Neuroradiology: Spectrum and Evolution of Disease [1st Edition] 9780323447256, 9780323447263

Table of contents :
Cover......Page 1
Neuroradiology......Page 2
Copyright Page......Page 4
Dedication......Page 5
Contributors......Page 6
Preface......Page 8
Acknowledgments......Page 9
A Note on Gradient Echo Sequences......Page 10
Suggested Reading......Page 14
Introduction......Page 15
Subdural Hematoma Evolution: Overview......Page 16
Differential Diagnosis......Page 21
Suggested Reading......Page 28
Imaging Appearance......Page 29
Complications......Page 38
Mimics and Differential Diagnosis......Page 39
Suggested Reading......Page 41
Epidemiology, Pathology, and Clinical Presentation......Page 42
Nonhemorrhagic Manifestations of Cerebral Amyloid Angiopathy......Page 43
Risk Factors and Treatment......Page 45
References......Page 50
Differential Diagnosis......Page 52
References......Page 57
Introduction......Page 58
Acute Phase......Page 59
Mimics and Differential Diagnosis......Page 60
Suggested Reading......Page 62
Introduction......Page 63
Temporal Evolution: in Greater Depth......Page 64
Human Herpesvirus 6 Encephalitis......Page 66
References......Page 68
Evolution of Disease......Page 69
Mimics and Differential Diagnosis......Page 70
References......Page 73
Colloidal Vesicular......Page 74
Granular-Nodular Stage......Page 75
Classification According to Location......Page 78
Differential Diagnosis......Page 82
References......Page 93
Introduction......Page 94
Imaging Appearance......Page 95
Multiple Sclerosis......Page 102
Vascular Causes......Page 106
Suggested Reading......Page 110
Autoimmune Encephalitis Subtypes: Overview......Page 111
Limbic Encephalitis......Page 112
BrainStem Encephalitis......Page 113
Differential Diagnosis......Page 116
Conclusion......Page 117
References......Page 118
Progressive Multifocal Leukoencephalopathy Imaging Evolution......Page 119
Differential Diagnosis......Page 120
References......Page 123
Central Nervous System–Immune Reconstitution Inflammatory Syndrome Imaging Spectrum......Page 125
Rare Forms of Central Nervous System–Immune Reconstitution Inflammatory Syndrome......Page 127
Differential Diagnosis......Page 129
References......Page 131
Neurosarcoidosis: In Greater Depth......Page 133
Neuroimaging Evolution: Overview......Page 134
Spine......Page 135
Hydrocephalus......Page 145
Mimics and Differential Diagnosis......Page 149
Summary......Page 150
Suggested Readings......Page 153
Immediate Postoperative Period: Pearls and Pitfalls......Page 154
Local Chemotherapy or Brachytherapy......Page 155
Definition and Epidemiology......Page 157
Imaging Findings......Page 159
Useful Advanced Imaging Techniques and Protocols......Page 160
Optimal Imaging Techniques and Protocols......Page 164
Introduction......Page 165
Summary......Page 167
References......Page 170
Imaging Appearance......Page 171
Conclusion......Page 172
Suggested Reading......Page 175
Evolution: Overview......Page 176
Mimics and Differential Diagnosis......Page 178
References......Page 180
Evolution: Overview......Page 181
Mimics and Differential Diagnosis......Page 182
References......Page 184
Introduction......Page 185
References......Page 190
Evolution: in Greater Depth......Page 191
Mimics and Differential Diagnosis......Page 193
References......Page 199
Computed Tomography......Page 200
Magnetic Resonance Imaging......Page 201
Mimics and Differential Diagnosis......Page 202
Suggested Readings......Page 204
Temporal Evolution: Overview......Page 205
Mimics and Differential Diagnosis......Page 206
Suggested Readings......Page 207
Pathophysiology......Page 208
Treatment and Complications......Page 210
Differential Diagnosis......Page 216
Suggested Reading......Page 218
Interbody Fusion Approaches and Techniques......Page 219
Posterior Lumbar Interbody Fusion......Page 220
Natural Evolution in Depth......Page 221
Computed Tomography Evaluation of Interbody Fusion......Page 222
Differential Diagnosis......Page 224
Suggested Reading......Page 228
Mimics and Differential Diagnosis......Page 229
Suggested Reading......Page 234
