellum, 116. See also Posterior fossa malformations developmental of, 116–117 Cerebral aneurysm, 158–160, 160f Cerebral astroblastoma, 354, 355f Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), 244, 246f Cerebral blood flow, 633. See also Infarction and ischemia, 634 Cerebral cortex development of, 88–90, 89f, 90f protomap hypothesis, 89, 89f, 90f tangential cell migration routes, 90, 90f malformations, 89 due to abnormal neuronal and glial proliferation or apoptosis, 90–96 secondary to abnormal cortical organization and late migration, 101–107 secondary to abnormal neuronal migration, 96–101 Cerebral lacunae, 820, 820t Cerebral proliferative angiopathy (CPA), 574–575, 575f clinical features, 574 imaging characteristics, 574–575, 574f–575f pathologic findings, 574 vs. AVM, 574 Cerebral vascular disease, 833–836. See also Vascular dementia clinical–pathologic correlation, 834–835 2193

dementia in elderly due to, 833–834 epidemiology, 834 imaging for, 835–836, 835f, 836f Cerebral venous thrombosis, 1505–1506 Cerebritis, 758–759, 758f, 759f meningitis and, 769, 771 subdural empyema and, 758f Cerebrospinal fluid (CSF), 949, 1029 clefts, 292, 295f, 305–306, 306f leak, 919, 920f MR spectroscopy of, 1135 Cervical disc, herniation of, 1224, 1227f–1233f, 1228–1229, 1232 Cervical spinal stenosis about, 1236, 1237, 1239, 1239f–1242f, 1242 spondylolisthesis, 1242–1243, 1242f, 1243f CES. See Cauda equina syndrome (CES) CEST (Chemical Exchange Saturation Transfer) agents, 71 Chagas disease, 813, 815 Chaotic lipomas, 1131 Chemical exchange saturation transfer (CEST) imaging, 333 Chemical shift artifacts, 31, 31f fat in tumors and, 319–320, 320f Chemical shift selection suppression (CHESS) imaging, 1021 CHESS. See Chemical shift selection suppression imaging (CHESS) Chiari type III malformation (C3M), 141, 142f, 1512f Chiari type II malformation (C2M), 138–141, 1117–1120, 1117f, 1118t DTI studies, 141, 142f imaging findings posterior fossa, 139–140, 139f, 140f supratentorial features, 140, 141f pathogenesis of, 138–139 and thoracic syringohydromyelia, 140f vanishing cerebellum in, 140f Chiari type I malformation (C1M), 135–138, 136f pathogenesis of, 136–137 pathology and imaging findings in CSF flow studies, 138, 138f syringohydromyelia, 136f, 138 tonsillar protrusion, 136f, 137, 137f spontaneous resolution of, 137f surgical decompression for, 136, 136f Childhood ataxia with diffuse CNS hypomyelination. See Vanishing white matter (VWM) disease Children ischemic injury in, 676–679, 676f–680f neuroblastoma in, 1263, 1265–1266 pituitary adenomas in, 478 Cholesteatoma, 909, 915f middle ear, 940 Cholesterol cyst, 898f Cholesterol granuloma, 909 treatment of, 908 Chondrification, 1172–1173 Chondrosarcomas, 891, 902, 903f–904f, 904, 905f, 1267–1269 imaging, 1267, 1268f, 1269, 1269f pathology, 1267 recurrent epidural, 1269f signs and symptoms, 1267 2194

treatment, 1269 Chordoid glioma, 352, 353f Chordomas, 901, 903f, 992–993, 995f–996f, 1263 cervical, 1264f and cord compression, 1263 imaging, 1263, 1264f pathology, 1263 sacral, 1264f treatment, 1263 Chorea, 851 Choroidal detachment, 1040–1044, 1043f–1048f Choroidal melanoma, 1045 in adults, 1032t with detachment, 1033f Choroidal vascular tumors, 1039–1040 Choroid plexus papilloma (CPP), 442–443, 444f CT findings, 443, 444f MRI findings, 443, 444f MRS of, 1621f Chromosomal disorders, and WM abnormalities, 271–272, 272f Chronic focal encephalitis. See Rasmussen encephalitis Chronic inflammatory demyelinative polyneuropathy (CIDP), 1429, 1429f–1430f Chudley–McCullough syndrome, 124 Churg–Strauss syndrome, 1069 Ciliochoroidal detachments, 1043, 1044 Circumscribed neurofibromas, 1062 Cirsoid aneurysm, 604, 608f CISS. See Constructive interference in steady state (CISS) CJD. See Creutzfeldt-Jakob disease (CJD) Clivus, 882, 884f CMs. See Cavernous malformations (CMs) CMV. See Cytomegalovirus (CMV) CNAD. See Cochleovestibular nerve aplasia or dysplasia (CNAD) Coats disease, 1039, 1041f Cobblestone malformation, 96–97 and congenital muscular dystrophy, 96 muscle-eyebrain disease and, 97, 98f neuropathology and imaging findings, 96–97, 97f, 98f Walker–Warburg syndrome and, 97, 97f Cobb syndrome, 1380 Coccidioidomycosis, 1440–1442 MR findings, 1441, 1441f, 1442f Coccidiomycosis, 788, 791, 791f–792f basilar meningitis from, 791f spinal meningitis from, 792f Coccygeal dimples, 1124–1125, 1124f–1125f Cochlear duct, 926 Cochlear hemorrhage, 913f Cochlear malformation, 931 Cochlear otosclerosis, 943 Cochleovestibular nerve aplasia or dysplasia (CNAD), 914 Cockayne syndrome, 269–271, 271f Cogan syndrome, 935, 936f Coils 32-channel cardiac research coil, 18, 18f gradient, 10–11, 10f radiofrequency, 11–13 2195

research, 18 shim, 5, 8–9 Colloid cysts, 377–379, 381f Colobomas, 1045, 1046f, 1046t Compressed sensing, 19–20 Compression fractures, 1247, 1250f, 1251 in hemangiomas, 1251 Computed tomography (CT) hyperostosis, 891 of spondylolisthesis, 1242f Computed tomography angiography (CTA), 1014 Computer servers, 18 Conal cyst, 1144–1145 Concurrent malformations, lipomas, 1135 Condylar emissary vein, 161, 161f Congenital bilateral perisylvian syndrome, 292, 293f Congenital fibrosis of extraocular muscles (CFEM), 134–135 Congenital vertebral dislocation, 1176, 1177f Conjunctival diffuse B-cell lymphoma, 1082f Constructive interference in steady state (CISS), 928 Contrast, 15, 22, 33–34, 59 definition of, 33 epidural tumors, 1251 magnetic susceptibility of tissue and, 46 magnetization transfer, 45–46 paramagnetic agents for, 61 Rose criterion, 34 Contrast agents, 59, 68 cell labels, 68 CEST agents, 71 delivery methods, 68–69 Gd-DTPA and carrier macromolecules, 69 and hyperpolarization, 71–72 intravascular blood pool, 69 liposome-based, 69 macromolecular, 69 nanoparticles, use of, 69–70 for NMR and other modalities, difference between, 62 PARACEST agents, 71 smart, 68, 70 susceptibility agents, 72–77, 73f–76f, 76t targeted, 68, 70–71 Contrast-to-noise ratio (CNR), 33 Contusions, 703, 705f–708f, 706 acute hemorrhagic, 708f cortical, 705f frontotemporal hemorrhagic, 705f Conus medullaris, position of dural sac, configuration and termination of, 1137–1140, 1138t–1140t, 1139f normal filum, thickness of, 1140 Conus medullaris syndrome, 1345, 1346f Cord retethering, 1116, 1116t Cornea, 1028f, 1030 Corpus callosotomy, 280t Corpus callosum Aicardi syndrome, 86, 87f anomalies of, 82–88 2196

complete agenesis of, 83f, 84f, 85f with interhemispheric cysts, 86f diffusion tensor imaging (DTI) finding, 86, 87f, 88, 88f fetal DTI, 86, 88f fiber tractography (FT), 86, 88 neonatal head ultrasound, 88, 88f normal cingulate gyrus and sulcus, 85f partial agenesis of, 84f Probst bundles, 85, 86, 86f, 87f, 88f Correlation time, 62f, 63, 64–66 and relaxation rates, 64 Cortical dysgenesis, 296 Corticobasal degeneration syndrome (CBS), 847–849, 848f features, 847 neuroimaging and pathology, 848f, 849 and progressive supranuclear palsy, 849 Cowden disease, 361 CPA. See Cerebello-pontine angle (CPA) CPP. See Choroid plexus papilloma (CPP) Craniopharyngioma, 975–976, 975f–979f. See also Sella turcica and parasellar region adamantinomatous, 975–976 papillary, 976 Craniopharyngiomas, 474–475, 475f CT findings, 475, 475f MRI findings, 475, 475f–477f Creatine deficiency syndromes, MRS of, 1622 Creutzfeldt–Jakob disease (CJD), 748–749, 749f–750f, 849, 850f diagnosis of, 748 familial, 748 iatrogenic, 748 incidence, 748 MR findings, 748–749, 749f–750f pathology in, 748, 748f pulvinar sign, 749, 750f sporadic, 748 variant, 748, 749, 750f–751f Cryomicrotome, 1193 Cryptococcal spondylitis, 1442, 1445f Cryptococcomas, 785–786. See also Cryptococcosis Cryptococcosis, 785–788, 785f–787f, 1442, 1445f in AIDS patients, 785 gelatinous pseudocyst, 785, 786f, 787f meningitis, 785, 785f Currarino triad, 1175–1176, 1177t Cushing disease, 962, 966f Cysticercosis, 804–810, 804f–810f, 811t, 1003, 1004f intraparenchymal cysticercosis phases, 804, 805f, 806 intraventricular, 808, 809f, 810f parenchymal, 809f racemose, 808, 808f–810f reactivation, 805, 807f Cysticercosis, spinal, 1445–1450 classification of, 1446t diagnostic criteria, 1445 intradural extramedullary, 1447f–1448f intramedullary, 1448f leptomeningeal form, 1446, 1446f, 1447f 2197

MRI for, 1446, 1446f–1449f, 1450 subarachnoid, 1446f Cystic leukoencephalopathy without megalencephaly, 269t Cystic meningioma, 308f Cystic necrosis, 311, 312f and hemorrhage in thyroid metastasis, 315f in high-grade glioma, 314f–315f in metastases, 316f Cyst(s), 311, 313, 313t aneurysmal bone, 1259, 1260f arachnoid, 416–417, 418f cholesterol, 898f colloid, 377–379, 381f colobomatous, 1045 conal, 1144–1145 dermoid, 420–421, 420f–421f, 1060–1065, 1062f–1066f epidermoid, 417, 419f, 420, 1060–1065, 1062f–1066f formation of, 901 hematic, 1065, 1065f hydatid, 812–813, 813f inclusion, 1111 neurenteric, 417, 419f, 1154, 1155f, 1156, 1157t, 1158 pineal, 376–377, 380f of Rathke cleft, 976, 980f synovial, 1235, 1238f Tarlov, 1219f teratogenous, 1166f in tuberous sclerosis, 183, 187f Cytomegalovirus (CMV), 727–730 congenital infection, 729–730, 730f encephalitis, 728, 729f neuropathologic changes, 728, 728f owl’s-eye appearance, 728, 728f with polymicrogyria, 730, 730f polyradiculopathy, 1456, 1457f ventriculitis, 728, 728f D Dandy–Walker malformation (DWM), 118–121, 119f, 120f, 121f dysgenesis of corpus callosum in, 120, 120f and hypoplasia of inferior part of cerebellar vermis, 120 pathologic and imaging findings in, 119, 119f, 120f brainstem, 120 cerebellum, 119 cranium, 120 dura and sinuses, 120 fourth ventricle, 119–120 supratentorial brain, 120 prenatal diagnosis of, 120, 121f Data processing, 17–18 DAVF. See Dural arteriovenous fistula (DAVF) Deformity orthopedic, 1150 Sprengel’s, 1175 Dementia with Lewy bodies (DLB), 836–837, 837f cingulate island sign in, 837, 837f clinical features, 836 cognitive symptoms in, 836 2198

imaging in, 837, 837f pathology, 836–837 Dengue encephalitis, 754f Dermoid cysts, 420–421, 420f–421f, 1060–1065, 1062f Dermoid tumors, 147–148, 985, 987–988, 987f–988f, 1125–1127, 1126f imaging findings, 148, 149f ruptured, 149f spinal, 1303, 1304f–1305f Dermomyotomes, 1167–1168 Desmoplastic infantile ganglioglioma (DIG), 455, 456f Developmental abnormalities cell proliferation, abnormal, 290–291, 290f, 291f classification of, 289–290, 289t epilepsy and, 289–296, 289t, 290f–296f, 294t HIPPO SAGE mnemonic, 296f neuronal migration, abnormal, 292, 292f postmigrational development, abnormal, 292, 293f Developmental venous anomaly (DVA), 163–166, 165f, 166f, 589–592, 589f–592f brain and, 589–590 clinical symptoms and, 590 in spinal cord, 590 Devic’s disease. See Neuromyelitis optica (NMO) Diabetes insipidus, 1015–1016, 1018, 1018f Diamagnetism, 485–486, 485f Diastematomyelia, 1113. See also Notochord, embryogenesis of about, 1158–1160, 1158t, 1159f–1160f, 1159t dual dural–arachnoid tubes, 1160–1161, 1161f, 1162f single dural–arachnoid tube, 1160, 1161f variant forms, 1161, 1163, 1164f–1167f, 1165 Dielectric current effects, 15 Dielectric resonances, 15 Diencephalon, 80 Diffuse encephalitis, 727 Diffuse large B-cell lymphoma (DLBCL), 379, 1080 Diffuse orbital infiltration, 1069 Diffusion imaging effects of higher field strength on, 15–16 physical underpinnings of, 1528–1531 Diffusion tensor imaging (DTI), 1073 for Alzheimer disease, 831 ellipsoid orientation/direction and, 1535–1536, 1536f–1539f ellipsoid shape and, 1534–1535 ellipsoid size and, 1534, 1535f fiber tractography, 1536, 1537f–1539f geometric representation for, 1531–1532, 1532f, 1533f for head injury, 695–696, 696f longitudinal studies and, 1540–1541 multisite studies and, 1540–1541 myelination, development of, 206 quantitative, 1532–1534, 1533f, 1534f spinal cord, 1352–1354 of spinal cord injury, 1354–1355, 1355f, 1356f thalamic nuclei in, 1542f Diffusion tensor tractography (DTT), 330, 331f, 332, 332f Diffusion-weighted imaging (DWI), 47–48, 47f, 48f, 909, 914, 1531 Alzheimer disease, 831 artifacts, 1536–1540 2199

bacterial abscess, 762–763, 762f, 763f, 764f, 766, 766f brain tumors, 330, 331f cysticercosis, 808, 810f gelatinous pseudocysts, 788 infarction and, 640f–641f, 646–647, 646f, 647f, 648, 650f, 651–652 Krabbe disease, 254 metachromatic leukodystrophy, 252 of orbit, 1022 spinal cord, 1352–1354, 1352f–1354f spinal cord injury, 1354–1355, 1355f, 1356f Digital subtraction of postcontrast from precontrast MR images, 333 Diplopia, 995, 1011f DIR. See Double inversion recovery (DIR) Dirac comb function, 28 Disc herniations, 1325 Disc injury, traumatic, 1325, 1326f Discitis, 1196 Discogenic sclerosis, 1197 Discogram, 1196f Discrete orbital mass, 1056 Discrete-time pulse sequence simulations, 36–38, 37f, 38f Disruption definition of, 81 genetic predisposition to disruptive lesions, 82, 82f prenatal, 81, 81f Disseminated candidiasis, 784 Disseminated histoplasmosis, 792, 794 Disseminated intravascular coagulopathy, 584, 584f Dixon fat suppression techniques, 1022 DLB. See Dementia with Lewy bodies (DLB) DLBCL. See Diffuse large B-cell lymphoma (DLBCL) DNET. See Dysembryoplastic neuroepithelial tumor (DNET) Dorsal dermal sinus, 1120, 1122, 1122f–1124f, 1124 Dorsal enteric fistula, 1154, 1155f, 1156, 1157t, 1158 Dorsal lipomas, 1130 Double inversion recovery (DIR), 1072 Driven equilibrium (DRIVE), 928, 929f Drugs of abuse, and leukoencephalopathy, 242, 243f DSC. See Dynamic susceptibility contrast (DSC) Duane syndrome, 135 Dural-arachnoid tube dual, 1160–1161, 1161f, 1162f single, 1160, 1161f Dural arteriovenous fistula (DAVF), 531, 592–610, 1501–1502, 1503f anterior fossa, 603f of cavernous sinus, 597 classification, 597 clinical features, 593–598, 593f–603f with cortical venous drainage and venous hypertension, 604f hemorrhage in, 597 with intraparenchymal hemorrhage, 596f, 597 of left transverse–sigmoid sinus, 593, 593f–594f, 597 middle cranial fossa, 605f–607f MRA in, 604 MR characteristics, 598, 603, 603t, 604f–610f, 610 MR findings in, 603t natural history and clinical symptoms of, 593, 597 2200

posterior fossa, 593, 593f, 602f spontaneous regression of, 593, 595f with venous hypertension, 605f venous hypertension and dementia from, 597f–598f Dural lesions, 891, 891f, 892f–893f Dural sac, configuration and termination of, 1137–1140, 1138t–1140t, 1139f Dural tail sign, 982 Duret hemorrhages, 708 DVA. See Developmental venous anomaly (DVA) DWM. See Dandy-Walker malformation (DWM) Dynamic contrast-enhanced MRI (DCE), 329, 1552 and vascular permeability, 329–330 Dynamic susceptibility contrast (DSC) MRI, 329 cerebral blood volume and, 329, 1549, 1550, 1550f contrast agents for arterial concentration measurement in, 1550–1551, 1550f delayed arrival of, 1552 effect of, 1547–1550, 1547f–1250f neural tissues and, 1546, 1546f, 1547f dispersion and, 1552 single-voxel, 1549, 1549f tissue permeability effects in, 1552 tissue signal correction for, 1551–1552, 1551f, 1552f Dysembryoplastic neuroepithelial tumor (DNET), 366, 367f, 456, 458, 458f, 459f Dysmyelinating disorders, 205, 205t Dysplastic gangliocytoma of cerebellum, 361–362, 361f–362f pilocytic astrocytoma of cerebellum and, 362f Dystonia, 851 E Ear, inner anatomy of bony and membranous labyrinth, 925–926, 927f cochlear duct or scala media, 926 endolymphatic duct and sac, 927 vascular system, 927 vestibular sense organs, 926–927 congenital malformations of, 930–931 Early-onset cerebellar ataxia with retained tendon reflexes (EOCA), 866 Ecchordosis, 993, 997f ECD. See Erdheim-Chester disease (ECD) Echinococcosis, spinal, 1452–1454, 1452f, 1453f Echo-planar imaging (EPI), 16, 19, 27, 27f gradient echo, 49 multi-shot, 49 rapid image acquisition by, 49 spin echo, 49 ECVL. See Encapsulated cavernous venous lesion (ECVL) Edema abscess and, 760 spinal cord, 1315f, 1317f–1322f, 1344 EDHs. See Epidural hematomas (EDHs) Ehlers–Danlos syndrome, 1152 Electromagnets, 6 Electromicroscopy, 943 Electron spin, 4 ELST. See Endolymphatic sac tumors (ELST) Embolic infarction, 661f 2201

hemorrhage with, 640f MR appearance, 662, 663f septic emboli with, 662, 663f Embryogenesis normal, and anatomy caudal cell mass and canalization, 1135–1137, 1136f retrogressive differentiation, 1137 overview of notochordal process, 1098 prechordal plate, 1098 Embryogenesis (continued) primitive node (Hensen’s node), 1098 three-layered germinal disc and gastrulation, 1096, 1097f, 1098 two-layered germinal disc, 1096, 1097f Empty sella turcica, 959, 960f Empyema, 772–774, 773f, 774f. See also Subdural empyema (SDE) causes of, 772 complications, 772 DWI for, 773f, 774, 774f MRI for, 772, 774 Encapsulated cavernous venous lesion (ECVL), 1058 Encephalitis cytomegalovirus, 728, 729f diffuse, EBV infection and, 727 enterovirus, 751, 752f herpes simplex, 719–725, 720f–725f herpes zoster, 726–727, 727f HIV, 731–732, 731f, 732f, 734f, 735f HSV-2, 725–726 influenza virus associated, 754–755, 755f Listeria, 771f Lyme disease and, 774 neonatal, 725–726 Rasmussen, 756–758, 757f, 758f Toxoplasma, 795–803, 796f–803f West Nile, 751, 752f–753f Encephaloceles, 918 and seizures, 296, 297f Encephalopathy gluten sensitivity, 297 hepatic, 1631 human immunodeficiency virus, 233, 235f–237f, 236 hypertensive, 242, 244, 244f, 245f, 246–247, 246f, 247f Wernicke, 856–858, 857f Encephalotrigeminal angiomatosis. See Sturge-Weber syndrome; Sturge–Weber syndrome Endolymphatic duct and sac, 927 Endolymphatic hydrops, 942–943 Endolymphatic sac tumors (ELST), 910, 910f, 943 Endovascular coils, 617 Endovascular therapy, for ischemic stroke, 638 Enteroviruses, 749, 751, 752f Eosinophilic granuloma, 1248f, 1261–1263 imaging, 1248f, 1262–1263 pathology, 1262 symptoms, 1261 vertebra plana, 1262 Eosinophilic granulomatosis, 1000, 1002f, 1003f 2202

