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

For more than 25 years, Magnetic Resonance Imaging of the Brain and Spine has been the leading textbook on imaging diagn

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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 e