Introduction......Page 235
Late Disease (Weeks to Months)......Page 236
Posttreatment and Follow-Up......Page 237
Mimics and Differential Diagnosis......Page 238
Suggested Reading......Page 243
Imaging Evolution: Overview......Page 244
Imaging Evolution: in Greater Depth......Page 246
Mimics and Differential Diagnosis......Page 247
Suggested Reading......Page 248
Evolution: Overview......Page 249
Spectrum: Overview......Page 250
Mimics and Differential Diagnosis......Page 251
References......Page 255
Evolution: in Greater Depth......Page 256
Differential Diagnosis......Page 259
References......Page 260
Introduction......Page 261
Pathophysiology......Page 262
Differential Diagnosis......Page 264
References......Page 265
Vascular Anatomy......Page 267
Clinical Syndromes......Page 268
Evolution: in Greater Depth......Page 270
Differential Diagnosis......Page 272
References......Page 275
Temporal Evolution: Overview......Page 276
Differential Diagnosis......Page 277
Suggested Readings......Page 280
Mimics and Differential Diagnosis......Page 281
Treatment and Temporal Evolution......Page 282
Differential Diagnosis......Page 283
Suggested Reading......Page 293
Evolution: Overview......Page 294
Evolution: in Greater Depth......Page 299
Mimics and Differential Diagnosis......Page 300
Suggested Reading......Page 305
Overview......Page 306
Neutral Position Imaging Findings......Page 307
Natural History of Hirayama Disease......Page 310
Suggested Readings......Page 311
Anatomic Principles of the Spinal Meninges......Page 312
Arachnoid Cysts and Pouches......Page 313
Arachnoid Bands and Webs......Page 315
Natural History and Evolution......Page 316
Epidermoid Cyst......Page 317
Neurocysticercosis......Page 318
Ventral Cord Herniation......Page 319
Suggested Readings......Page 320
Introduction......Page 321
Intraorbital Abscess......Page 322
Dacryoadenitis......Page 323
Intraorbital Abscess......Page 324
Dacryocystitis......Page 326
Suggested Readings......Page 327
Mimics and Differential Diagnosis......Page 328
Suggested Readings......Page 332
Evolution: In Greater Depth......Page 333
Pathogenesis: In Depth......Page 335
Mimics and Differential Diagnosis......Page 337
References......Page 338
Histopathology......Page 339
Thyroid (Riedel Thyroiditis)......Page 340
Orbit......Page 341
Thyroid (Riedel Thyroiditis)......Page 342
Hypertrophic Pachymeningitis......Page 345
Other Head and Neck Manifestations of IgG4-Related Disease......Page 347
References......Page 348
Temporal Evolution: Overview......Page 349
Mimics and Differential Diagnosis......Page 350
Suggested Readings......Page 352
Pars Flaccida......Page 353
Pars Tensa......Page 355
External Auditory Canal......Page 356
Mimics and Differential Diagnosis......Page 358
References......Page 362
Temporal Evolution: Overview......Page 363
Chronic Labyrinthitis......Page 364
Mimics and Differential Diagnosis......Page 368
References......Page 370
Introduction......Page 371
Imaging......Page 372
Glomus Vagale and Carotid Body Tumor Mimics......Page 374
Glomus Jugulare Mimics......Page 377
Suggested Readings......Page 378
Introduction......Page 379
Temporal Evolution: in Greater Depth......Page 381
Craniofacial Resection......Page 382
Mimics and Differential Diagnosis......Page 384
Papilloma......Page 385
Meningioma......Page 386
References......Page 389
Temporal Evolution: Overview......Page 391
Mimics and Differential Diagnosis......Page 395
Suggested Readings......Page 396
Introduction......Page 397
By Location......Page 398
By Phase of Disease......Page 399
Mimics and Differential Diagnosis......Page 401
Suggested Reading......Page 402
Temporal Evolution: Overview......Page 403
Temporal Evolution: in Greater Depth......Page 406
Spine......Page 411
Suggested Reading......Page 416
Introduction......Page 417
Temporal Evolution: Overview......Page 419
Mimics and Differential Diagnosis......Page 422
Suggested Reading......Page 423
B......Page 424
C......Page 425
E......Page 426
H......Page 427
L......Page 428
O......Page 429
R......Page 430
T......Page 431
X......Page 432