Ependymitis granularis, 835 Ependymoma, 1294–1297 calcification, 518f cervical, 1294f with cyst formation and hemorrhage, 1291f with diffusion tensor imaging and tractography, 1295f–1296f hemosiderin cap sign, 1291f–1292f imaging, 1291f–1298f, 1296–1297 multiple, 1292f–1293f myxopapillary, 1294, 1297, 1298f pathology, 1296 of posterior fossa, 440–442, 440f–443f, 631t CT findings, 441, 441f dissemination, 440 fourth ventricle, 440, 440f incidence of, 440 microscopic features, 441f MRI findings, 441–442, 441f–443f postoperative follow-up, 442, 443f spinal cord astrocytoma versus, 1297, 1297f supratentorial, 463–465, 466f–467f CT imaging, 464, 466f, 467f MRI of, 464–465, 467f treatment, 1297 EPI. See Echo-planar imaging (EPI) Epiblast cells, 80 Epidermal ectoderm (ECT), 1102f Epidermoid cysts, 417, 419f, 420, 1060–1065, 1062f–1066f Epidermoid tumors, 147–148, 149–150, 150f, 909, 985, 987–988, 987f–988f, 1125–1127, 1126f Epidural hematomas (EDHs), 520, 523–528, 528t, 708–709, 710f posterior fossa, 709, 710f spinal, 1325, 1326f–1328f venous, 709, 710f Epidural lymphoma, 304f Epidural metastases, 410–412, 412f Epilepsy, 277 autoimmune-mediated encephalopathy and, 297, 297f causes of, by age of seizure onset, 278t chronic, 296 CNS infections and, 296–297 cortical gliosis and, 296–298 definition of, 277 developmental malformations and, 289–296, 289t, 290f–296f, 294t epilepsy syndromes, classification of, 277–278, 278t focal seizures, 277, 277t, 278 generalized seizure, 277, 278 gliosis and miscellaneous abnormalities, 296–298, 297f, 298f hippocampal sclerosis and, 282–289, 282f, 283t, 284f–288f investigative modalities, 278–279, 279t MRI of, 279–282, 280t, 281t advanced imaging techniques and, 301 diffusion imaging, 301 pitfalls to consider, 300 practical issues in, 298–300, 299f, 300f proton MRS, 300–301 substrate category and, 282–298 neoplasms and, 289 2203

posttraumatic, 296 seizure classification, 277, 277t Sturge–Weber syndrome and, 297 surgery for, 278 localization of seizure focus and assessment of resectability, 279, 280f, 281t MRI in, 279–282, 281t presurgical evaluation, 279 procedures in, 280t SISCOM localization, 281 transient MR signal changes and, 298, 298f vascular malformations and, 289 Epstein–Barr virus (EBV), 727 spinal cord, 1456 Erdheim–Chester disease (ECD), 1000, 1003, 1089 Esthesioneuroblastoma, 887f–888f with intracranial extension, 900f skull base tumors and, 900f, 901f Esthesioneuroblastomas, 899 Ethmoid, 882 malignancy, 887f–888f Ewing sarcoma, 1269 imaging, 1269, 1270f, 1271f pathology, 1269 treatment, 1269 Exchange forces, 486 Extra-axial mass lesions, 304–306, 304t, 305f–307f, 310 boundary layers, 305, 308f cerebrospinal fluid cleft, 305–306, 306f and edema, 306, 306f enhancement of, 310 magnetic resonance findings in, 304t meningeal tumors, 393–414 nerve sheath tumors, 414–416, 414f–416f vascular clefts, 306 Extra-axial metastases, 410–414, 411f–413f Extraocular muscles, enlargement of, 1050, 1050t Extrapyramidal nuclei, 851 Extraventricular neurocytoma (EVNCT), 364 Eye and orbit. See Orbit Eye makeup artifact, 1022f F Fabry disease clinical features, 255–256 MRI findings, 256, 256f Facet synovitis, 1189f, 1215, 1217f, 1236 Facial nerve. See also Inner ear anatomy, 922, 923f benign venous malformations of, 914, 915f palsy, 924f, 925f pathology, 922–925, 923f–926f schwannoma, 925f Fahr disease, 516f Fast imaging employing steady state (FIESTA), 928 Fast spin echo (FSE), 49–51, 953, 1022, 1185, 1232 Fat-containing neoplasms, 319–320, 320f Fat suppression, 1072 in skull base imaging, 882 2204

Fat–water chemical shift, 31, 31f FCD. See Focal cortical dysplasia (FCD) FD. See Fibrous dysplasia (FD) Ferrimagnetism, 486 Ferritin, 504 Ferromagnetism, 486 Fetal brain/spine imaging brain development, normal, 1510, 1511f CNS anomalies in, 1510–1516, 1511f, 1512f acquired brain pathologies, 1516 callosal agenesis, 1512–1516, 1515f complex malformations, 1516 cortical development, disorders of, 1510–1512 ventriculomegaly, 1512 counseling and, 1524–1525 fast MR techniques for ultrasound vs., 1509t preparation of patient for, 1524 prerequisites for, 1524 reporting in, 1524 sacrococcygeal teratoma in, 1520, 1523f, 1524f safety issues in, 1510 Fiber tractography, for SCI, 1355, 1357f–1358f Fibrillary astrocytoma, 334–336, 335f–338f pediatric, 458–460, 460f CT findings, 460, 460f MRI findings, 460, 460f Fibrosing sclerosis in children with HIV infection, 738–739 Fibrous dysplasia (FD), 891, 895f, 1084, 1085f, 1086f Field focusing technique, 2 Field of view (FOV), 8, 18–19, 28–30, 30f Field strength effects, 489–491 FIESTA. See Fast imaging employing steady state (FIESTA) Filar lipomas, 1141, 1142f Filtering, 32 Fluctuation–dissipation theorem, 13 Fludarabine-induced toxicity, 241, 243f Fluid-attenuated inversion recovery (FLAIR), 928, 933f, 937f, 944f arachnoid cyst, 313, 313f infarction and, 644–646, 645f, 646f subarachnoid hemorrhage, 519, 520f–522f fMRI. See Functional magnetic resonance imaging (fMRI) Focal cortical dysplasia (FCD), 92–93, 296. See also Epilepsy bottom-of-sulcus dysplasia, 93 neuropathology and imaging findings, 92–93, 93f, 94f presurgical localization of, 93 type IIb, 290–292, 290f, 291f types, 92 Foci of abnormal signal intensity (FASI), NF1, 169, 170f Foix–Alajouanine syndrome, 1373, 1425 Foraminal stenosis, 1236, 1240f Fourier techniques, 2 Fourier transform nuclear magnetic resonance (FT-NMR) spectroscopy, 602 FOV. See Field of view (FOV) Fragile X–associated tremor/ataxia syndrome (FXTAS), 861 diagnosis of, 861–862 2205

neuroimaging and pathology, 862–863, 862f Free induction decay (FID), 10, 32, 33f Frequency encoding, 10 Friedreich ataxia, 864–865, 865f Frontonasal dysplasia, 958 Frontotemporal dementia (FTD), 844. See also Frontotemporal lobar degeneration (FTLD) behavioral-variant (bvFTD), 844 primary progressive aphasia (PPA), 844 Frontotemporal lobar degeneration (FTLD), 844–846, 845f clinical phenotypes, 844 imaging findings, 845–846, 845f pathology, 844–845 FSE. See Fast spin echo (FSE); Fast spin-echo imaging (FSE) FTD. See Frontotemporal dementia (FTD) FTLD. See Frontotemporal lobar degeneration (FTLD) Fukuyama congenital muscular dystrophy (FCMD), 96, 97. See also Cobblestone malformation Functional independence measure (FIM), SCI, 1346 Functional magnetic resonance imaging (fMRI), 332, 333f, 1641 for ADHD, 1568, 1569t for alcohol use disorder, 1589, 1590t for Alzheimer disease, 831 for anxiety disorders, 1575–1577, 1576t arteriovenous malformations, 569, 571f–573f for bipolar disorder, 1573–1574 BOLD, 1641–1653 borderline personality disorder, 1585–1587 for head injury, 697–698, 698f for obsessive–compulsive disorder, 1581–1582 for panic disorder, 1577–1578 pitfalls in, 1664 for posttraumatic stress disorder, 1583–1584 presurgical planning of, 1656–1664 language mapping, 1660, 1661f–1663f, 1664 memory mapping, 1664 motor and somatosensory mapping, 1657–1660, 1658f–1660f, 1661f resting-state, 1664–1667 (See also Resting-state fMRI (rs-fMRI)) for spinal cord injury, 1359–1361, 1359f, 1360f statistical analysis, 1653–1656 Fungal colonization, 896 Fungal infections, 783–794 aspergillosis, 788, 789f–790f candidiasis, 784–785, 784f coccidiomycosis, 788, 791, 791f–792f cryptococcosis, 785–788, 785f–787f histoplasmosis, 791–792, 794, 794f–795f mucormycosis, 788, 790f, 791f paracoccidioidomycosis, 791, 792t, 793f, 794f of spine and spinal cord, 1440–1445 Fungal sinusitis, 888f G Gadavist, 329 Gadolinium-based contrast agents (GBCA), 329, 882, 884f, 891, 1218–1219 Gadolinium chelates, 68 Gadolinium–diethylenetriamine penta-acetic acid (Gd-DTPA), 966f Galactosemia, MRS of, 1622 Gamma-knife stereotactic radiosurgery, 974 Gangliocytoma, 360. See also Ganglion cell tumors 2206

Ganglioglioma, 358, 359f, 360, 360f. See also Ganglion cell tumors pediatric, 452–455, 453f–455f, 454t anaplastic, 455f calcifications, 453, 455f cystic and solid, 453, 454f histopathologic features, 452, 453f Ganglion cell tumors, 358–361, 359f, 360f pineal, 377f Ganglioneuroblastoma, 1263, 1265–1266 Ganglioneuroma, 992f, 1263, 1265–1266, 1265f–1266f imaging, 1265 pathology, 1263, 1265 treatment, 1265–1266 Gastrulation, 80, 1096, 1097f, 1098 Gaucher disease clinical features, 256 MRI findings, 256, 257f Gauss, 4 GBS. See Guillain-Barré syndrome (GBS) Gelatinous pseudocyst, 785, 786f, 787f Generalized autocalibrating partially parallel acquisition (GRAPPA), 55–56, 56f, 57f Germ cell tumors, pineal, 372–375 Germinal disc three-layered, 1096, 1097f, 1098 two-layered, 1096, 1097f Germinal matrix, 89, 90f Germinomas, 982, 984–985, 984f–986f pineal, 371t, 372–373, 372f–374f, 470, 472f–473f Gerstmann–Straussler–Scheinker (GSS) disease, 747, 748, 849 GHD. See Growth hormone deficiency (GHD) Ghosting artifacts, orbital imaging and, 1021f Giant cell arteritis, 1076f Giant cell lesions, 894 Giant cell tumors, 1259, 1261 imaging, 1261, 1261f pathology, 1259, 1261 symptom, 1259 treatment, 1261 Gibbs ringing, 53, 53f Glaucoma, 1045 Glioblastoma, 328f hemorrhagic, 510f, 511f, 512f Glioblastoma multiforme (GBM), 310 in children, 461–462 differential diagnosis, 351, 351f DSC perfusion, 350, 351f enhancement features, 347, 349f, 350f gross specimen, 347, 347f histopathologic specimens, 347, 348f hypercellular, 349f MRI features, 347, 348f–349f MRS of, 1617–1620, 1621f sites of localization, 344, 347, 347f treatment, 351 Glioma(s), 333, 888 angiocentric, 352, 354, 354f astroblastoma, 354, 355f 2207

brainstem, 354–355, 355f chiasmatic, 988, 989f–994f chordoid, 352, 353f glioblastoma multiforme, 343–344, 347–351, 347f–351f hypothalamic, 988, 989f–994f low-grade, 1617f NF1 and, 169, 170f–171f, 171–172 optic nerve, 169, 170f–171f, 171–172 tectal, 354–355, 355f visual pathway, 170f–171f Gliomatosis cerebri (GC), 341–343, 345f–346f, 460–461, 461f CT findings, 461, 461f MRI findings, 461, 461f Glioneuronal tumors, rosette-forming, 191 Gliosarcoma, 351–352, 352f Globe muscles of, 1025, 1025f–1029f orbit and, 1030–1032 shape abnormalities of, 1044–1047, 1046t Globoid cell leukodystrophy (GLD). See Krabbe disease Globus pallidus, 851 Glomus tumors. See Paragangliomas Glomus tympanicum tumors, 913, 914f Glomus vagale paragangliomas, 913 Glossopharyngeal nerve, 913 Glutaric aciduria type I, 267t Gluten sensitivity encephalopathy, 297 Glycine encephalopathy, MRS of, 1622, 1622f GM1 and GM2 gangliosidoses, 254–255 clinical features, 254 MRI findings in, 255, 255f Goldenhar complex, 1176 Gómez–López–Hernández syndrome, 123 Gout, 1402–1403, 1403f GPA. See Granulomatosis with polyangitis (GPA) GPR56-related polymicrogyria, 125, 126f Gradient and spin echo imaging (GRASE), 51, 51f Gradient coils, 10–11, 10f components of, 11 transverse, 10, 10f z-gradient coil, 10, 10f Gradient-echo (GE) methods, 953 Gradient-recalled echo (GRE), 1185, 1228f Granular cell tumors, 993–994, 994f, 998f Granulomata histoplasmosis with, 794f–795f tuberculous, 780–781, 781f, 782f Granulomatosis with polyangitis (GPA), 1069, 1070f 1069, 1070f Granulomatous angiitis, 662f Granulomatous giant cell hypophysitis, 1006, 1007f Graves’ ophthalmopathy. See Thyroid orbitopathy GRE. See Gradient-recalled echo (GRE) Growth hormone deficiency (GHD), 955, 958 Guglielmi detachable coil (GDC), 612 Guillain–Barré syndrome (GBS), 1427–1428 differential diagnosis, 1428t 2208

MR findings in, 1428, 1428f Gusher ear, 931, 933f Gyromagnetic ratio, 10 H Hallervorden–Spatz syndrome, 853–855, 854f eye-of-the-tiger sign, 853, 854f neuroimaging and pathology, 853–855, 854f subtypes, 853 Hamartomas, 999 Hand–Schüller–Christian syndrome, 1000 HD. See Huntington disease (HD) Head injury, 687 brainstem injury, 706–708, 709f classification for, 700, 700t contusions, 703, 705f–708f, 706 CT for, 690, 692 diagnostic flow chart for, 691t epidemiology of, 687–688 Glasgow Coma Scale (GCS) score, 687, 687t MR strategies/techniques for, 693 conventional imaging protocols, 693–695, 694f–695f diffusion tensor imaging, 695–696, 696f functional MRI, 697–698, 698f magnetic resonance perfusion, 699–700 magnetic resonance spectroscopy, 699, 699f susceptibility-weighted imaging, 696–697, 697f pathophysiology of, 688–690, 688f–691f primary hemorrhages, 708, 710f–714f, 711–713 primary intra-axial lesions, 700–708 role of imaging studies in, 690, 691t, 692–693 role of MRI in, 692–693 traumatic axonal injury, 700–703, 701f–704f vascular injuries, 713, 714f–716f, 715–717 Hearing loss, 942 Hemangioblastoma, 366–368, 367f–369, 1297–1299, 1299f cerebellar, 196f cystic, 196f–197f gross and histopathologic features, 367, 367f imaging, 1298–1299, 1299f, 1300f pathology, 1298 retinal, 195, 1039 spinal, 195, 197f, 198 treatment, 1299 types of, 367, 368f–371f VHL syndrome and, 195, 196f–198f, 198, 366–367, 1300f Hemangioma cavernous, 1057 infantile, 1056–1057, 1057f, 1058f osseous, 911 periocular, 1057f PHACES syndrome and, 1058f vertebral, 1251–1252, 1252f–1253f Hematic cyst, 1065, 1065f Hematogenous pyogenic facet joint infection, 1395, 1397 imaging studies, 1397 MRI for, 1396f, 1397, 1397f, 1398t symptoms, 1397 2209