Citation preview

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Neuroradiology: Spectrum and Evolution of Disease

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Neuroradiology: Spectrum and Evolution of Disease JUAN E. SMALL, MD, MSc Section Chief, Neuroradiology Lahey Hospital and Medical Center Burlington, Massachusetts

DANIEL L. NOUJAIM, MD Neuroradiologist Department of Radiology Beaumont Hospital Dearborn, Michigan

DANIEL T. GINAT, MD, MS Department of Radiology Pritzker School of Medicine The University of Chicago Chicago, Illinois

HILLARY R. KELLY, MD Radiologist Massachusetts Eye and Ear Infirmary Neuroradiologist Massachusetts General Hospital Assistant Professor of Radiology Harvard Medical School Boston, Massachusetts

PAMELA W. SCHAEFER, MD Associate Director of Neuroradiology Clinical Director of MRI Massachusetts General Hospital Associate Professor of Radiology Harvard University Boston, Massachusetts

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1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899

NEURORADIOLOGY: SPECTRUM AND EVOLUTION OF DISEASE

ISBN: 978-0-323-44549-8

Copyright © 2019 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Control Number: 2018945279

Publisher: Russell Gabbedy Senior Content Development Specialist: Ann Anderson Publishing Services Manager: Catherine Jackson Senior Project Manager: Amanda Mincher Design Direction: Ryan Cook

Printed in China Last digit is the print number: 9 8 7 6 5 4 3 2 1

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To Kirstin, Nathan, and Sean. You are the light, the joy, and the love in my life. —Juan E. Small

I dedicate this book to my wife and three wonderful children for their love and support and also to my father who has inspired my professional curiosity. —Daniel L. Noujaim

To my parents, Roselyne and Jonathan. —Daniel T. Ginat

To my husband and best friend, Jason, and my children, Quinn and Jude, for their endless love, understanding, and happiness. To my colleagues at Massachusetts General Hospital and Massachusetts Eye and Ear. Thank you for the teaching, support, and unwavering commitment to patient care. To the residents and fellows who have taught me more than I could ever teach them. Thank you for challenging me to never stop learning. —Hillary R. Kelly

To Doug and Sarah, who always give me unconditional love, support, and encouragement; and to the residents, fellows, and attendings at MGH, who make me a better neuroradiologist on a daily basis. —Pamela W. Schaefer

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Contributors Sama Alshora, MD

Assistant Professor of Radiology Lahey Hospital and Medical Center Burlington, Massachusetts Assistant Professor of Radiology King Saud University Medical City Riyadh, Saudi Arabia Arwa O. Badeeb, MBBS

Chief Resident, Diagnostic Radiology Lahey Clinic Burlington, Massachusetts Lawrence Bahoura, MD

Oakland University William Beaumont School of Medicine Royal Oak, Michigan Girish Bathla, MBBS, FRCR, DMRD, MMeD

Resident Department of Radiology University of Iowa Hospitals and Clinics Iowa City, Iowa Adam P. Bryant, MD

Resident Department of Radiology University of Iowa Hospitals and Clinics Iowa City, Iowa Paul M. Bunch, MD

Assistant Professor of Radiology Wake Forest School of Medicine Wake Forest Baptist Health Winston-Salem, North Carolina Walter L. Champion, MD