Hematoma, 484t acute, 497, 500–501, 500f, 501f chronic, 505f–506f epidural, 520, 523–528, 528t etiology of, determination of, 528t hyperacute, 497, 497f–499f intraparenchymal evolution of, 495, 495t, 496f, 496t MR appearance of operator-dependent factors and, 484t physiologic factors and, 484t pontine, 502f remote, and residual iron, 504–506, 505f–506f subacute, 501, 503–504, 503f, 504f subdural, 520, 523–528, 525f–527f, 528t with underlying metastatic tumor, 515f Hematopoietic marrow, 882 Hemimegalencephaly (HME), 93–96 advanced neuroimaging in, 94, 96 forms of, 93 Klippel–Trenaunay–Weber syndrome and, 95f Hemimegalencephaly (HME) (continued) megalencephaly–capillary malformation and, 95f neuropathology and imaging findings, 94, 95f, 96f Hemimyelocele, 1113 Hemispherectomy, 280t Hemochromatosis, 1018 Hemorrhage, 313, 313t, 484, 886 cavernous angioma and, 507f in dural arteriovenous fistula, 597 Duret, 708 in elderly, 508f goals in imaging of, 485t hypertension-associated, 508f infarction and, 507f, 508f intracranial neoplasm and, 508–512, 510f–515f intraparenchymal dural arteriovenous fistula, 596f, 597 etiologies of, 506–512, 506t, 507f–515f evolution of, 496f pattern recognition clues to etiologies of, 509t intratumoral, 313, 315, 317f–319f, 317t, 969 delayed evolution, 512f vs. benign hemorrhage, 510t vs. benign intracranial hematomas, 317t intratumoral melanin vs., 321t intraventricular, 521f iron metabolic states in, 496t localization of, 484 MRI in, use of, 484–485 MR mimics of, 515–516, 516f–519f, 516t MR techniques and, 491–495, 492f, 493f echo planar imaging (EPI), 493, 495, 495f fast spin echo (FSE) sequence, 493, 494f gradient-recalled echo sequence, 491, 494f, 508f spin-echo sequence, 491 susceptibility-weighted imaging (SWI), 491, 493f 2210

periventricular, 676, 676f relaxation mechanisms in, 487–489, 488f, 488t, 490f, 491f, 491t, 496t and retinal detachment, 1046f spinal, 1388 subarachnoid, 516, 519–520, 519t, 520f–524f suprasellar and pineal germinoma with, 374f thrombosed giant aneurysm, 509f, 509t traumatic, 708, 710f–714f, 711–713 traumatic axonal injury and, 691f Hemorrhagic infarction, 507f, 508f, 509t MR appearance, 662–664, 664f Hemorrhagic necrosis, 311, 312f Hemosiderin, 504, 1008 Hemosiderosis, 914 Hensen’s node, 1098, 1101 Hepatic encephalopathy, 1631 Hepatolenticular degeneration. See Wilson disease (WD) Hereditary spastic paraplegias (HSPs), 871 Hermitian symmetry, 19, 53–54, 53f Herniation. See also Spine, degenerative disease of cervical disc, 1224, 1227f–1233f, 1228–1229, 1232 of disc inflammatory component, 1215 of disc involution, 1214 disc vs. disc space infection vs. tumor, 1215 lumbar disc, 1201, 1206, 1207f mimics of, 1215, 1218, 1218f, 1219f MRI of, 1206–1214, 1213f–1215f paramagnetic contrast in routine lumbar spine MRI, 1214–1215, 1215f–1217f postoperative lumbar spine and MRI, 1218–1219, 1220f–1226f of nucleus pulposus, 1201 thoracic disc, 1224, 1226f, 1227f Heroin inhalation–induced leukoencephalopathy, 242, 243f Herpes simplex encephalitis (HSE), 719–725 cortical enhancement, 722f–723f end-stage, 723f glutamine–glutamate complex, increase in, 725f with HIV infections, 724, 725f in immunocompetent individuals, 722 in infants and young children, 724, 724f restricted diffusion and high cerebral blood volume, 720f–721f restricted diffusion areas, 724f Herpes simplex infection, spine, 1454, 1455f Herpes simplex virus type 1 (HSV-1), 719–725. See also Herpes simplex encephalitis (HSE) Herpes simplex virus type 2 (HSV-2), 725–726 Herpes simplex virus type 6 (HSV-6), 730 Herpes simplex virus type 7 (HSV-7), 730 Herpesvirus, spine, 1454, 1456 Herpes zoster, 922, 924f, 1068f Herpes zoster encephalitis, 726–727, 727f Herpes zoster myelitis, 1454, 1456f Heterotopic gray matter, 292 HH. See Hypothalamic hamartomas (HH) Highly active antiretroviral therapy (HAART), 731, 733–734 High-temperature superconductors (HTS), 10 HIMAL (hippocampal malrotation), 293, 299–300 Hippocampal sclerosis, 282–289, 282f, 283t, 284f–288f amygdala and hippocampus, MRI of, 284, 285f 2211

bilateral, 287–288, 288f dual pathology, 287f, 288–289, 300 hippocampal and limbic anatomy and, 283–284, 283t, 284f–285f histology, 282, 282f MR findings with, 284, 285f–287f, 287 surgical treatment, 283 types, 282 unilateral, 286f Hippocampal volume, quantitative evaluation of, 287–288, 288f Histiocytic infiltrative disorders, 1087, 1089 Histoplasmosis, 791–792, 794, 794f–795f, 1444–1445 HIV. See Human immunodeficiency virus (HIV) HIV-associated neurocognitive disorders (HAND), 233 HIV encephalopathy, 233, 236, 738 clinical features, 233, 235f MRI findings, 236, 236f, 237f multinucleated giant cells in, 236 pathologic findings, 233, 236 and progressive multifocal leukoencephalopathy, 236t HME. See Hemimegalencephaly (HME) Holoprosencephaly (HPE), 107–112 alobar, 109, 110f DTI and FT findings in, 112 fetal imaging, 111, 112f lobar, 111, 111f middle hemispheric variant of, 112–113, 113f neuropathologic and imaging findings, 109, 109f semilobar, 109–111, 110f Homodyne reconstruction, 19 Horizontal gaze palsy with progressive scoliosis (HGPPS), 134 Hox code, 1169 HPE. See Holoprosencephaly (HPE) HSE. See Herpes simplex encephalitis (HSE) Human immunodeficiency virus (HIV), 730–739, 1457–1459 brain atrophy, 731, 732f with dementia, 735 encephalitis, 731–732, 731f, 732f, 734f, 735f and progressive multifocal leukoencephalopathy, 731–732, 732f–733f HAART for, 733–734 and immune reconstitution inflammatory syndrome, 735–737, 736f, 737f mI/Cr ratio in, 734 neurologic manifestations, 731 pediatric, 737–739, 738f, 739f proton MR spectroscopy, 734, 735f vacuolar myelopathy, 1458–1459 Human T-cell lymphotropic virus type 1 (HTLV-1) infection, 746–747, 747f myelopathy, 1459, 1459f Hunter disease, 256, 257f Huntington disease (HD), 851–853 clinical manifestations, 852 fMRI in, 853 MRS studies in, 853, 1630 neuroimaging and pathology, 852–853, 852f Hurst disease. See Acute hemorrhagic leukoencephalitis Hyaline chondrosarcomas, 904 Hybrid magnets, 6, 6f Hydatid cyst, 812–813, 813f, 1452–1454, 1452f, 1453f 2212

Hydrocephalus, 982 CNS cryptococcosis and, 785 histoplasmosis with, 794f–795f meningitis and, 772 tuberculous meningitis and, 780 Hydromyelia, 1111–1113, 1112f–1114f Hypermagnesemia, 1018 Hyperostosis, 891 Hyperpolarized imaging, 71–72 Hypertension, multiple microhemorrhages in, 669–670f Hypertensive encephalopathy clinical features, 242, 244 MRI findings, 244, 244f, 245f, 246–247, 246f, 247f Hypertrophic pachymeningitis, 1408, 1408f Hypoparathyroidism, 517f–518f Hypopituitarism, 1014 Hypoplasia, 917f pituitary gland, 955–958, 956f, 957f Hypothalamic hamartomas (HH), 292, 294f, 477–478, 479f Hypothyroidism primary, 1018, 1018f Hypoxic–ischemic encephalopathy, 676 I IAC. See Internal auditory canal (IAC) IAD. See Intracranial atherosclerotic disease (IAD) ICAs. See Internal carotid arteries (ICAs) Idiopathic orbital inflammatory pseudotumor (IOIP), 1051–1053, 1053f–1055f, 1066 Idiopathic pachymeningitis, 942f IgG4-related disease, 1069, 1070f Image bandwidth (BW), 28–30, 30f Image contrast. See Contrast Image data acquisition 2D images, acquisition of, 22–23, 22f, 23f 3D images, acquisition of, 23–25, 24f, 25f image generation by MRI, 22 Image reconstruction, 17–18 Image space, 22 Immune reconstitution inflammatory syndrome (IRIS), 232, 233, 235f, 735–737 cryptococcal, 737 HAART and, 735 progressive multifocal leukoencephalopathy and, 736, 736f, 737f risk factors, 736 Immunohistochemical staining, 904 Inclusion cysts, 1111 Infantile hemangioma, 1056–1057, 1057f, 1058f Infantile neuroaxonal dystrophy (INAD), 863, 865f Infantile paralysis. See Poliomyelitis Infarction, 633, 834 anterior cerebral artery, 656f basilar artery thrombosis with, 658f cardioembolic, 636 cerebral, 635–636 chronic, 643–644, 644f CT, evolution on, 639t diffusion-weighted imaging, 640f–641f, 646–647, 646f, 647f in distribution of artery of Percheron, 659f evolution of, 634f 2213

FLAIR imaging, 644–646, 645f, 646f hemorrhagic, 507f, 508f, 509t, 641f–642f, 662–664, 664f hyperacute, 646f large-artery/atherosclerotic, 636, 638 meningitis and, 769, 770–771, 771f middle cerebral artery, 657f MR appearance, by etiology embolic infarction, 662, 663f hemorrhagic infarction, 662–664, 664f large-artery infarction, 654–662, 655f–660f small-vessel infarction, 665–666, 668, 668f, 669f–671f, 670 venous infarction, 670–671, 670t, 672f–674f, 674, 675f, 676 watershed infarction, 664–665, 665f MRI findings (conventional), 639–644, 639f–644f, 639t perfusion-weighted imaging, 647–648, 648f, 649f periventricular hemorrhagic, 676, 676f pontine, 645f posterior cerebral artery territory, 660f posterior circulation, 680f small-vessel/lacunar, 636–637 spinal cord, 1386–1388, 1388f subacute, with contrast enhancement, 642f, 643, 643f superior cerebellar artery territory, 660f traumatic axonal injury and, 690f tuberculous meningitis with, 780f, 782f with vasculitis, 661, 661f, 662f venous, 637–638, 638–639 in young adults and children, 678–679, 680f Infection, 719. See also Intervertebral disc inflammatory lesions, 1001 intervertebral disc, 1196–1197, 1199f, 1200f intracranial bacterial, 758–783 fungal, 783–794 parasitic, 794–815 viral, 719–758 orbital involvement in, 1066, 1067f, 1068, 1068f parasellar, 1003, 1004f, 1005f spinal, 1391, 1391t (see also specific infection) spinal cord, 1429 bacterial, 1429–1440 fungal, 1440–1445 parasitic, 1445–1454 viral, 1454–1459 Infectious spondylodiscitis, 1391–1395. See also Spondylodiscitis Inferior vermian hypoplasia (IVH), 120 Inflammatory demyelinating pseudotumor clinical features, 226–227, 227f imaging findings, 227 pathologic features, 227 Influenza-associated encephalitis/encephalopathy (IAEE), 754, 755f Influenza virus, 754–755, 755f Infundibuloneurohypophysitis, 1005 Inner annular disruption, 1202 Internal auditory canal (IAC), 911, 912f, 927 Internal carotid arteries (ICAs), 154, 951, 1030 agenesis of, 154, 155f 2214

hypogenesis of, 154 Interspinous ligaments (ISP), spine, 1316, 1317f, 1324 Intervertebral disc age-related changes in, 1192–1193, 1193f, 1194f anatomy of, 1190–1192, 1190f–1192f degeneration of, 1194, 1194f–1196f magnetic resonance of, 1196, 1196f–1199f, 1198t infection, 1196–1197, 1199f, 1200f Intra-axial mass lesions, 304, 305, 307f–309f Intracerebral hemorrhage (ICH), traumatic, 712, 713f Intracranial aneurysm, 610–628, 1494 diagnosis of, 1496 endovascular coiling, 610 false-negative MRA for follow-up of aneurysm coiling, 617, 617f formation of, risk factors for, 1494 giant aneurysms, 618–622, 618f–625f high-risk populations, screening of, 1495 imaging techniques, 1494–1495 incidental unruptured aneurysms (IUA), 1495–1496 MR angiography for, 622, 624, 625f–628f, 627–628 MRA techniques for, 1495, 1497f optic nerve and chiasm compression by, 614f–616f perianeurysmal hemorrhage and, 625f population at higher risk for, 627t post treatment, 1497–1499, 1498f risk of rupture, 1494 ruptured, 611, 611f saccular aneurysms, 610–618, 611f–617f signal void of looping vessel masquerading as, 626f subarachnoid hemorrhage and, 610, 611, 612f, 613f, 625f symptomatic, 1495 treatment planning, 1496–1497 unruptured, 610, 611, 624, 626f–627f Intracranial atherosclerotic disease (IAD), 1491 cerebrovascular hemodynamics, 1494 fractional flow reserve, 1494 high-risk patients, identification of, 1494 imaging methods in, 1491–1494, 1492f–1493f quantitative MRA, 1494 Intradiscal gas, 1196 Intralabyrinthine hemorrhage, 910 posttraumatic, 933f Intraventricular hemorrhage (IVH), 712–713 Invasive mucormycosis, 1068f IOI. See Idiopathic orbital inflammatory pseudotumor (IOI) IRIS. See Immune reconstitution inflammatory syndrome (IRIS) Iron deposition, with aging, 820, 822f–825f, 823, 825 Ischemia, 633 children and, 676–679, 676f–680f pathophysiology of, 634–636, 634f preterm infant and, 676–677, 676f–678f spinal cord, 1386–1388, 1387f stroke from, 633 imaging of, 633–634 MRI criteria for treatment of, 651–654, 651f–654f MR techniques in, 639–650, 639f–650f, 639t risk factors, 636 2215

subtypes, 636–638, 637f treatment of, 638–639 term infant and, 677–678, 678f–679f IVH. See Intraventricular hemorrhage (IVH) J Jacobson nerve, 913 Jarcho-Levin syndrome, 1178 Joubert syndrome (JS), 129–132 clinical phenotypes, 129–130 fetal, 132f imaging findings, 130, 130f, 131f, 132f brainstem, 131 cephaloceles, 131 cerebellum, 130–131, 130f fourth ventricle, 131 posterior fossa, 131 superior cerebellar peduncles (SCP), 130f, 131 supratentorial findings, 131, 131f molar tooth sign (MTS), 129, 129f pathologic findings, 130 JPAs. See Juvenile pilocytic astrocytomas (JPAs) JS. See Joubert syndrome (JS) Junctional neurulation, 1098 Juvenile amyotrophy of distal upper extremity, 871 Juvenile angiofibroma, 906, 906f Juvenile pilocytic astrocytomas (JPAs), 431, 431t, 432f, 434 K Kallmann syndrome (KS), 116 Kearns–Sayre syndrome (KSS), 260, 262, 262t, 263f–264f Kennedy disease, 871 Klippel–Feil syndrome, 1175 Klippel–Trenauney syndrome, 1380 Korsakoff syndrome, 856 Krabbe disease clinical features, 254 MRI findings, 254, 254f pathologic findings, 254 k-space, 22–23, 23f alternative trajectories, 26–27 echo-planar imaging and, 27, 27f properties of, 25–26, 25f, 26f, 27t radial sampling of, 27, 27f sampling in, 28, 28f–30f spiral trajectories and, 27, 28f three-dimensional (3D), 24, 25f two-dimensional (2D), 23, 23f Kuru, 748 L Labyrinth. See also Skull base bony, 925–926 lesions of, 941–942 lesions of congenital malformations of inner ear, 930–931 endolymphatic hydrops, 942–943 hemorrhage of, 931, 933f 2216

labyrinthitis, 931, 934f–936f, 935–936 lesions of bony labyrinth, 941–942 neoplasms of, 937–941 perilymphatic fistula, 936–937 membranous, 925–926 MR techniques for, 927–930, 927f–931f Labyrinthine hemorrhage, 931, 933f Labyrinthine schwannomas, 937–940 Labyrinthitis, 931, 934f–936f, 935–936 Lacrimal epithelial neoplasms, 1083–1084, 1084f, 1085f Lacrimal gland, 1030 enlargement, 1080, 1081t Lacunar infarctions, 636–637 clinical presentation, 637 MR appearance, 665–666, 668, 668f, 669f–671f, 670 multiple, 669f Lacunar state, 834 Langerhans cell histiocytosis (LCH), 894, 897f, 941, 1087, 1089, 1089f Large-artery infarction, MR appearance, 654–662, 655f–660f Large-artery thromboembolic stroke, 636 causes of, 636 treatment for, 638 Large vestibular aqueduct syndrome, 942 Larmor frequency, 4, 10 L-asparaginase, 241 Lateral disc herniations, 1214 Lateral lumbar and thoracic meningoceles, 1152, 1154f Lateral recess stenosis, 1236 Latex anaphylaxis, 1110 LCH. See Langerhans cell histiocytosis (LCH) Leigh disease, 260, 262–265 MRI findings, 264–265, 264f–265f Leptomeningeal carcinomatosis, 413–414, 413f Leptomeningeal metastatic disease, 1277f Leptomeningeal tumor, spinal, 1286–1288 imaging, 1287–1288, 1287f treatment, 1288 Lesionectomy, 280t Leukemia, 1269, 1271–1272 acute lymphoblastic, 1271 imaging, 1271–1272, 1272f orbit and, 1080–1082 Leukemic meningitis, 410f Leukoariosis, 668, 671f Leukocoria, 183, 1036f Leukodystrophy, 249. See also Dysmyelinating disorders adrenoleukodystrophy, 258, 259f–260f distinguishing features, 250t globoid cell, 254, 254f with macrocrania, 265–269 metachromatic, 251–252, 253f sudanophilic, 269–271, 270f–271f Leukoencephalopathy cystic, 269t drugs of abuse and, 242, 243f megalencephalic, 269t progressive multifocal, 230, 232–233, 232f–235f 2217

vacuolating, 269t Leukomyelopathy, 204 Lhermitte–Duclos disease (LDD). See Dysplastic gangliocytoma of cerebellum Ligamentum flavum (LF), spine, 1316, 1317f, 1324 Limbic encephalitis, 297 Limbic system, 283, 283t, 284f. See also Hippocampal sclerosis Lipoma, 145–147, 913, 913f, 928f classification chaotic lipomas, 1131 dorsal lipomas, 1130 transitional lipomas, 1130–1131 corpus callosum, 421 of filum terminale, 1141–1142, 1141t, 1142f imaging findings, 146–147, 146f, 147f, 148f intradural, 1131f midline craniofacial dysraphism, 146, 147f pathogenesis of, 146, 146f pericallosal, 421, 421f–422f quadrigeminal cistern, 148f Lipoma (continued) spinal, 1127–1128, 1127f–1129f, 1127t, 1128t, 1130f–1135f, 1303, 1304f classification, 1130–1131 concurrent malformations, 1135 conservative management of, 1135 with intact dura, 1128–1130, 1128f–1130f MR spectroscopy of CSF, 1135 prophylactic surgery, 1135 surgical considerations, 1131, 1134 subarachnoid, 421, 421f–422f suprasellar, 148f Lipomyeloceles, 1133f Lipomyelomeningocele, 1132f, 1133f LIS. See Lissencephaly (LIS) Lissencephaly (LIS), 1513f with cerebellar hypoplasia, 98 due to ARX mutation, 98, 100f Miller-Dieker syndrome and, 98, 99f neuropathology and imaging findings, 98, 99f, 100f with pontocerebellar hypoplasia (PCH), 98 and subcortical band heterotopia (SBH), 97–98, 99f, 100f Listeria encephalitis, 771f Listeria meningitis, 1433 Listeriosis, 1433, 1435, 1435f Liver disease, chronic, 517f Lobar holoprosencephaly, 111, 111f. See also Holoprosencephaly (HPE) interhemispheric variant, 114f Local wound infection, 1109 Locked-in syndrome, 237 Longitudinal measurement techniques, for Alzheimer disease, 830 L1 syndrome due to mutations in L1CAM, 134 Lumbar disc. See also Spine, degenerative disease of bulge in, 1200 disc protrusion, 1201–1202 extrusion of, 1202, 1204 herniation of, 1201, 1206, 1207f mimics of, 1215, 1218, 1218f, 1219f MRI of, 1206–1214, 1213f–1215f 2218

paramagnetic contrast in routine MRI, 1214–1215, 1215f–1217f postoperative lumbar spine and MRI, 1218–1219, 1220f–1226f Schmorl nodes, 1215, 1218f pathology, classification of, 1200–1206, 1200f–1206f Lumbar kyphosis, 1115 Lumbar lordosis, 1115 Lumbar spinal stenosis, 1233–1236, 1234f–1239f Lumbosacral agenesis, ckassification of, 1151t Lumbosacral dermal sinuses, 1120 Lumbosacral myelomeningocele, 1521f Lung carcinoma, lytic vertebral metastases from, 1277f Lupus vasculopathy, 246, 246f Lyme disease, 774–775, 774f, 922 clinical features, 248 MRI findings, 248, 249f spinal involvement in, 1432–1433, 1434f Lyme meningitis, 1434f Lymphatic malformation (LM), 1058–1060, 1059f–1060f Lymphocytic hypophysitis, 1003, 1005f, 1006f Lymphoma, 322, 323f–324f, 409–410, 904, 912f, 1081, 1081f in acquired immunodeficiency syndrome, 383f diffuse large B-cell, 379 with extracranial component, 409f non-Hodgkin, 1272, 1273f in pediatric AIDS patients, 738 primary CNS, 379, 381–385, 382f–385f, 409, 1617f toxoplasmosis encephalitis and, 803f Lymphomatous meningitis, 410f Lymphoproliferative disease of orbit, 1080–1083, 1081f–1083f Lysosomal disorders, 251–258, 251t, 252t. See also specific disorders Lytic vertebral metastases, from lung carcinoma, 1277f M Machado–Joseph disease, 863, 864f hot cross bun, 864f Macroadenoma, pituitary, 968–975, 968f–975f Macrocerebellum, 125–126, 127f Macrophthalmos, 1045 Macula, 927 Magnetic field coils, 5 types of, 5 Magnetic field strength, unit of, 4 Magnetic resonance angiography (MRA), 1464, 1480t arteriovenous malformations, 568–569, 568f, 570f artifacts and limitations, 1476 black blood, 1477 contrast-enhanced, 1477–1478, 1478f dynamic imaging, 1480 extracranial circulation, 1482 carotid and vertebral artery dissection, 1488–1490, 1489f carotid flow and atherosclerosis, 1482–1483 carotid screening, 1483, 1483f–1485f carotid stenosis treatment, 1483 clinical evaluation, 1485–1486, 1486f plaque imaging, 1487–1488, 1487f subclavian steal, 1488 vertebral stenosis, 1486–1487 in fistula tract detection, 1014 2219

flow phenomena and, 1464–1466, 1464f–1466f flow-related artifacts, 1468 gradient moment reduction and nulling, 1469, 1469f at higher fields, 1481–482 image contrast, methods for improvement of, 1471–1472 intracranial circulation arteriovenous malformations, 1499–1501 dural arteriovenous fistulas, 1501–1502 intracranial aneurysms, 1494–1499 intracranial atherosclerotic disease, 1491–1494, 1492f–1493f stroke, MR imaging of, 1490–1491 k-space acquisition schemes, 1478–1480, 1479f maximum intensity projection (MIP), 1474, 1475f motion, effects of, 1466 neurovascular compression syndromes, 1502–1505 overlapping slab acquisition, 1470–1471, 1472f parallel imaging and, 1480–1481 phase-contrast imaging, 1475 phase effects, 1467–1468, 1468f postprocessing and display, 1473–1475, 1475f–1477f postprocessing by volume rendering, 1475, 1475f pulsatile flow, 1467 pulse sequence considerations, 1468 gradient-echo (GE) sequences, 1468 spin-echo (SE) sequence, 1468 rapid imaging through undersampling, 1481, 1482f sella turcica, 951 time of flight, 1466–1467, 1470 artifacts and limitations, 1472, 1472f entry slice phenomenon, 1467 flow-related enhancement, 1466, 1467, 1467f optimizing performance of, 1472–1473, 1472f, 1473t, 1474f three-dimensional, 1470, 1470f, 1471f two-dimensional, 1470, 1470f venous occlusive disease, 1505–1506 Magnetic resonance imaging (MRI), 2 advantages of, 16, 22 for cavernous sinus invasion, 971, 972 development of, 2 fetal, 1510 of fibrous dysplasia, 891, 895f functional (see Functional magnetic resonance imaging (fMRI)) at higher field strengths, 13, 14f on contrast and sensitivity, 15–16 image uniformity, 13–15 human body and, 4 impact of, 3–4 intracranial extension and, 896 of lumbar spine, paramagnetic contrast in routine, 1214–1215, 1215f–1217f of macroadenoma resection, 974f main field magnets, 5–8 of pituitary gland, 948 postmortem, 1523 regulatory requirements, 2 RF surface coil arrays and accelerated imaging, 18–20 safety of, 16, 16t schwannomas, 910 2220

system architecture, 16, 17f data processing and image reconstruction, 17–18 gradient and RF waveforms, 16–17 technical and scientific milestones in, 3t Magnetic resonance spectroscopy (MRS), 71, 1608–1609, 1609f age-dependent metabolic changes and, 1632f, 1633 brain tumors, 330 clinical applications of brain masses/tumors, 1615–1621 cardiac arrest, 1626, 1628f drowning, 1626 epilepsy, 1626–1629, 1628f, 1629f extraaxial tumors, 1621 focal CNS infections, 1624–1625, 1626f hepatic encephalopathy, 1631 hypoxia, 1626 inborn errors of metabolism, 1621–1624 ischemia, 1625–1626, 1627f mitochondrial disorders, 1623–1624, 1624f multiple sclerosis, 1630–1631 neurodegenerative diseases, 1629–1630 psychatric disorders, 1563, 1564t–1565t, 1565f, 1631–1633 radiation necrosis vs. tumor, 1617–1620, 1619f, 1620f traumatic brain injuries, 1631 Coats disease and, 1039 craniopharyngioma, 975 of CSF, 1135 cysticercosis, 808, 810f metabolites, 1604–1606, 1606t, 1607t nonproton, 1613–1614, 1614f overview, 1601 physics of chemical shift, 1603 free induction decay, 1602 J coupling, 1603, 1603f nuclear magnetism, 1601 nuclei used in, 1602t relaxation, 1602 resonance, 1602 for spinal cord injury, 1358–1359, 1358f in TBI, 699, 699f in vivo absolute quantification in, 1612–1613 acquisition parameters in, 1610–1611, 1610f biological basis of, 1614–1633 chemical basis of, 1604–1614 editing techniques in, 1611–1612 fast CSI and, 1609, 1614f field strength and, 1611, 1611f limitations of, 1613, 1613f localization techniques for, 1608, 1608f major resonances in, 1604–1605, 1606t, 1607t minor resonances in, 1605–1606 regional variations in, 1612, 1612f vs. ex vivo NMR, 1607f water/fat suppression and, 1609–1610, 1610f Magnetic susceptibility, 15, 46, 486–487, 487f 2221

differences in, 487 induced magnetic field and, 486t Magnetic susceptibility weighted imaging, 46–47, 47f Magnetic units, 4 Magnetism, 4 Magnetism, origin of, 485–486 Magnetization-prepared gradient echo sequences, T1 imaging with, 42–43, 43f Magnetization transfer (MT) imaging, 45–46, 46f, 47f Magnetization transfer MRI (MTI), for spinal cord injury, 1359 Magnetization transfer ratio (MTR), 46 Magnetization transfer saturation technique, 329 Magnet shielding, 9 active shielding, 9 passive shielding, 9 Main field magnets, 5 characteristics of, 5 design and construction of, options for, 6 secondary features of, 6 Malformation arteriovenous (see Arteriovenous malformations (AVMs)) cavernous (see Cavernous malformations (CMs)) Dandy–Walker, 118–121, 119f, 120f, 121f definition of, 81 gene mutations causing, 81 posterior fossa (see Posterior fossa malformations) spinal cord arteriovenous, 1373t, 1380–1381, 1380f–1383f, 1383–1384 spinal cord cavernous, 1384–1386, 1386f vascular (see Vascular malformations, brain; Vascular malformations, CNS) venous, 1057–1058, 1058f, 1059f Malignant melanoma, 1032 MALT. See Mucosa-associated lymphoid tissue (MALT) Manganese neurotoxicity, 838, 838f Mantle cell lymphoma (MCL), 1080 Maple syrup urine disease (MSUD), 266f, 267t MRS of, 1622, 1622f Marchiafava–Bignami disease with cavitary lesions of corpus callosum, 239f clinical features, 237–238 MRI findings, 239, 239f pathologic findings, 238–239 Marfan syndrome, 1047, 1047f, 1152 MATLAB code, for simulating signal evolution of MR sequence, 57 Matrix metalloproteinases (MMPs), 663 Maximum-intensity projection (MIP) images, 918 McCune–Albright syndrome, 1084 McLone–Knepper hypothesis, 1118 MEB. See Muscle-eye-brain disease (MEB) Meckel’s cave, 904, 906, 951 Medullary cavity, 882 Medulloblastoma, MRS of, 1616f Mega cisterna magna (MCM), 122–123, 122f Megalencephalic leukoencephalopathy with subcortical cysts, 269t Melanin, in tumor, 320, 321f, 321t melanoma metastasis, 321f Melanoma, 886 melanotic, 1033 of nasopharynx, 899f 2222

MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes), 260, 262, 262t, 263f Melting brain, 162 Membrane development, 1169–1170, 1172 Ménière’s disease, 943, 944f Meningioangiomatosis (MA), 406, 408 Meningioma, 393–403, 414, 888, 891, 891f, 892f–893f, 901, 979, 982, 982f–983f with adjacent bone invasion, 306f angiomatous, 403, 405f bony hyperostosis and invasion, 396, 399f and brain edema, 403, 404f brain invasion by, 401, 401f calcified convexity, 396, 398f calvarial invasion, 403–404, 406 classification, 393 and contrast enhancement, 406 CSF clefts, 400 with dense calcification, 362, 363f–364f dural margin interface, 400 extra-axial lesion, 306f fatty cell change in, 395 hyperintense, 394, 394f hyperostosis on MRI, 396, 399f hypointense, 394, 395f internal carotid artery encasement, 401, 402f intraosseous, 1084, 1086, 1086f intra-Sylvian, 394f intraventricular, 406, 407f–408f left sphenoid wing, 397f–398f lipomatous, 394–395, 396f malignant, 409 meningioma en plaque, 400f metastatic disease from, 409 NF2 and, 179–181, 180f–181f perioptic, 1076 pial blood vessel interfaces, 400 radiation-induced tumor, 408–409, 408f sites of localization, 393 spinal, 1281, 1285 imaging, 1285, 1286f pathology, 1285 symptoms, 1285 treatment and prognosis, 1285 as subdural hematoma, 403, 406f transdural invasion, 403, 403f venous sinus invasion, 401, 402f Meningitis, 767, 769–772, 771f, 1152 basilar, 791f candidiasis and, 784 causative agents, 767 complications, 767, 769, 771 cryptococcal, 785, 785f, 786f DWI in, 770 and empyema, 774f histoplasmosis with, 794f–795f leukemic, 410f Lyme disease and, 774 2223

lymphomatous, 410f meningococo, with infarction, 769, 771f MRI in, 770–771 spinal, 792f tuberculous, 778–780, 779f, 780f, 782f, 783 and ventriculitis, 761f West Nile, 751 Meningocele, 909, 918 lateral lumbar and thoracic, 1152, 1154f thoracic, 1152, 1154f MERCI (Mechanical Embolus Removal in Cerebral Ishcemia) retriever, 638 MERRF (myoclonic epilepsy with ragged red fibers), 260, 262, 262t Mesencephalon (midbrain), 80 Metabolic disorders, 249–251. See also Sella turcica and parasellar region diabetes insipidus, 1015–1016, 1018, 1018f hemochromatosis, 1018 1H MR spectroscopy findings in, 250–251, 251t hypermagnesemia, 1018 MRI findings in, 250, 250t non–organelle–based, 251t organelle–based, 251t primary hypothyroidism, 1018, 1018f Metachromatic leukodystrophy (MLD) clinical features, 251 diagnosis of, 251 forms of, 251 metachromatic granules in, 251–252 MRI findings, 252, 253f pathologic findings, 251–252 Metastases, 891 blastic, 908 brain, 385, 387–391, 388f–391f breast carcinoma, 413f epidural, 410–412, 412f extra-axial, 410–414, 411f–413f to facial nerve, 923 hematogenous, 908 hemorrhagic, 512, 512f leptomeningeal, 413–414, 413f mucinous adenocarcinoma, 518f orbital, 1068–1069, 1069f sella turcica and parasellar region, 997, 999f to sphenoid triangle, 896f spinal, 1272, 1273f–1277f, 1278 subdural, 412–413 thyroid carcinoma, 411f Methemoglobin, 1033 Methylprednisolone (MPS), for spinal cord injury, 1351 Microadenoma, pituitary, 953, 961–968, 962f–967f Microcephaly, 90–92 associated abnormalities, 92 congenital, 90–91 neuropathology and imaging findings, 91, 92f primary, 90, 91f, 92f secondary, 90 Microhemorrhage, and amyloid angiopathy, 835, 836f Microinfarcts, 834 2224

Microphthalmia, 1045, 1046t Middle cerebral artery (MCA), 154, 655, 655f infarctions, 657f Middle ear inflammatory/obstructive disease, 914 Middle interhemispheric variant of HPE (MIVH). See Syntelencephaly Miller–Dieker syndrome, 98, 99f Miller Fisher syndrome (MFS), 1427. See also Guillain–Barré syndrome (GBS) Mirror movement synkinesis, 116 MISME (multiple inherited schwannomas, meningiomas, and ependymomas), Neurofibromatosis type 2 (NF2) Mitochondrial deletion syndrome, 261f Mitochondrial disorders, 251t, 260, 260t, 261f clinical features and MR findings, 262t Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) MRS of, 1623–1624, 1624f Mixed hyaline/myxoid chondrosarcomas, 904 MLD. See Metachromatic leukodystrophy (MLD) Moebius syndrome, 135 Molecular imaging, 59 of AD-related pathology, 831–832, 832f Mood disorders DTI of, 1570, 1571t–1572f MRI of, 1570–1573 MRS of, 1573, 1631–1632 Motion, and image quality, 30–31 Motor neuron diseases, 867 amyotrophic lateral sclerosis, 867–871, 867f–871f juvenile amyotrophy of distal upper extremity, 871 primary lateral sclerosis, 871 spinal muscular atrophy, 871 spinobulbar muscular atrophy, 871 Moyamoya disease, 558, 562f NF1 and, 173, 174f–175f MPR. See Multiplanar reconstructions (MPR) MRI magnet, current trends and future developments, 9–10, 9f MRS. See Magnetic resonance spectroscopy (MRS) MRSI. See Magnetic resonance spectroscopic imaging (MRSI) MR venography (MRV), for dural venous thrombosis, 772 MS. See Multiple sclerosis (MS) MSA. See Multiple system atrophy (MSA) MTR. See Magnetization transfer rate (MTR) Mucinous adenocarcinoma metastases, 518f Mucinous carcinoma, metastases from colon carcinoma, 322, 324f–326f Mucinous metastases, 513f Mucoceles, 896–898, 898f Mucopolysaccharidoses classification of, 257t clinical features, 256 MRI findings, 256, 257f, 258 Mucormycosis, 788, 790f, 791f invasive, 1068f Mucosa-associated lymphoid tissue (MALT), 1080 Multi-band imaging, 56–57 Multifocal eosinophilic granulomatosis, 1000 MultiHance, 329 Multiplanar reconstructions (MPR), 927 Multiple myeloma, 1272, 1273f–1275f, 1278 2225

181.