Lahey Hospital and Medical Center Burlington, Massachusetts

Merav Galper, MD

Radiologist Kaiser Permanente Mid-Atlantic Permanente Medical Group (MAPMG) Rockville, Maryland Daniel T. Ginat, MD, MS

Department of Radiology Pritzker School of Medicine The University of Chicago Chicago, Illinois Louis Golden, MD

Neuroradiology Section Stanford University Stanford, California Jason Handwerker, MD

Associate Clinical Professor of Radiology University of California, San Diego San Diego, California Jeffrey A. Hashim, MD

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Dann Martin, MD

Radiology Lahey Hospital and Medical Center Burlington, Massachusetts William A. Mehan Jr., MD

Attending Neuroradiologist Massachusetts General Hospital Boston, Massachusetts

Daniel L. Noujaim, MD

Staff Neurologist Lahey Hospital and Medical Center Burlington, Massachusetts Dean T. Jeffery, MD

Radiology and Diagnostic Imaging University of Alberta Edmonton, Alberta, Canada Hillary R. Kelly, MD

DaeHee Kim, MD

Director, Ophthalmic Plastic Surgery Department of Ophthalmology Massachusetts Eye and Ear Infirmary Associate Professor of Ophthalmology Harvard Medical School Boston, Massachusetts

Pritzker School of Medicine University of Chicago Chicago, Illinois

Doreen T. Ho, MD

Lindsay A.N. Duy, MD

Suzanne K. Freitag, MD

Daniel Lam, MD

Toshio Moritani, MD, PhD

Chief Resident Department of Radiology Lahey Hospital and Medical Center Burlington, Massachusetts Assistant Professor of Radiology Wake Forest Baptist Medical Center Winston-Salem, North Carolina

Assistant Professor of Radiology Tufts University School of Medicine Section Head of Neuroradiology Department of Radiology Lahey Hospital and Medical Center Burlington, Massachusetts

Assistant Professor of Radiology Diagnostic Radiology Lahey Hospital and Medical Center Burlington, Massachusetts

Radiologist Massachusetts Eye and Ear Infirmary Neuroradiologist Massachusetts General Hospital Assistant Professor of Radiology Harvard Medical School Boston, Massachusetts

Pauley Chea, MD

Mara Kunst, MD

Chief Resident Department of Radiology Lahey Hospital and Medical Center Burlington, Massachusetts Philip D. Kousoubris, MD

Neuroradiology Lahey Clinic Burlington, Massachusetts

Clinical Professor of Radiology University of Michigan Medicine Ann Arbor, Michigan Neuroradiologist Department of Radiology Beaumont Hospital Dearborn, Michigan Samir Noujaim, MD

Professor of Radiology Division of Neuroradiology Oakland University William Beaumont School of Medicine Royal Oak, Michigan Omar Parvez, MD

Neuroradiology Clinical and Research Fellow Massachusetts General Hospital Boston, Massachusetts Aaron B. Paul, MD

Staff Neuroradiologist Lahey Hospital and Medical Center Burlington, Massachusetts Victor Hugo Perez Perez, MD

Neurosurgeon UMAE Centro Médico Nacional Mexico City, Mexico Bruno Policeni, MD

Clinical Professor of Radiology University of Iowa Hospital and Clinics Iowa City, Iowa

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Contributors

Otto Rapalino, MD

Instructor in Radiology Harvard Medical School Assistant Radiologist Massachusetts General Hospital Boston, Massachusetts Katherine L. Reinshagen, MD

Instructor in Radiology Harvard Medical School Massachusetts Eye and Ear Boston, Massachusetts Seyed Rezapour, MD

Hospital Medicine/Internal Medicine Lahey Hospital and Medical Center Burlington, Massachusetts Emily Rutan, BS

Department of Radiology Lahey Hospital and Medical Center Burlington, Massachusetts

Juan E. Small, MD, MSc

Section Chief, Neuroradiology Lahey Hospital and Medical Center Burlington, Massachusetts Nathaniel Temin, MD