See

also

Multiple sclerosis (MS), 205t, 1040 acute (Marburg type), 223 and atrophy, 219, 219f chronic active lesions, 214 clinical features, 210 concentric sclerosis (Balò type), 223, 225f cortical lesions in, 214, 216f cortical lesions on double inversion recovery (DIR), 217, 218f diagnosis, 210, 210f, 211t diffusion-weighted MRI in, 220 early lesions (active plaques), 213–214, 215f fiber tractography in, 220, 220f mouse model of, 217 MRI findings, 204f, 216–219, 216f–219f MRS of, 1630–1631 myelinoclastic diffuse sclerosis, 223, 224f neurodegeneration in, 215 optic nerve imaging in, 222, 223f pathologic findings, 210, 211f–216f, 213–216 periventricular involvement, 211f progressive disease, 210 quantitative techniques in, use of, 219–220, 220f relapsing–remitting disease, 210 remyelination in, 214–215 2010 revised McDonald criteria for, 211t 2010 revised MRI criteria for, 211t Multiple sclerosis (MS) (continued) spinal cord, 213f–214f, 221–222, 221f–222f, 1416–1419, 1418f steroid therapy, lesion appearance after, 217, 217f tumefactive, 217, 218f variants of, 222–223, 224f, 225f Multiple subpial transection, 280t Multiple system atrophy (MSA), 840–844, 841f–843f cerebellar type (MSA-C), 842–844, 842f–843f glial cytoplasmic inclusions (GCIs) in, 841, 841f hot cross bun sign, 842f, 844 parkinsonism (MSA-P), 841–842, 841f Shy–Drager syndrome, 842 Multiple vertebral segmentation disorders, 1178 Jarcho–Levin syndrome, 1178 spondylocostal dysostosis, 1178 spondylothoracic dysostosis, 1178 Multi-slice imaging, 23–24 Multislice inversion recovery, 953 Mumps labyrinthitis, 933f Muscle–eye–brain disease (MEB), 96, 97, 98f. See also Cobblestone malformation Mycobacterium avium–intracellulare epidural abscess, 1440, 1440f Mycotic aneurysm, 767, 769f–770f Myelin, 205, 205f Myelination anatomic landmarks at birth, 206t of CNS, 205–206 diffusion tensor MRI and, 206 milestones after birth, 206t, 207t and MRI findings, 206–207 progression of, 206, 206t after 6 months of age, 206, 208f 2226

first 6 months of life, 206, 207f by 24 months of age, 206, 208f proton MR spectroscopy and, 206–207, 209f Myelocele, 1103 repaired, 111f Myelocystocele, 1120, 1121f, 1122f terminal, 1145–1147, 1146f–1147f Myelomeningocele cervical, 1120, 1121f, 1122f fetal repair of, 1116–1117, 1116f spina bifida aperta and, 1103 spinal curvature in, 1113, 1113t lumbar kyphosis, 1115 lumbar lordosis, 1115 thoracic kyphosis, 1115 untreated, 1110f Myopia, 1044 Myositis, paraspinal, 1215 Myxoid chondrosarcoma, 904 N N-acetylaspartate (NAA), 206, 300, 330 in brain development, 206–207, 209f MS and, 220, 220f in temporal lobe epilepsy, 300 NAION. See Nonarteritic anterior ischemic optic neuropathy (NAION) Nasal dermoid, 920f Nasal polyps, 901 Nasopharyngeal carcinoma, 884f, 885f, 904 Necrosis astrocytomas and, 311 cystic, 311, 312f effects of, on MRI, 311t glioblastoma and, 347, 347f hemorrhagic, 311, 312f hemorrhagic tumors, 511f intratumoral, 311 from radiation, 392, 392f Necrotizing myelopathy, 1425–1426 Nelson syndrome, 962 Neonatal encephalitis, 725–726 Neonatal hypoxic–ischemic encephalopathy, 677, 678f Nerve sheath tumors, 414–416, 414f–416f, 905f, 1278–1281 imaging, 1280, 1280f–1285f, 1281 location, 1279 malignant, 1284f–1285f pathology, 1279–1280, 1279f symptoms of, 1279 Nerves of orbit, 1029–1030 Neural cell adhesion molecule (N-CAM), 1101 Neural crest migration, 1098 Neural folds forming, 1098 fusion of, 1098 Neural tube, 80, 81f defects, 1104 points of closure of, 1098, 1101 Neurenteric cysts, 417, 419f, 1154, 1155f, 1156, 1157t, 1158 2227

Neuroblastoma, 1263, 1265–1266 imaging, 1265 metastatic, 1087f pathology, 1263 treatment, 1265–1266 Neuroborreliosis. See Lyme disease Neurocutaneous syndromes. See Phakomatoses Neurocysticercosis, 804. See also Cysticercosis Neurocytoma central, 305f, 362–364, 363f extraventricular, 364 Neurodegeneration with brain iron accumulation type 1 (NBAI-1), 853, 854f Neurofibrillary tangles, 827, 827f. See also Alzheimer disease (AD) Neurofibroma, 908f, 1062, 1062f–1064f. See also Nerve sheath tumors Neurofibromatosis, 937, 941f, 993f, 994f Neurofibromatosis type 1 (NF1), 169–175, 1279, 1282f–1283f aneurysms in, 173, 174f callosal lesions in, 173, 173f cutaneous neurofibromas in, 173, 175f diagnostic criteria for, 169t dural ectasia, 177f foci of abnormal signal intensity (FASI), 169, 170f manifestations, 169, 169t moyamoya in, 173, 174f–175f neurofibromas of neck, 173, 176f optic nerve gliomas in, 169, 170f–171f, 171–172 sphenoid dysplasia in, 172–173, 172f spine lesions in, 176f–177f Neurofibromatosis type 2 (NF2), 175–181, 1279 cervical ependymoma with, 1294f diagnostic criteria for, 178t intracranial schwannomas, 179, 179f intramedullary ependymomas and, 181, 182f meningiomas, 179–181, 180f–181f multiple ependymomas with, 1292f–1293f spinal schwannomas, 181, 182f types, 175 vestibular schwannoma in, 178–179, 178f, 179f Neuroglial cells, 206 Neurologic level of injury (NLI), SCI, 1350, 1350f Neuromyelitis optica (NMO), 1073, 1419–1421 bright spot lesions, 1422f clinical features, 223, 226f diagnostic criteria, 223, 226 differential diagnosis, 1421 imaging findings, 226 MRI of, 1420, 1420f–1422f and multiple sclerosis, 1421t pathologic features, 226 Neuronal heterotopia, 98, 100–101, 101f. See also Subcortical band heterotopia (SBH) periventicular heterotopia, 98, 100–101, 101f subcortical, 101 types, 98 Neurovascular compression syndromes, 1502–1505, 1504f Neurulation body axes, patterning, 1102–1103 normal, 1099f, 1100f–1105f 2228

convergent extension, 1098 fusion of neural folds, 1098 molecular signaling, 1101, 1102 neural crest migration, 1098 neural folds, forming, 1098 neural from epidermal ectoderm, disjunction of, 1101 neural tube, points of closure of, 1098, 1101 primary, deranged, 1103–1116 (see also Spina bifida aperta) secondary caudal cell mass and canalization, 1135–1137, 1136f conus medullaris, position of, 1137–1140, 1138t–1140t retrogressive diff erentiation, 1137 secondary, deranged anorectal and urogenital malformations, 1145 anterior sacral meningoceles, 1152, 1153f caudal regression, syndrome of, 1147–1150, 1149f–1151f, 1151t lateral lumbar and thoracic meningoceles, 1152, 1154f lipoma of filum terminale, 1141–1142, 1141t, 1142f sacrococcygeal teratoma, 1142–1144, 1142f–1144f sirenomelia, 1150, 1152f terminal myelocystocele (syringocele), 1145–1147, 1146f–1147f terminal ventricle and conal cyst, 1144–1145 tight filum terminale syndrome, 1140–1141 Niobium–titanium alloy, 6, 7 NMO. See Neuromyelitis optica (NMO) NMR. See Nuclear magnetic resonance (NMR) Noise sources, 13 Nonarteritic anterior ischemic optic neuropathy (NAION), 1073, 1074, 1075f Nondecussating retinal fugal fiber syndrome, 115 Non-Hodgkin lymphoma, 1272, 1273f imaging, 1272, 1273f pathology, 1272 primary, 1272 Nonketotic hyperglycinemia, 267t Nonlesional cortical resection, 280t Normal-pressure hydrocephalus (NPH), 849–851, 850f clinical symptoms, 849 MRI findings, 849–851, 850f patient selection for surgery, 850 North American blastomycosis, 1440, 1441f Notochord, 80 Notochordal process, 1098 Notochord, embryogenesis of. See also Diastematomyelia deranged, 1154, 1155f diastematomyelia, 1158–1165, 1158f–1166f, 1158t, 1159t dorsal enteric fistula and neurenteric cyst, 1154, 1155f, 1156, 1157t, 1158 normal, 1152, 1154, 1154f Novel influenza A (H1N1)–associated meningoencephalitis, 755 NPH. See Normal-pressure hydrocephalus (NPH) Nuclear magnetic resonance (NMR), 2, 4, 59–61 diffusion, 1528–1531, 1528f, 1529f tissue microstructure and, 1540 Nyquist relation, 13 Nyquist–Shannon sampling theorem, 28 O OA. See Ophthalmic artery (OA) Obsessive–compulsive disorder (OCD) 2229

DTI of, 1579–1581, 1579t–1580t fMRI of, 1581–1582 MRS of, 1582, 1633 pthophysiology, model of, 1581f Occipital cephalocele, 144, 144f Occult cerebrovascular malformations, 578. See also Cavernous malformations OCD. See Obsessive–compulsive disorder (OCD) Ocular and orbital anatomy, 1031f Ocular implant, 1048 Ocular lesions choroidal and retinal vascular tumors, 1039–1040, 1041f, 1042f Coats disease, 1039, 1041f ocular melanoma, 1032–1034, 1032t, 1033f, 1033t, 1034f ocular metastases, 1033–1034, 1035f persistent hyperplastic primary vitreous, 1036, 1039, 1039f–1040f retinoblastoma, 1034–1036, 1036f–1038f, 1036t Ocular melanoma, 1032–1034, 1032t, 1033f, 1033t, 1034f Ocular metastases, 1033–1034, 1035f Ocular prosthesis, 1049 Ocular trauma, 1047–1048 Oculomotor nerve, 1029 ODs. See Oligodendrogliomas (ODs) OEIS complex, 1175 Off-resonance effects, 49 Olfactory neuroblastomas, 899 Oligodendrocyte, 205–206, 205f Oligodendrogliomas (ODs), 339, 341, 341f–344f cortical thickening, 341, 342f differential diagnosis of, 341, 343f, 344f fried egg appearance, 341, 341f and mixed oligoastrocytomas, 339 treatment, 341, 343f, 344f Olivopontocerebellar degeneration (OPCD), 840, 842–844, 842f–843f ON. See Optic neuritis (ON) ONSM. See Optic nerve sheath meningioma (ONSM) Opacification, 894 OPCD. See Olivopontocerebellar degeneration (OPCD) OPG. See Optic pathway gliomas (OPG) Ophthalmic artery (OA), 1024 Ophthalmic nerve, 1030 Optic nerve cavernous malformation, 1079 ischemia, 1073–1075, 1074f–1076f in skull base tumors, 888 Optic nerve gliomas, NF1 and, 169, 170f–171f, 171–172 Optic nerve/sheath complex, enlargement of, 1070, 1071f, 1072t Optic nerve sheath meningioma (ONSM), 1073, 1076, 1078, 1079, 1079f, 1080, 1080f, 1081t Optic neuritis (ON), 993f, 1072–1073, 1072f MS and, 222, 223f multiple sclerosis and, 1073f, 1074f Optic pathway gliomas (OPG), 1075–1076, 1077f–1079f Optic sheath hematoma, 1071f Orbit bony, lesions of, 1084 dermoid/epidermoid cysts, 1060, 1062f hematic cyst, 1065, 1065f neurofibroma and schwannoma, 1062, 1062f–1064f 2230

orbital infiltrative processes, 1065, 1066f rhabdomyosarcoma, 1062–1065, 1064f disease of, 1049–1050 cavernous sinus thrombosis, 1053, 1056 discrete orbital mass, 1056 extraocular muscles, enlargement of, 1050, 1050t idiopathic orbital inflammatory pseudotumor (IOIP), 1051–1053, 1053f–1055f superior ophthalmic vein (SOV) abnormalities, 1053, 1055f, 1056 thyroid orbitopathy (TO), 1050–1051, 1050f–1052f fibrous dysplasia, 1084, 1085f, 1087f globe, 1030–1032 granulomatosis with polyangitis (GPA), 1069, 1070f histiocytic infiltrative disorders, 1087, 1089 IgG4-related disease, 1069, 1070f infection, 1066, 1067f, 1068, 1068f intraosseous meningioma, 1084, 1086, 1086f lacrimal epithelial neoplasms, 1083–1084, 1084f, 1085f lacrimal gland, 1030 enlargement, 1080, 1081t langerhans cell histiocytosis, 1087, 1089, 1089f lymphoproliferative disease of, 1080–1083, 1081f–1083f metastatic disease, 1068–1069, 1069f, 1087, 1087f MR techniques for, 1021–1022, 1021f, 1022f, 1023t muscles of globe, 1025, 1025f–1029f nerves of, 1029–1030 normal anatomy of, 1022–1025 ocular implant, 1048 ocular lesions choroidal and retinal vascular tumors, 1039–1040, 1041f, 1042f Coats disease, 1039, 1041f ocular melanoma, 1032–1034, 1032t, 1033f, 1033t, 1034f ocular metastases, 1033–1034, 1035f persistent hyperplastic primary vitreous, 1036, 1039, 1039f–1040f retinoblastoma, 1034–1036, 1036f–1038f, 1036t optic nerve ischemia, 1073–1075, 1074f–1076f optic nerve/sheath complex, enlargement of, 1070, 1071f, 1072t optic nerve sheath meningioma, 1076, 1078, 1079f, 1080, 1080f, 1081t optic neuritis, 1072–1073, 1072f optic pathway gliomas, 1075–1076, 1077f–1079f Paget disease, 1087, 1088f retinal lesions, 1042f, 1043f globe shape abnormalities, 1044–1047, 1046t ocular trauma, 1047–1048 retinal and choroidal detachment, 1040–1044, 1043f–1048f sarcoidosis, 1082–1083, 1083f, 1084f sinonasal disease, 1089, 1090f–1091f trauma to, 1069, 1070, 1071f vasoformative lesions arteriovenous malformation (AVM), 1060, 1061f infantile hemangioma, 1056–1057, 1057f, 1058f lymphatic malformations (LM), 1058–1060, 1059f–1060f venous malformation (VM), 1057–1058, 1058f, 1059f venous varix, 1060, 1061f vessels of, 1030 walls and canals, 1023–1025, 1024f Orbital cellulitis, 896, 1067f Orbital imaging protocol, high-resolution, 1023 2231

Orbital infiltrative processes, 1065, 1066f Orbital nerve sheath tumors, 1062 Orbital soft tissue anatomy, 1025f, 1026f Orbital varix, 1061f–1062f Ornithine transcarbamylase deficiency, 266f, 267t Osmotic demyelination. See Central pontine and extrapontine myelinolysis Osseous hemangiomas, 911 Osseous injuries, spinal trauma and, 1312, 1312f–1317f, 1316 Osseous lesions, 908 Ossification of PLL, 1242 vertebrae formation and, 1173 Ossifying hemangiomas. See Benign venous malformations Osteoarthritis, 1232–1233, 1234f, 1235 Osteoblastomas, 1257–1259 imaging, 1258–1259, 1258f pathology, 1258 treatment, 1259 Osteoblasts, 894 Osteochondroma, 1253–1254, 1254f imaging, 1253–1254, 1254f pathology, 1253 signs and symptoms, 1253 treatment, 1254 Osteochondrosis intervertebral, 1196 vertebral, 1239 Osteogenic sarcoma, 894f Osteoid osteoma, 1254–1257 imaging, 1256, 1256f–1257f pathology, 1254, 1255f, 1256 symptoms, 1254 treatment, 1257 Osteomyelitis, vertebral, 1197 Osteophytes, 1232 Osteosarcomas, 1266–1267 imaging, 1267 pathology, 1267 telangiectatic, 1267 treatment, 1267 Otic artery, 157, 157f Otosclerosis, 941 Ovarian carcinoma osteoblastic metastasis from, 1276f spinal cord metastasis from, 1301f–1302f Overscan lines, 54 P Pachygyria, 292, 292f Pachymeningitis interna hemorrhagica, 412 Paget disease, 894 of orbital bone, 1087, 1088f Panic disorder (PD) fMRI of, 1577–1578 MRI of, 1577 MRS of, 1578–1579, 1578t Pantopaque, subarachnoidal, 517f Pantothenate kinase–associated neurodegeneration (PKAN), 853, 854f 2232

Papillary craniopharyngiomas, 976 Papillary cystadenomatous tumors, 910 Papillary tumor of pineal region (PTPR), 372, 375, 379f Papilledema, 1040, 1043f Papillitis, 1043f Papilloma, inverted, 890f Paracoccidioidomycosis (PCM), 791, 792t, 793f, 794f, 1442, 1443f–1444f Paragangliomas, 913, 914f Parallel imaging (pMRI), 19–20, 54 compressed SENSE, 56 generalized autocalibrating partially parallel acquisition (GRAPPA), 55–56, 56f, 57f multi-band or multiplexed imaging, 56–57 sensitivity encoding (SENSE), 54–55, 54f, 55f Paramagnetic relaxation, 61–68 correlation time and, 62f, 64–66 distance and, 67–68 enhancement effects and, 65, 67 exchange effects and, 68 frequency and, 66–67 Paramagnetism, 485f, 486 Paranasal sinuses, 886, 887f, 888f Paraplegia, 1308 Parasellar infections, 1003, 1004f, 1005f Parasitic infection amebiasis, 811–812, 811f, 812f American trypanosomiasis, 813, 815 cysticercosis, 804–810, 804f–810f, 811t hydatid disease, 812–813, 813f malariasis, 813 schistosomiasis, 813, 814f spinal cord, 1445–1454 toxoplasmosis, 794–803, 795f–803f Paraspinal myositis, 1215 Parkinson disease (PD), 838–840, 838f–840f, 1630 Parkinsonism, 837–838, 838t corticobasal degeneration syndrome, 847–849, 848f frontotemporal lobar degeneration, 844–846, 845f manganese neurotoxicity and, 838, 838f multiple system atrophy, 840–844, 841f–843f Parkinson disease, 838–840, 838f–840f primary, 838 progressive supranuclear palsy, 846–847, 846f, 847f secondary, 838 Partial Fourier acquisitions, 19, 52 Hermitian symmetry, 53–54, 53f zero-padding, 52–53, 52f, 53f Passive shimming, 8–9 Patient-generated noise, 13 Pediatric brain tumors, 430 atypical teratoid/rhabdoid tumor, 439–440, 440f brainstem gliomas, 443, 445–448, 445f–449f cerebellar astrocytoma, 431–434, 432f–434f children younger than 2 years of age, 480–481, 481f choroid plexus papilloma, 442–443, 444f craniopharyngiomas, 474–475, 475f–477f development of, 430 ependymomas 2233

posterior fossa, 440–442, 440f–443f, 631t hypothalamic hamartomas, 477–478, 479f imaging evaluation for CT, 430 diffusion imaging, 430–431 MRI, 430–431 incidence of, 430 infratentorial tumors, 431–449 pineal region tumors, 469–470, 469t, 470f CT findings, 469–470, 471f germinomas, 470, 472f–473f MRI findings, 470, 471f pituitary adenomas, 478 posterior fossa tumors, 431t Pediatric brain tumors (continued) primitive neuroectodermal tumors, posterior fossa, 434–439, 435f–439f Rathke cleft cyst, 475–477, 478f second, 481 sellar and suprasellar masses, 474, 478–479 signs and symptoms of, 430 skull base tumors metastases, 479, 479f, 480f plexiform neurofibromas, 479–480, 480f schwannomas and meningiomas, 480 supratentorial tumors, 449, 454t atypical teratoid and rhabdoid tumor, 463, 466f choroid plexus papilloma and carcinoma, 467–469, 468f, 469f desmoplastic infantile ganglioglioma, 455, 456f dysembryoplastic neuroepithelial tumor, 456, 458, 458f, 459f ependymoma, 463–465, 466f–467f fibrillary astrocytomas, 458–460, 460f ganglioglioma, 452–455, 453f–455f, 454t glioblastoma multiforme, 461–462 gliomatosis cerebri, 460–461, 461f hemispheric tumors, 465, 467 pilocytic astrocytomas, 449–452, 450f–453f pleomorphic xanthoastrocytomas, 455–456, 457f primitive neuroectodermal tumors, 462–463, 463f–465f subependymal giant cell tumors, 462, 462f, 463f Pelizaeus–Merzbacher disease, 269–271, 270f–271f Percutaneous sclerotherapy, 1060 Perfusion imaging. See also Dynamic susceptibility contrast techniques, 1545 tracers, 1545, 1545f Perfusion-weighted imaging (PWI) brain tumors, 329–330 infarction and, 647–648, 648f, 649f, 651 in left middle cerebral artery occlusion, 649f Pericallosal lipomas, 421 curvilinear type, 421, 421f–422f tubulonodular type, 421, 422f Perilymphatic fistula, 909f, 936–937, 937f Perineural spread, of lesions of central skull base, 906–908 Perioptic meningiomas, 1076 Peripheral facial nerve palsy, 922, 926f Perisylvian polymicrogyria, 292, 293f Perivenous encephalomyelitis. See Acute disseminated encephalomyelitis (ADEM) 2234

Periventicular heterotopia (PNH), 98, 100–101, 101f Periventricular leukomalacia (PVL), 209f, 677, 677f Permanent magnets, 6 Peroxisomal disorders, 251t, 258–260, 258t. See also specific disorders Persistent hyperplastic primary vitreous (PHPV), 1036, 1039, 1039f–1040f PET. See Positron emission tomography (PET) Petechial hemorrhage, 664, 664f Petro-occipital (petroclival) synchondrosis, 904 Petrous apex lesions, 908, 909f PHACES, 199f, 200 PHACES syndrome, 1058f Phakomatoses, 168 ataxia-telangiectasia, 199–200 encephalotrigeminal angiomatosis, 189–195 genes involved in, 168t neurofibromatosis type 1, 169–175 neurofibromatosis type 2, 175–181 neuroimaging in, role of, 168 PHACES, 200 tuberous sclerosis, 181–189 types of, 168t von Hippel–Lindau disease, 195–199 Phase-wrap, 30 Phenylketonuria (PKU), 267t, 1622 Pheochromocytoma, in VHL patients, 195 PHPV. See Persistent hyperplastic primary vitreous (PHPV) Pick’s disease, 845 Pilocytic astrocytoma, 354, 356t, 362f, 445, 445f juvenile, 171 in supratentorial space, 449–452, 450f–453f chiasmatic hypothalamic, 450, 450f, 451f CT findings, 450 cystic, 452f with dissemination, 450f MRI findings, 450, 452, 452f, 453f Pilomyxoid astrocytoma (PMA), 450, 453f Pineal cell tumors, 375, 376f–378f Pineal cysts, 376–377, 380f Pineal germinomas, 371t, 372–373, 372f–374f Pineal parenchymal tumor of intermediate differentiation (PPTID), 372, 373, 376f Pineal parenchymal tumors (PPTs), 372, 375, 376f–378f Pineal region tumors, 369–378, 371t Pineal rhabdoid tumor, 466f Pineal teratoma, 371t, 373–375, 374f, 469t, 474t Pineoblastoma, 373, 376f–377f, 463f, 469–470, 469t, 471f Pineocytoma, 378f PION. See Posterior ischemic optic neuropathy (PION) Pipeline embolization device, 1499 Pituicytoma, 993–994, 998, 998f Pituitary abscess, 1002–1003, 1003f Pituitary adenomas, in children, 478 Pituitary apoplexy, 1008–1009, 1012f, 1013f, 1014 Pituitary duplication, 958–959, 958f–959 Pituitary gland duplication of, 958–959, 958f–959f hypoplasia, 955–958, 956f, 957f Pituitary hemorrhage, 513f 2235

Pituitary macroadenoma, 968–975, 968f–975f Pituitary microadenoma, 953, 961–968, 962f–967f PKU. See Phenylketonuria (PKU) Placode, devascularization of, 1109 Plasmacytoma, 894, 911, 912f, 1275f–1276f, 1278 Pleomorphic xanthoastrocytoma (PXA), 356–358, 358f–359f calcification, 519f pediatric, 455–456, 457f Plexiform neurofibroma, 1063, 1284f NF1 and, 173, 176f PLL. See Posterior longitudinal ligament (PLL) PMG. See Polymicrogyria (PMG) PML. See Progressive multifocal leukoencephalopathy (PML) Pneumatization of petrous apices, 908 Pneumococcic labyrinthitis, 934 Pneumosinus dilatans, 891 PNH. See Periventicular heterotopia (PNH) Poliomyelitis, 1456–1457, 1457f, 1458f Poliovirus infection, 1456–1457, 1457f, 1458f Polymicrogyria (PMG), 101–106, 292, 293f bilateral PMG, 102–103f and closed-lip schizencephaly, 102, 104f congenital cytomegalovirus infection and, 105, 105f focal unilateral PMG, 102, 102f malformations associated with, 105–106 neuropathology and imaging findings, 102–103f, 102f, 105–106, 106f and open-lip schizencephaly, 102, 103f perisylvian, 105 Zellweger syndrome and, 105, 105f Pontine gliomas, 445, 446f CT findings, 447–448, 447f and medullary tumor, 447, 447f MRI findings, 448, 448f Pontine tegmental cap dysplasia (PTCD), 133–134, 133f, 134f Pontocerebellar hypoplasia, 126–128, 127f, 128f Poretti–Boltshauser syndrome, 124–125, 125f Positron emission tomography (PET), 974 Posterior cerebral artery (PCA), 655, 655f infarction, 660f Posterior fossa malformations, 116 cerebellar and brainstem malformations, 126–134 cerebellar agenesis, 129, 129f Joubert syndrome, 129–132 pontine tegmental cap dysplasia, 133–134, 133f, 134f pontocerebellar hypoplasia, 126–128, 127f, 128f cerebellum, normal development of, 116–117 neuroimaging in, role of, 116 predominantly brainstem malformations, 134–135 Athabascan brainstem dysgenesis syndrome, 134 Bosley–Salih–Alorainy syndrome, 134 brainstem disconnection, 134, 135f horizontal gaze palsy with progressive scoliosis, 134 L1 syndrome due to mutations in L1CAM, 134 predominantly cerebellar malformations, 117–126 arachnoid cysts, 122, 122f Blake’s pouch cyst, 121, 121f cerebellar dysplasia, 124, 125f 2236

cerebellar hyperplasia, 125–126, 127f cerebellar hypoplasia, 117–118, 118f Chudley–McCullough syndrome, 124 cystic malformations of posterior fossa, 118–123 Dandy–Walker malformation (DWM), 118–121, 119f, 120f, 121f GPR56-related polymicrogyria, 125, 126f mega cisterna magna, 122–123, 122f Poretti–Boltshauser syndrome, 124–125, 125f rhombencephalosynapsis, 123–124, 123f, 124f Posterior fossa tumors, in childhood, 431t. See also specific tumors Posterior inferior cerebellar artery (PICA), 655, 656 Posterior ischemic optic neuropathy (PION), 1073, 1076 Posterior longitudinal ligament (PLL), spine, 1192, 1316, 1317, 1317f, 1324 Posterior spinal arteries (PSAs), 1367, 1368 Postgadolinium coronal T1-weighted image, 885 Postinfectious encephalomyelitis. See Acute disseminated encephalomyelitis (ADEM) Postpartum pituitary necrosis, 1014, 1014f Postseptal orbital cellulitis, 1066 Posttransplant lymphoproliferative disorder (PTLD), 385, 386f, 387f Posttraumatic stress disorder (PTSD) fMRI of, 1583–1584 MRI of, 1582–1583, 1583t MRS of, 1584 Postvaccinal encephalomyelitis. See Acute disseminated encephalomyelitis (ADEM) Postvaricella arteriopathy, 727 Prechordal plate, 1098 Premature gyration, 1513f Presomites, 1165 Preterm infant, ischemic injury in, 676–677, 676f–678f Primary CNS lymphoma (PCNSL), 379, 381–385, 382f–385f, 409 Primary demyelinating diseases, 204, 205t Primary hypothyroidism, 1018, 1018f Primary lateral sclerosis, 871 Primary progressive aphasia (PPA), 844. See also Frontotemporal lobar degeneration (FTLD) Primary vitreoretinal lymphoma (PVRL), 1081 Primitive neuroectodermal tumors (PNETs) posterior fossa, 431t, 434–439, 435f–439f CT findings, 436–437, 436f, 437f disseminated tumor, 437f, 438 high-risk tumors, 439 incidental, 438, 438f low-risk tumors, 439 MRI findings, 436f–439f, 437–439 preoperative evaluation of, 438 radiation injury/necrosis, 439, 439f symptoms, 436 tumor location and enhancement patterns, 436 supratentorial, 462–463, 463f–465f CT imaging of, 463, 464f, 465f MRI of, 463, 464f, 465f Primitive streak, 80 Prion diseases, 747–749, 747t, 748f–751f acquired diseases, 748 familial, 747–748 Progressive cavitating leukoencephalopathy, 269t Progressive multifocal leukoencephalopathy (PML), 230, 232–233, 731–732, 732f–733f, 739–746, 740f– 746f 2237

acquired immunodeficiency syndrome and, 233f AIDS and, 739 brain biopsies in diagnosis of, 739 clinical features, 230, 232, 739 definite PML, 744 diagnosis of, 232 HAART and, 744, 746 HIV dementia and, 236t HIV infection and, 745f–746f human immunodeficiency virus and, 747t imaging of, 739–744, 741f–746f by JC polyomavirus, 739 MRI findings, 232–233, 233f–235f MS and, 230 pathologic findings, 232, 232f presumptive PML, 744 Progressive rubella panencephalitis, 230 Progressive supranuclear palsy (PSP), 846–847, 846f, 847f and corticobasal syndrome, 847, 848f, 849 diagnostic criteria for, 846 histologic findings in, 847f morning glory sign, 846, 846f pathology and neuroimaging, 846–847, 846f Prolactin, 948, 962 Prolactinoma, 962, 964f, 965f Prophylactic surgery, spinal lipomas, 1135 Prosencephalon (forebrain), 80, 89 Prostate carcinoma, 1088f dural metastases, 308f Proton, 4 Proton magnetic resonance spectroscopy adrenoleukodystrophy, 258 for Alzheimer disease, 830, 830f Pseudoaneurysm, 715–716, 716f Pseudobulging, 1243 Pseudohyphae, 783 Pseudoprogression (PsP), 392–393, 393f Pseudoresponse, 393, 393f Pseudotumor, orbital. See Idiopathic orbital inflammatory pseudotumor (IOIP) PSP. See Progressive supranuclear palsy (PSP) Psychotic disorders MRI of, 1562–1563 MRS of, 1563, 1564t–1565t, 1565f PTCD. See Pontine tegmental cap dysplasia (PTCD) Pterygopalatine fossa, 906, 907f Pthisis bulbi, 1046t, 1047 PTSD. See Posttraumatic stress disorder (PTSD) Pulse sequence diagram, 36 for CPMG Fast Spin Echo sequence, 50f for diffusion-weighted spin echo sequence, 48f for double inversion recovery (DIR) sequence, 41f for gradient echo imaging sequence, 37f for GRASE sequence, 51f for magnetization-prepared spoiled gradient echo sequences, 43f for MT experiment, 46f for rapid spoiled gradient echo (GRASS) sequence, 42f Purkinjie cells, 117 2238

PVRL. See Primary vitreoretinal lymphoma (PVRL) PXA. See Pleomorphic xanthoastrocytoma (PXA) Pyogenic abscess, 760, 760f, 761f, 764f, 765f Pyogenic facet joint infection, 1395, 1397 imaging studies, 1397 MRI for, 1396f, 1397, 1397f, 1398t symptoms, 1397 Pyogenic spondylitis, 1391 tuberculous spondylitis and, 1436t Pyogenic ventriculitis, 760 Q Q-space imaging, spinal cord, 1355–1356 18q-syndrome clinical features, 271 MRI findings, 271–272, 272f R Radial sampling, 27, 27f Radiation effects, 240–241, 242f chemotherapy and, 241, 242f, 243f Radiation myelopathy, 1423–1424, 1424f Radiation necrosis, 392, 392f arteriovenous malformations, 563, 566f Radiculitis, 1215 Radiculomedullary arteries, 1367, 1368f Radiculopial arteries, 1367, 1368f Radiofrequency (RF) coils, 11–13 body coils, 11 functions of, 11 head coils, 11–12, 12f surface coil, 12 Ramsay Hunt syndrome, 726 Rapid acquisition with relaxation enhancement (RARE), 49 Rapid image acquisition, 49 techniques, 49 echo-planar imaging, 49 fast spin echo imaging, 49–51 gradient and spin echo imaging, 51, 51f steady-state imaging methods, 51–52 Rasmussen encephalitis, 756–758, 757f, 758f cerebral gliosis and atrophy, 297 hemispherectomy and, 756 Rasmussen encephalitis syndrome, 297, 300 Rathke cleft cyst, 475–477, 478f, 976, 979f–982f Reelin, 117 Region of interest (ROI), 25 Reissner’s membrane, 926 Relapsing polychondritis, 936 Relaxation biophysical basis of, 34–36, 35f, 36f BPP theory of, 35, 36f Relaxation mechanisms exchange processes, 489 in hemorrhage, 487–489 paramagnetic, 61–68 relaxivity effects, 487–488, 488f, 488t solutions and, 59–61, 60f, 61f 2239

susceptibility effects, 488–489, 490f, 491f, 491t Relaxation rate, 61–62. See also Contrast agents correlation time and, 64 in liquids, 61 Solomon–Bloembergen–Morgan (SBM) equations and, 64 for various ions, 63t Relaxation time, 15, 59, 1185 Renal cell carcinoma (RCC) metastasis, as hypervascular hemorrhagic mass, 322f vascular metastasis from, 1249f–1250f VHL disease and, 198–199 Rendu–Osler–Weber syndrome, 1380 Repetition time (TR) sequence, 884 RES. See Rhombencephalosynapsis (RES) Resistive magnets, 6 Responsive neurostimulation, 280t Resting-state fMRI (rs-fMRI) acquisition and analysis methods, 1665–1666 advantages and disadvantages of, 1666 applications of, 1667 background on, 1664–1665 independent component analysis, 1666, 1667f networks, 1665, 1665f presurgical planning of, 1667, 1668f seed-based analysis of, 1666, 1666f Retention cysts, 894 Retethering by scar, 1110–1111, 1110f–1112f Retinal angiomas, 1039 Retinal detachments, 1042f Retinal vascular tumor, 1039–1040, 1041f, 1042f Retinoblastoma (Rb), 1034–1036, 1036f–1038f, 1036t, 1037f Retinocochleocerebral vasculopathy. See Susac’s syndrome Retrobulbar hematoma, 1071 Retrofenestral otosclerosis, 942 Retrogressive differentiation, 1137 Retrolisthesis, 1243 Retrovermian epidermoid, 151f Reversible posterior leukoencephalopathy. See Hypertensive encephalopathy Rhabdomyosarcoma, 899, 901f, 1062–1065, 1064f metastatic, 1050f Rheumatoid arthritis, 1239, 1241f, 1398–1401 atlantoaxial instability, 1398, 1399f–1400f cervical spine involvement in, 1398 manifestations of synovitis in, 1398 MRI for, 1398, 1401, 1401f subaxial subluxations, 1398, 1398f Rhombencephalon (hindbrain), 80 Rhombencephalosynapsis (RES), 123–124, 123f, 124f imaging and pathologic findings brainstem, 123, 124f cerebellum, 123 supratentorial findings, 124, 124f prenatal diagnosis of, 124 Root entry zone (REZ), 914, 915, 919f Rosai–Dorfman disease, 1000, 1089 Rosette-forming glioneuronal tumor (RFGT), 364, 366, 366f Rostrocaudal patterning, 1102–1103, 1105f 2240

of somites, 1169 (see also Dorsoventral patterning of somites) rs-fMRI. See Resting-state fMRI (rs-fMRI) S Saccular aneurysms, 610–618, 611f–617f, 1008, 1011f Sacrococcygeal teratoma (SCT), 1142–1144, 1142f–1144f, 1261, 1520, 1523f, 1524f imaging, 1261, 1262f pathology, 1261 prenatal diagnosis/prognosis, 1144 treatment, 1261 SAH. See Subarachnoid hemorrhage (SAH) Sampling, 28, 28f–30f in 2D and 3D, 30 Sarcoidosis, 410, 411f, 1006–1007, 1007f, 1008f, 1074f, 1082–1083, 1083f, 1084f clinical features, 247 of internal auditory canals, 912f MRI findings, 247–248, 248f spinal, 1424–1425, 1425f, 1526f Sarcoma, granulocytic, 1082 Scalp arteriovenous fistula, 604, 608f Scar tissue, 1219, 1221f, 1222f Schilder disease, 223, 224f Schistosomiasis, 813, 814f spinal cord, 1450–1452, 1450f–1451f Schizencephaly, 101–106, 107f, 292, 293f. See also Polymicrogyria (PMG) closed-lip, 104f open-lip, 103f Schizophrenia MRI of, 1562–1563 MRS of, 1563, 1564t–1565t, 1565f, 1631 Schmorl nodes, 1215, 1218f Schwannoma, 910–913, 911f–913f, 994–995, 998f, 1062, 1062f–1064f, 1216f, 1278–1281, 1279f–1282f. See also Nerve sheath tumors intracranial, 179, 179f NF2 and, 175, 178–179, 178f, 179f, 181, 182f spinal, 181, 182f trigeminal nerve, 416, 416f–417f vestibular, 178–179, 178f, 179f, 414–416, 414f–416f SCI. See Spinal cord injury (SCI) SCIM (spinal cord independence measure), 1346 Sclera, 1030 Sclerotomes, 1168 SCT. See Sacrococcygeal teratoma (SCT) SDAVFs. See Spinal dural arteriovenous fistulas (SDAVFs) SDH. See Subdural hematoma (SDH) SEA. See Spinal epidural abscess (SEA) Secondary demyelinating diseases, 204, 205t, 227 Segmental spinal dysgenesis, 1176, 1177f Seizures, 277. See also Epilepsy posttraumatic, 296 stroke and, 296 Sella turcica and parasellar region congenital abnormalities cephaloceles, 960–961, 961f empty sella turcica, 959, 960f pituitary duplication, 958–959, 958f–959 pituitary gland hypoplasia, 955–958, 956f, 957f inflammatory lesions 2241