Radiologist South Shore Radiology Associates South Weymouth, Massachusetts Jaclyn A. Therrien, DO

Department of Diagnostic Radiology Lahey Hospital and Medical Center Burlington, Massachusetts Marie Tominna, DO

Oakland University William Beaumont School of Medicine Royal Oak, Michigan Pankaj Watal, MD

Department of Radiology University of Iowa Hospitals and Clinics Iowa City, Iowa

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Gene M. Weinstein, MD

Clinical Fellow Department of Radiology Massachusetts General Hospital Boston, Massachusetts Yun Sean Xie, MD

Neuroradiologist Department of Radiology Baptist M&S Imaging San Antonio, Texas Fang Frank Yu, MD

Neuroradiology Fellow Massachusetts General Hospital Boston, Massachusetts

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Preface One of the few guarantees in life is that things will change. Disease is dynamic. The human body’s interaction with disease is adaptive. Our management of disease results in alterations. Therefore, it is important to consider that our most utilized imaging modalities take only a snapshot of the current state of a disease process. As such, they provide us with a static depiction of a disease entity. Inevitably, there will be gaps when we base our understanding of

viii

disease on a static visual database. These gaps lead to a partial and inadequate conceptualization of disease. It follows that when a disease presentation varies from what we have seen before, we are naturally confused. Doesn’t it make sense to learn about a disease process not as a static entity with a classic appearance, but instead as a dynamic process which evolves? This book is meant to bridge the gaps.

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Acknowledgments The editors would like to gratefully acknowledge the wonderful team at Elsevier including Robin Carter and Russell Gabbedy (Content Strategists), Ann R. Anderson (Content Development Specialist), Mandy Mincher (Production Manager), and Ryan Cook (Designer) for their help, support, and guidance throughout the making of this book. It has been a privilege and a pleasure to work with you. In addition, we are indebted to the talented team

at Amirsys including Laura C. Wissler, MA, for her beautiful and inspired illustrations, as well as Richard Coombs, MS, and Lane R. Bennion, MS (contributing illustrators). Lastly, the completion of this book would not have been possible without the help of Carol Spencer, the Medical Library Director at Lahey Hospital and Medical Center.

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SECTION I Brain

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Brain Parenchymal Hematoma Evolution Juan E. Small

INTRODUCTION Magnetic resonance imaging (MRI) can differentiate between acute, subacute, and chronic hemorrhage because of its sensitivity and specificity to hemoglobin degradation products. Therefore the imaging interpreter is, with proper knowledge, able to estimate the age of a brain parenchymal hematoma. The blood products in a hematoma evolve through a predictable variation in hemoglobin oxygenation states and hemoglobin byproducts. This predictable pattern of hematoma evolution over time leads to a specific pattern of changing signal intensities on conventional MRI. There are limitations to the accuracy of hematoma age interpretation. Several direct and indirect factors, including the operating field strength of the magnet, the mode of image acquisition, and a wide range of biologic factors particular to the patient, may affect the imaging evolution of a parenchymal hematoma. Despite substantial variability, it is generally accepted that five stages of parenchymal hemorrhage can be distinguished by MRI. A basic understanding of the biochemical evolution of brain parenchymal hemorrhage and magnetic properties that affect MRI signal are essential for interpretation.

TEMPORAL EVOLUTION: OVERVIEW A well-described pathophysiologic process of evolution and resorption for parenchymal hemorrhage involves five distinct phases (Fig. 1.1). With this knowledge, the imaging interpreter can often identify the relative age of a brain parenchymal hematoma based on the T1 and T2 characteristics of the collection. However, it is important to realize that hematoma evolution is a fluid process (without static or punctuated steps). Therefore, stages of hemorrhage commonly coexist within the same hematoma because hemoglobin degradation proceeds at variable rates in the center versus the periphery of a single hematoma cavity. By convention, the most mature form of hemoglobin present defines the stage of hematoma evolution (Fig. 1.2).