infections, 1001 parasellar infections, 1003, 1004f, 1005f pituitary abscess, 1002–1003, 1003f metabolic disorders diabetes insipidus, 1015–1016, 1018, 1018f hemochromatosis, 1018 hypermagnesemia, 1018 primary hypothyroidism, 1018, 1018f noninfectious inflammatory lesions granulomatous giant cell hypophysitis, 1006, 1007f infundibuloneurohypophysitis, 1005 lymphocytic hypophysitis, 1003, 1005f, 1006f sarcoidosis, 1006–1007, 1007f, 1008f Tolosa–Hunt syndrome, 1007–1008, 1009f, 1010f, 1011f normal anatomy, 948–952, 949f–952f technique, 952–955, 953f–955f Sella turcica and parasellar region (continued) tumor-like conditions arachnoid cyst, 999, 1000f eosinophilic granulomatosis, 1000, 1002f, 1003f tuber cinereum hamartomas, 999, 1000f, 1001f tumors chiasmatic and hypothalamic gliomas, 988, 989f–994f chordoma, 992–993, 995f–996f craniopharyngioma, 975–976, 975f–979f ecchordosis, 993, 997f epidermoids and dermoids, 985, 987–988, 987f–988f germinoma and teratoma, 982, 984–985, 984f–986f meningioma, 979, 982, 982f–983f metastases, 997, 999f pituicytomas and granular cell tumors, 993–994, 998f pituitary macroadenomas, 968–975, 968f–975f pituitary microadenoma, 961–968, 962f–967f rathke cleft cyst, 976, 979f–982f schwannoma, 994–995, 998f vascular and ischemic lesions aneurysms, 1008, 1011f, 1012f carotid cavernous fistulas, 1014, 1015f, 1016f cavernous malformation, 1014–1015, 1017f cavernous sinus dural arteriovenous malformations, 1014, 1015f, 1016f pituitary apoplexy, 1008–1009, 1012f, 1013f, 1014 Sheehan syndrome, 1014, 1014f Semilobar holoprosencephaly, 109–111, 110f. See also Holoprosencephaly (HPE) Sensitive point, 2 Sensitivity-encoding (SENSE) technique, 19, 54–55, 54f, 55f compressed SENSE, 56 Sensorineural hearing loss, 942 Septic emboli, 767 with abscess formation, 768f–769f development of, 767 and infarction, 662, 663f with infarction and microabscesses, 767, 768f and mycotic aneurysm, 767, 769f–770f Septo-optic dysplasia (SOD), 113–116 fetal imaging, 116, 116f hypoplasia of optic nerves and chiasm, 114f, 115 neuropathologic and imaging findings, 113, 114f, 115, 115f 2242

optic chiasm, agenesis, 115, 115f with schizencephaly, 115f see-saw nystagmus, 115, 115f Sequence timing diagram, for 2D acquisition, 22, 22f and k-space position, relationship between, 22, 23f Sequestrated disc fragment, 1204, 1207 Seronegative spondyloarthritis, 1401–1402 Andersson aseptic spondylodiscitis, 1401 Andersson fractures, 1402 arthritis of facet and costal joints, 1401 bamboo spine, 1402 histopathologic examinations, 1401 imaging in, 1401 Romanus spondylitis, 1401 sacroiliac involvement, 1402 SGCA. See Subependymal giant cell astrocytoma (SGCA) Shaken-baby syndrome, 711 Sharpey fibers, 1193 Sheehan syndrome (postpartum pituitary necrosis), 1014, 1014f SHH. See Signal sonic hedgehog (SHH) Shim coils, 5, 8–9 resistive, 9 superconducting, 9 Short inversion-time inversion recovery (STIR), 1022, 1188 Shy–Drager syndrome, 840, 842 Siderosis, 914, 918, 919f Siderosis, intraventricular, 520f Signal Enhancement by Extravascular water Protons (SEEP) effect, 1359 Signal evolution and relaxation, 32–33, 32f, 33f Signaling, molecular, 1101, 1102 Signal sonic hedgehog (SHH), 1101 Signal-to-noise ratio (SNR), 4, 13, 24, 1021 Signal void, 882, 884f, 886, 901, 906 Silicone injection, 1043f Simultaneous acquisition of spatial harmonics (SMASH), 19 Single-voxel spectroscopy, 1608 Sinonasal disease, 1089, 1090f–1091f Sinus histiocytosis, 1089 Sinusitis, 1083 allergic fungal, 1090–1091 Sinus pathology, 894–899, 897f–899f Sirenomelia, 1150, 1152f Sjögren syndrome (SS), 1074 Skull base bone, 882–884, 884f, 885f carotid artery and optic nerve, 886, 888, 889f–890f and congenital abnormalities, 918, 920f–922f congenital defects and arachnoid granulations, 918, 920f–922f facial nerve anatomy, 922, 923f pathology, 922–925, 923f–926f imaging of, 882, 883f inner ear, anatomy of, 925–927 masses, anatomic sites of, 883f MR techniques for labyrinth, 927–930, 927f–931f labyrinthine lesions, 930–943 paranasal sinuses, 886, 887f, 888f 2243

posterolateral benign venous malformations, 914, 915f congenital deafness and internal auditory canal, 914, 916f–918f endolymphatic sac tumors, 910, 910f middle ear inflammatory/obstructive disease, 914, 915f paragangliomas, 913, 914f petrous apex lesions, 908, 909f schwannomas, 910–913, 911f–913f siderosis, 914, 918, 919f soft tissues, 884–886, 885f tumor/mass and infection, 888–889 anterior skull base, 899–901, 900f–902f bone lesions, 891, 894, 894f–896f central region, 901–904, 903f–906f central region, secondary lesions of, 904–908 dural lesions, 891, 891f, 892f–893f posterolateral region, 908–918 sinus pathology, 894–899, 897f–899f Small-vessel infarction, 636–637 diabetes mellitus and, 637 MR appearance, 665–666, 668, 668f, 669f–671f, 670 SNR. See Signal-to-noise ratio (SNR) SOD. See Septo-optic dysplasia (SOD) 23Na MRI, 333 Somites, 80, 1165–1166 dorsoventral patterning, 1167, 1168f dermomyotomes, 1167–1168 sclerotomes, 1168 syndetomes, 1169 rostrocaudal patterning of/Hox code, 1169 Somitomeres, 1165–1166, 1167f Sonic hedgehog (SHH), 80 SOV. See Superior ophthalmic vein (SOV) Specific absorption rate (SAR), 1021 Sphenoid dysplasia NF1 and, 172–173, 172f Sphenoid encephalocele, 920f Sphenoid sinus, carcinoma of, 889f Sphenomaxillary encephaloceles, 918 Sphenomaxillary meningocele, 920f Spina bifida aperta, 1103–1109 cord retethering/release of retethered cord, 1116, 1116t diastematomyelia and hemimyelocele, 1113 hydromyelia, 1111–1113, 1112f–1114f inclusion cysts, 1111 latex anaphylaxis, 1110 local wound site, 1109 myelomeningocele, spinal curvature in, 1113, 1113t lumbar kyphosis, 1115 lumbar lordosis, 1115 scoliosis, 1115 thoracic kyphosis, 1115 placode, devascularization of, 1109 retethering by scar, 1110–1111, 1110f–1112f untethering on spinal curvature, 1115–1116 Spinal blastomycosis, 1440, 1441f Spinal column, embryogenesis of 2244

deranged, 1174–1175 congenital vertebral dislocation, 1176, 1177f Currarino triad, 1175–1176, 1177t Goldenhar complex, 1176 Klippel-Feil syndrome, 1175 multiple vertebral segmentation disorders, 1178 OEIS complex, 1175 VATER association, 1175 elongation of body axis, 1166, 1168f somites, patterning, 1166–1169 somitomeres and somites, 1165–1166, 1167f vertebrae, formation of, 1169–1173, 1169f–1173f Spinal cord in multiple sclerosis, 213f–214f subacute, 214f subacute combined degeneration of, 239–240, 240f vascular anatomy of, 1367–1369, 1368f–1369f arterial regions, 1368f intrinsic supply, 1369, 1370f, 1396f superficial arteries, 1368f vascular lesions of classification of, 1370–1372, 1371t, 1372t evaluation of, 1370 Spinal cord arteriovenous fistula (SCAVFs), 1384, 1384f, 1385f angiographic evaluation of, 1384 MRI for, 1384 Spinal cord arteriovenous malformations (SCAVMs), 1373t, 1380–1381, 1380f–1383f, 1383–1384 anatomy and pathophysiology, 1380 arterial supply of, 1380 clinical presentation, 1380 glomus-type, 1380, 1382f imaging of, 1380–1381, 1381f–1383f, 1383 juvenile-type, 1380 and neurologic dysfunction, 1380 treatment of, 1383–1384 Spinal cord cavernous malformation (CM), 1384–1386, 1386f clinical presentation, 1384–1385 management of, 1386 MRI findings, 1386, 1386f Spinal cord infections, 1429 bacterial, 1429–1440 fungal, 1440–1445 parasitic, 1445–1454 viral, 1454–1459 Spinal cord injury (SCI), 1308 biomechanics and distribution of, 1332–1334, 1333f–1335f blood–spinal cord barrier disruption, evaluation of, 1356, 1358 characterization of, 1311–1312, 1311f clinical measures of, 1345–1348, 1345f–1348f contrast-enhanced MRI for, 1356, 1358 demographics of, 1308 disc injury, 1325, 1326f DWI/DTI of, 1354–1355, 1355f, 1356f epidural hematoma, 1325, 1326f–1328f fiber tractography for, 1355, 1357f–1358f fMRI for, 1359–1361, 1359f, 1360f GRASE (gradient spin echo) sagittal image of, 1309, 1310f 2245

imaging considerations for, 1309, 1309f imaging methods for, 1309–1311, 1310f ligamentous and joint disruption, 1316, 1317f–1324f, 1324–1325 limitations of conventional MRI in, 1351–1352 magnetically labeled neurotransplants, MRI tracking of, 1361, 1361f magnetization transfer MRI for, 1359 MRI findings of, 1339, 1339f, 1340f clinical significance of, 1348–1351, 1350f edema and, 1315f, 1317f–1322f, 1344 effects of methylprednisolone on, 1351, 1351f hemorrhage and, 1339–1340, 1340f–1344f, 1344, 1349 swelling and, 1318f, 1319f, 1342f, 1344–1345 MRS for, 1358–1359, 1358f osseous injury, 1312, 1312f–1317f, 1316 q-space imaging, 1355–1356 spinal instability, assessment of, 1336–1338, 1337f, 1338f survey method for imaging of, 1310, 1310f vascular injury, 1329, 1329f–1331f, 1331–1332 Spinal cord injury without radiographic abnormality (SCIWORA), 1334, 1335f Spinal cord ischemia and infarction, 1386–1388, 1387f, 1388f Spinal cord metastasis, 1299, 1301–1303 imaging, 1301, 1301f–1303f from ovarian carcinoma, 1301f–1302f therapy, 1303 Spinal cord schistosomiasis, 813, 814f Spinal dural arteriovenous fistulas (SDAVFs), 1372–1373, 1376–1377 anatomy and pathophysiology, 1372–1373, 1372f clinical presentation, 1373, 1373t with intramedullary enhancement, 1375 MRA techniques, 1375f–1377f, 1377 MR findings, 1373, 1374f–1379f, 1376–1377 treatment of, 1377 Spinal epidural abscess (SEA), 1403–1408 causative agents, 1403 concomitant infections with, 1404, 1404t differential diagnosis, 1408 diffuse, 1403, 1405f–1406f features, 1403, 1404f, 1405f foacl, 1403, 1407f MR for, 1404, 1406–1407 patterns of enhancement in, 1405f–1407f, 1406 spinal DWI for, 1407, 1407f Spinal hemorrhage, 1388 Spinal hypertrophic pachymeningitis, 1408, 1408f Spinal instability, 1332 assessment of, 1336–1338, 1337f, 1338f Spinal metastases, 1272 imaging, 1272, 1273f–1277f, 1278 symptoms, 1272 treatment, 1278 Spinal muscular atrophy (SMA), 871 Spinal nerves, 80 Spinal subdural abscess (SSA), 1408–1409 Spinal tumors, 1245 dermoids, 1303, 1304f–1305f extradural, 1245, 1245f MR technique for, 1246–1251, 1248f–1250f 2246

primary, 1251–1272 secondary, 1272–1278 intradural extramedullary, 1245, 1246f MR technique for, 1278 primary, 1278–1286 secondary, 1286–1288 intramedullary, 1245, 1246f MR technique for, 1288 primary, 1288–1299 secondary, 1299–1303 lipomas, 1303, 1304f Spine and spinal cord cervical myelomeningocele and myelocystocele, 1120, 1121f, 1122f chiari II malformation, 1117–1120, 1117f, 1118t coccygeal dimples, 1124–1125, 1124f–1125f dermoid and epidermoid tumors, 1125–1127, 1126f dorsal dermal sinus, 1120, 1122, 1122f–1124f, 1124 embryogenesis of notochord, 1152, 1154, 1154f deranged, 1154–1165, 1155f, 1157t, 1158f–1166f, 1158t, 1159t embryogenesis of spinal column body axis, elongation of, 1166, 1168f deranged, 1174–1178 somites, patterning, 1166–1169 somitomeres and somites, 1165–1166, 1167f vertebrae, formation of, 1169–1173, 1169f–1173f embryogenesis, overview of notochordal process, 1098 prechordal plate, 1098 primitive node (Hensen’s node), 1098 three-layered germinal disc and gastrulation, 1096, 1097f, 1098 two-layered germinal disc, 1096, 1097f fetal repair of myelomeningocele, 1116–1117, 1116f lipomas, spinal, 1127–1128, 1127f–1129f, 1127t, 1128t neurulation, body axes, patterning, 1102–1103 neurulation, normal, 1099f, 1100f–1105f convergent extension, 1098 fusion of neural folds, 1098 molecular signaling, 1101, 1102 neural crest migration, 1098 neural folds, forming, 1098 neural from epidermal ectoderm, disjunction of, 1101 neural tube, points of closure of, 1098, 1101 primary neurulation, deranged spina bifida aperta, 1103–1116 secondary neurulation conus medullaris, position of, 1137–1140, 1138t–1140t deranged, 1140–1152 normal embryogenesis and anatomy, 1135–1137, 1136f spinal lipomas with dural deficiency, 1130f–1135f complications of surgery, 1134–1135 concurrent malformations, 1135 lipoma classification, 1130–1131 MR spectroscopy of CSF, 1135 prophylactic surgery vs. conservative management of spinal lipomas, 1135 surgical considerations, 1131, 1134 spinal lipomas with intact dura, 1128–1130, 1128f–1130f vascular anatomy of, 1367–1369, 1368f–1369f 2247

vascular lesions of classification of, 1370–1372, 1371t, 1372t evaluation of, 1370 Spin-echo imaging, 2 Spin-echo (SE) imaging, 953, 1022, 1185 Spine, degenerative disease of articular facets, anatomy of, 1193 cervical disc herniations, 1224, 1227f–1233f, 1228–1229, 1232 cervical spinal stenosis about, 1236, 1237, 1239, 1239f–1242f, 1242 spondylolisthesis, 1242–1243, 1242f, 1243f intervertebral disc age-related changes in, 1192–1193, 1193f, 1194f anatomy of, 1190–1192, 1190f–1192f degeneration, 1194, 1194f–1196f lumbar disc herniation, 1206, 1207f mimics of, 1215, 1218, 1218f, 1219f MRI of, 1206–1214, 1213f–1215f paramagnetic contrast in routine lumbar spine MRI, 1214–1215, 1215f–1217f postoperative lumbar spine and MRI, 1218–1219, 1220f–1226f Schmorl nodes, 1215, 1218f lumbar disc pathology, classification of, 1200–1206, 1200f–1206f lumbar spinal stenosis, 1233–1236, 1234f–1239f MR pulse sequences about, 1185, 1186f–118f imaging strategies, 1186–1189, 1189f spinal stenosis/osteoarthritis/spondylosis, 1232–1233, 1234f thoracic disc herniation, 1224, 1226f, 1227f Spine magnetic resonance, contrast-enhanced, 1214t Spin–lattice relaxation. See T1 relaxation Spinobulbar muscular atrophy, 871 Spinocerebellar ataxias (SCA), 844, 863, 864f Spin–spin relaxation. See T2 relaxation Spiral acquisition strategies, 27, 28f Split notochord syndrome, 1155f Spondylocostal dysostosis, 1178 Spondylodiscitis causes of, 1391 childhood discitis, 1393 clinical features, 1391–1392 CT for, 1392 differential diagnosis, 1395, 1395f, 1395t, 1396f imaging of, 1392 MR findings of, 1392–1393, 1392f–1395f, 1395t MRI for diagnosis of, 1392 postoperative, 1394–1395 radiographs in, 1392, 1393 risk factors, 1391 treatment, 1393 Spondylolisthesis, 1242–1243, 1242f, 1243f Spondylosis, 1232–1233, 1234f Spondylothoracic dysostosis, 1178 Sprengel’s deformity, 1175 SS. See Sjögren syndrome (SS) SSFP. See Steady-state free-precession (SSFP) SSPE. See Subacute sclerosis panencephalitis (SSPE) Staphyloma, 1044, 1046f, 1046t 2248

Status epilepticus, 298, 298f Steady-state free-precession (SSFP) coronal, 1520f sagittal, 1519f sequences, 1510 Steady-state imaging methods, 51–52 Stenosis cervical spinal about, 1236, 1237, 1239, 1239f–1242f, 1242 spondylolisthesis, 1242–1243, 1242f, 1243f spinal, 1232–1233, 1234f Steroids, 1006 STIR. See Short inversion-time inversion recovery (STIR) Striatum, brain, 851 Stroke, 633. See also Infarction; Ischemia CT in, 634 diffusion imaging evolution in, 648, 649f emergent evaluation in, 634t imaging in, role of, 633 ischemic, 633 imaging of, 633–634 MRI criteria for treatment of, 651–654, 651f–654f MR techniques in, 639–650, 639f–650f, 639t risk factors, 636 subtypes, 636–638, 637f treatment of, 638–639 MR imaging of, 1490–1491 neonatal, 678 Strumpell–Lorrain syndrome. See Hereditary spastic paraplegias (HSPs) Sturge–Weber syndrome, 189–195, 563, 563f, 564f, 1039, 1041f atrophy in, 193f calcifications in, 189, 190f, 195 choroid plexus enlargement in, 189, 191f diagnostic criteria for, 189t features, 189 ischemia in, 192f–193f ocular findings in, 194, 194f port-wine stain in, 189, 194 pseudo-accelerated myelin maturation in, 189, 190f–191f recurrent seizures in, 297 venous abnormalities in, 192f Subacute combined degeneration (SCD) of spinal cord clinical features, 239 MRI findings, 239–240, 240f pathologic findings, 239 Subacute necrotizing encephalomyopathy, 260, 262–265, 264f, 265f Subacute sclerosis panencephalitis (SSPE), 230, 231f, 755–756, 756f Subarachnoid hemorrhage (SAH), 516, 519–520, 520f–524f, 713 acute, 519, 522f–523f acute aneurysmal, 521f acute hemorrhagic contusions with, 708f acute traumatic, 520f aneurysm rupture and, 516 benign perimesencephalic, 521f CT and CTA for, 519 etiologies of, 519t fluid-attenuated inversion recovery, 519, 520f–522f 2249

hemorrhagic contusion and, 689f intracranial aneurysms and, 610, 611, 612f, 613f, 625f MR for, 519, 520f superficial hemosiderosis, 524f superficial siderosis, 523f traumatic, 713, 714f Subarachnoid lipomas, 421, 421f–422f Subcortical band heterotopia (SBH), 97–98, 99f. See also Lissencephaly (LIS) Subcortical nodular heterotopia, 101 Subdural empyema (SDE), 772–774, 773f cerebritis and, 758f Subdural hematoma (SDH), 520, 523–528, 525f–527f, 528t, 709, 711–712, 711f–714f acute, 525f chronic, 523–524, 526f–527f complex, 527f empyema and, 772, 774 Subdural hematoma (SDH) (continued) frontotemporal hemorrhagic contusions and, 705f isodense, 523f, 525f MR images in, 711–712 subacute, 711f traumatic, 714f Subependymal giant cell astrocytoma (SGCA), 182, 184f, 185f, 188–189, 355–356, 356f, 356t, 357f microscopic sections, 356, 356f MR findings of, 356, 357f treatment, 356, 356f Subependymal giant cell tumors (SGCTs) in children, 462, 462f, 463f Subependymal heterotopia, 292, 292f Subependymal nodules (SEN), 182, 183, 183f–184f, 188 Subependymomas, 356t, 364, 365f, 366 Subperiosteal abscess, 1066, 1067f Substance-related disorder MRI of, 1588–1593 MRS of, 1633 Substantia nigra, 851 Subthalamic nucleus, 851 Subtotal annular disruption, 1202 Sudanophilic leukodystrophies clinical features, 269–270 MRI findings, 270–271, 270f–271f pathologic findings, 270 Superconducting magnets, 6–8, 7f magnet quench, 8 3-T magnet, 8f 7-T magnet, 8f Superconducting materials, for MRI magnets, 6 Superficial siderosis, microhemorrhages and, 835, 836f Superior ophthalmic vein (SOV) abnormalities, 1053, 1055f, 1056 orbital wall and, 1025, 1030 Superparamagnetism, 486 Supraspinous ligament (SSL), 1324 Surface coil arrays, 13, 18 Susac’s syndrome, 247, 247f Susceptibility agents, 68, 72–77, 73f–76f, 76t Susceptibility-weighted imaging (SWI), 47, 47f 2250

for head injury, 696–697, 697f Swelling, spinal cord, 1318f, 1319f, 1342f, 1344–1345 Syndetomes, 1169 Synovial cysts, 1235, 1238f Syntelencephaly, 112–113, 113f, 114f Syphilis, 775–776, 776f–778f, 922 meningovascular, 775, 776f–778f MRI in, 776, 776f–778f neurosyphilis, 775 primary, 775 secondary, 775 in spine, 1432, 1433f syphilitic gumma, 775, 778f Syphilitic gummas, 1432 Syphilitic labyrinthitis, 924f Syphilitic polyradiculopathy, 1432f Syringocele, 1145 Syringomyelia, tuberculous meningitis and, 1438f–1439f Systemic autoimmune disorders, 935 Systemic lupus erythematosus–related myelitis, 1414, 1416, 1417f T Tabes dorsalis, 775 TAI. See Traumatic axonal injury (TAI) T1 and proton density weighted imaging inversion recovery methods, use of, 38–39, 40f, 41f partial saturation and rapid gradient echo sequences, use of, 39, 41f, 42, 42f Tarlov cyst, 1219f Tay–Sachs disease, 254, 255f TB. See Tuberculosis (TB) TBI. See Traumatic brain injury (TBI) Tectal glioma, 354–355, 355f Telencephalon (cerebral hemispheres), 80 Temporal lobe herniation, 921f–922f Tenon’s capsule, 1032 Teratoma, 982, 984–985, 984f–986f pineal, 371t, 373–375, 374f sacrococcygeal, 1142–1144, 1142f–1144f, 1261 Terminal myelocystocele (syringocele), 1145–1147, 1146f–1147f Terminal ventricle and conal cyst, 1144–1145 Tesla, 4 Tetraplegia (quadriplegia), 1308 Thalamogeniculate arteries, 655 Thalamoperforating arteries, 655 Third nerve palsy, 611, 616f Thoracic disc herniation, 1224, 1226f, 1227f Thoracic kyphosis, 1115 Thoracic spine imaging, 1188 Three-dimensional Fourier transform (3D FT), 927 Thrombosis, cavernous sinus, 1005f, 1053 Thyroid orbitopathy (TO), 1050–1051, 1050f–1052f Tight filum terminale syndrome, 1140–1141 T2* imaging, using gradient echoes, 44–45 T2 imaging, using spin echoes, 43–44, 44f Tissue plasminogen activator (tPA), intravenous, for ischemic stroke, 638 TO. See Thyroid orbitopathy (TO) Tolosa-Hunt syndrome, 1007–1008, 1009f, 1010f, 1011f, 1052, 1054f–1055f 2251

Tophus, 1402. See also Gout Toxic leukoencephalopathy, 241t Toxoplasma encephalitis, 795–803, 796f–803f Toxoplasmosis, 794–803, 795f–803f in AIDS patients, 80, 795, 797f, 798f, 800f congenital, 803 encephalitis from, 795–803 SPECT in, 800, 801, 801f–802f spinal, 1454, 1454f, 1455f target sign, 798f, 799f Toxoplasma gondii life cycle, 794, 795f Tract pallor, 1458 “Tram track” pattern of enhancement, 1081 Transalar cephalocele, 145, 145f Transitional lipomas, 1130–1131 Transmissible spongiform encephalopathy. See Prion diseases Transsphenoidal cephalocele, 144, 145f Transverse electromagnetic (TEM) resonator, 13 Trauma head (see Head injury) intervertebral disc degeneration, 1194 ocular, 1047–1048 to orbit, 1069, 1070, 1071f Traumatic axonal injury (TAI), 689, 690f, 700–703, 701f–704f brainstem, 706 of corpus callosum, 702 definition for, 700 DWI for, 693–694, 694f, 695f grade 1, 701–702, 703f grade 2, 702 grade 3, 702f with hemorrhage, 691f Traumatic brain injury (TBI), 687. See also Head injury incidence of, 687–688 mild acute TBI (mTBI), 692 MRS of, 1631 pathophysiology of, 688–690, 688f–691f use of MRI for, 692 T1 relaxation, 34–36, 35f, 36t, 60 T2 relaxation, 34–36, 35f, 36t, 60 Trigeminal artery, 154, 156, 156f Trigeminal nerve, 906 schwannoma, 416, 416f–417f Trigeminal neuralgia, 1502–1505, 1504f Trigeminal schwannoma, 1063 Trilateral retinoblastoma, 1036f, 1038f Tropical spastic paraparesis (TSP), 1459, 1459f True fast imaging with steady-state precession (True-FISP), 45 TS. See Tuberous sclerosis (TS) Tuber cinereum hamartomas, 999, 1000f, 1001f Tubercular spinal arachnoiditis, 1436–1437, 1440 MR findings in, 1437, 1438f–1439f, 1440 Tuberculoma, 1004 Tuberculosis (TB), 776, 778–783, 779f–782f complications, 776, 778 HIV infection and, 776 tuberculous abscess, 783 2252

tuberculous granuloma, 780–781, 781f, 782f tuberculous meningitis, 778–780, 779f, 780f Tuberculous arachnoiditis, 1438f Tuberculous meningitis, 1439f syringomyelia and, 1438f–1439f Tuberculous spondylodiscitis, 1435–1436, 1436f, 1437f Tuberous sclerosis (TS), 181–189 calcifications in, 182, 183f–184f cerebellar lesions in, 183, 187f–188f cortical tubers in, 183, 188 cysts in, 183, 187f diagnostic criteria for, 182, 183t findings in, 189, 189t intrauterine, 1517f, 1519f and polycystic kidney disease, 189 radial lines in, 182, 186f retinal lesion of, 183 subependymal giant cell astrocytoma in, 182, 184f, 185f, 188–189 tubers in, 183, 185f–186f Tubulinopathies, 106–107, 108f Turbo spin echo (TSE), 49 Tysabri (natalizumab)-induced PML, 230. See also Progressive multifocal leukoencephalopathy (PML) U Ultrahigh-resolution imaging, 1032 Ultrashort TE imaging (UTE), 1338, 1338f Ultrasmall superparamagnetic iron oxide particles (USPIO), 552 Untethering on spinal curvature, 1115–1116 Urea cycle defects, 266f, 267t Urogenital malformations, 1145 V Vagal nerve stimulation, 280t Vagal schwannoma, 911f Vanishing white matter (VWM) disease, 269t clinical features, 269 MRI findings, 269, 270f pathologic features, 269 Varicella zoster virus (VZV), 726–727, 727f Vascular clefts, 306 Vascular cognitive impairment, 834 Vascular dementia, 834 Vascular injuries, traumatic, 713, 714f–716f, 715–717 Vascular malformations, brain, 531 arteriovenous malformations, 531–573 and cerebral proliferative angiopathy, 574–575 capillary telangiectasia, 584–588 cavernous malformation, 575–584 classification of, 531 developmental venous anomaly (DVA), 589–592 dural arteriovenous fistula (DAVF), 531, 592–610 role of MRI in, 531 Vascular malformations, CNS arterial anomalies azygos anterior cerebral artery, 157–158, 158f, 159f carotid agenesis or hypogenesis, 154, 155f cerebral aneurysm, 158–160, 160f normal arterial development, 154 2253

trigeminal artery and other variants, 154, 156–157, 156f, 157f venous anomalies arteriovenous malformations, 161–162, 163f, 164f cavernous angiomas and, 162–163, 165f developmental venous anomaly (DVA), 163–166, 165f, 166f normal venous development, 160–161, 161f, 162f Vascular metastasis from renal carcinoma, 1249f–1250f Vascular thrombosis, 1068 Vasculitis, 661 infarction with, 661, 661f, 662f Vasoformative lesions arteriovenous malformation (AVM), 1060, 1061f infantile hemangioma, 1056–1057, 1057f, 1058f lymphatic malformations (LM), 1058–1060, 1059f–1060f venous malformation (VM), 1057–1058, 1058f, 1059f venous varix, 1060, 1061f VATER association, 1175 Vein of Galen aneurysmal dilatation (VGAD), 162, 164f Vein of Galen aneurysmal malformation (VGAM), 162, 163f Vein of Galen malformation, 566f–567f Venereal Disease Research Laboratory (VDRL), 935 Venolymphatic malformation, 1058, 1058f–1059f Venous infarction, 637–638 causes of, 638 MR appearance, 670–671, 670t, 672f–674f, 674, 675f, 676 treatment for, 638–639 venous thrombosis and, 638 Venous malformation (VM), 1057–1058, 1058f, 1059f Venous occlusive disease, 1505–1506, 1506f Venous thrombosis, 671, 672f–675f Venous varix, 1060, 1061f Ventricle, terminal, 1144–1145 Ventriculitis, 760–761, 761f, 762f meningitis and, 769 Ventriculomegaly, 1512 Vertebrae bone marrow adjacent to endplate, 1198t formation of, 1169f–1173f (see also Spinal column, embryogenesis of) chondrification, 1172–1173 membrane development, 1169–1170, 1172 ossification, 1173 osteomyelitis, 1197 Vertebral artery, 655 dissection, 716, 1488, 1488f injuries of, 714f, 717, 1329, 1331f, 1332 (see also Spinal cord injury (SCI)) stenosis, 1486–1487 Vertebral artery thrombosis (VAT), 1329, 1331–1332. See also Spinal cord injury (SCI) Vertebral dislocation, congenital, 1176 Vertebral hemangiomas, 1251–1252 cord compression with, 1251 imaging, 1251–1252, 1252f–1253f pathology, 1251 symptoms, 1251 treatment, 1252 Vertebral subtraction osteotomy, 1111 Vestibular schwannomas, 414–416, 414f–416f, 940 cerebellopontine angle and, 414, 415f 2254

with cystic changes, 414, 415f histologic features, 414f intracanalicular, 414, 415f, 416f Vestibular sense organs, 926–927 Vestibulocochlear nerve, enhancement of, 911 Viral infections, 719 encephalitis, 719 enteroviruses, 749, 751, 752f herpesvirus family, 719–730, 720f–725f, 727f–730f human immunodeficiency virus, 730–739, 731f–739f human prion diseases, 747–749, 747t, 748f–751f human T-cell lymphotropic virus type 1 infection, 746–747, 747f imaging for, 719 influenza virus, 754–755, 755f JC polyomavirus, 739–746, 740f–746f, 747t meningoencephalitis, 719 Rasmussen encephalitis, 756–758, 757f, 758f spine, 1454–1459 subacute sclerosing panencephalitis, 755–756, 756f West Nile Virus infection, 751, 752f–753f Zika infection, 751, 754, 755f Viral labyrinthitis, 931 Viral myelitis, 1454, 1455f Virchow-Robin space (VRS), 820, 821f, 822f Virchow–Robin spaces, 665, 671f Vitamin B12 deficiency, 239. See also Subacute combined degeneration (SCD) of spinal cord Vitreal hemorrhage, 1048 VM. See Venous malformation (VM) Von Hippel–Lindau (VHL) disease, 195–199, 1298 angiographic characteristics, 198, 198f classification, 195t diagnostic criteria for, 195t hemangioblastoma in, 195, 196f–197f, 198, 1039 islet cell tumors and, 199 and microcystic adenomas, 199 and pancreatic masses, 199 and renal cell carcinoma, 198–199 Voxel-based morphometry (VBM) for Alzheimer disease, 829–830, 830f in dementia with Lewy bodies, 837 W Walker–Warburg syndrome (WWS), 96, 97, 97f. See also Cobblestone malformation Warburg syndrome, 1040f Watershed infarction, 664 MR appearance, 664–665, 665f WD. See Wilson disease (WD) Wegner’s granulomatosis. See Granulomatosis with polyangitis (GPA) Wernicke encephalopathy (WE), 856–858, 857f alcohol abuse and, 858f etiologies of, 856 neuroimaging and pathology, 857–858, 857f, 858f thiamine deficiency and, 856 West Nile poliomyelitis (WNP), 751 West Nile Virus (WNV) infection, 751, 752f–753f Weston–Hurst disease, 1422, 1422f White matter (WM), 205–206, 205f 2255

White matter disease, 204 classification of, 204–205 dysmyelinating disorders, 205, 205t MRI in, role of, 203, 203f, 204f nutritional and vitamin deficiency and, 236–240 physical/chemical agents and, 240–249 primary demyelinating diseases, 204, 205t secondary demyelinating diseases, 204, 205t viral agents and, 227–236 Whole-body magnets, 9 Wilson disease (WD), 855–856, 856f bright claustral sign, 855 face of the giant panda sign, 855 manifestations, 855 neuroimaging and pathology, 855–856, 856f WISCI (walking index for SCI.), 1346 Wolfram syndrome, 844 X X-linked adrenoleukodystrophy, 258, 259f–260f X-linked lissencephaly, 292 Z Zellweger syndrome (ZS), 258, 260 Zero-padding, 52–53, 52f, 53f Zika virus infection, 751, 754, 755f

2256

Table of Contents Title Page Copyright Dedication Contributing Authors Preface Contents PART I: PRINCIPLES

3 4 5 6 19 21 24

Chapter 1: Instrumentation: Magnets, Coils, and Hardware Chapter 2: From Image Formation to Image Contrast: Understanding Contrast Mechanisms, Acquisition Strategies, and Artifacts Chapter 3: Contrast Agents and Relaxation Effects

PART II: BRAIN AND SKULL BASE

25 55 105

134

Chapter 4: Disorders of Brain Development Chapter 5: Central Nervous System Manifestations of the Phakomatoses Chapter 6: White Matter Diseases and Inherited Metabolic Disorders Chapter 7: Epilepsy Chapter 8: Adult Brain Tumors Chapter 9: Pediatric Brain Tumors Chapter 10: Intracranial Hemorrhage Chapter 11: Intracranial Vascular Malformations and Aneurysms Chapter 12: Cerebral Ischemia and Infarction Chapter 13: Head Trauma Chapter 14: Intracranial Infection Chapter 15: Normal Aging, Dementia, and Neurodegenerative Disease Chapter 16: Skull Base Chapter 17: The Sella Turcica and Parasellar Region Chapter 18: Eye and Orbit

PART III: SPINE AND SPINAL CORD

135 246 289 388 423 578 647 708 824 895 938 1059 1153 1233 1325

1414

Chapter 19: Congenital Anomalies of the Spine and Spinal Cord: Embryology and Malformations Chapter 20: Degenerative Disease of the Spine Chapter 21: Neoplastic Disease of the Spine and Spinal Cord Chapter 22: MRI of Spinal Trauma Chapter 23: Vascular Disorders of the Spine and Spinal Cord Chapter 24: Spinal Infection and Inflammatory Disorders

PART IV: ADVANCED APPLICATIONS

1415 1537 1609 1686 1763 1798

1891

Chapter 25: MR Angiography: Techniques and Clinical Applications Chapter 26: MR of Fetal Brain and Spine Chapter 27: Diffusion and Diffusion Tensor MR Imaging: Fundamentals Chapter 28: Perfusion Magnetic Resonance Imaging Chapter 29: Psychiatric Disorders Chapter 30: MR Spectroscopy and the Biochemical Basis of Neurologic Disease Chapter 31: Functional MRI

Index

1892 1954 1980 2003 2028 2084 2143

2183

2257