TEMPORAL EVOLUTION: IN GREATER DEPTH Extravascular blood in a hemorrhagic collection remains as oxyhemoglobin for 2 to 3 hours. The immediate activation of the clotting cascade begins the process of clot formation. Deoxyhemoglobin begins to form at the periphery of the hematoma. Eventually, the failure of metabolic pathways preventing oxidation of heme iron results in conversion of hemoglobin to methemoglobin. In the hyperacute stage, parenchymal hemorrhage is a liquid almost completely composed of intracellular oxygenated hemoglobin.

Over the course of a few hours, a heterogeneous blood clot forms within the hematoma cavity, composed of red blood cells, platelets, and serum. In the acute phase, intracellular hemoglobin becomes deoxygenated. Vasogenic edema develops in the surrounding brain parenchyma. In the early subacute phase, deoxyhemoglobin is gradually converted to intracellular methemoglobin. Then, in the late subacute phase, lysis of red blood cells leads to the release of methemoglobin into the extracellular space. During this time, the surrounding vasogenic edema slowly begins to decrease and the clot slowly retracts. In the chronic stage, macrophages and glial cells phagocytose the hematoma, leading to intracellular ferritin and hemosiderin. Eventually, the hematoma resolves and leaves a posthemorrhagic cavity with hemosiderin-stained walls. It is critical to realize that Fig. 1.1 represents a simplified version of events designed to aid in memory. As noted previously, hematoma evolution is a fluid process (without static or punctuated steps). Stages of hemorrhage commonly coexist within the same hematoma because hemoglobin degradation proceeds at variable rates in the center versus the periphery of a single hematoma cavity (Figs. 1.3 and 1.4). Of note, chronic posthemorrhagic parenchymal cavities may collapse nearly completely and appear as thin, relatively linear cavities with associated chronic blood products (Fig. 1.5). Other sources of confusion include the presence of superimposed blood products of differing ages (acute or subacute hemorrhage in an area of subacute to chronic blood) or the presence of a hemorrhagic fluid level (Fig. 1.6). The presence of a blood-fluid level is moderately sensitive and highly specific for hemorrhage resulting from an underlying coagulopathy.

A NOTE ON GRADIENT ECHO SEQUENCES Gradient echo (GRE) sequences are extremely sensitive to the paramagnetic and superparamagnetic effects of some hemoglobin breakdown products (deoxyhemoglobin, intracellular methemoglobin, ferritin, and hemosiderin). Hyperacute hemorrhage on GRE demonstrates a hypointense rim (deoxyhemoglobin) surrounding the isointense core (oxyhemoglobin). Acute and early subacute hemorrhage demonstrates diffuse hypointensity (due to deoxyhemoglobin and intracellular methemoglobin respectively). Late subacute hemorrhage demonstrates a hypointense rim (ferritin and/or hemosiderin) surrounding the hyperintense core (extracellular methemoglobin). Large areas of chronic hemorrhage demonstrate a heterogeneous/irregular hypointense rim (due to ferritin and/or hemosiderin) surrounding a posthemorrhagic encephalomalacic cavity. GRE images are not very helpful in estimating the age of small hemorrhagic foci because these appear hypointense throughout.

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2

PART I  Parenchymal Hemorrhage and Trauma

Figure 1.1. Five stages of parenchymal hematoma evolution on magnetic resonance imaging. One can easily remember the T1 and T2 characteristics of an evolving hematoma by memorizing this figure. Start from the center of the figure and move according to the direction of the arrows to remember the signal characteristics of the five distinct phases of hematoma evolution.

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CHAPTER 1  Brain Parenchymal Hematoma Evolution

T1

T2

3

GRE

36 hours

1 month

Figure 1.2. Parenchymal hemorrhage at 36 hours and at 1 month after initial presentation. At 36 hours (acute phase), T2 signal is low and T1 signal remains intermediate consistent with intracellular deoxyhemoglobin. There is diffuse hypointensity on the gradient echo (GRE) image due to the paramagnetic effects of deoxyhemoglobin. At 1 month (end of late subacute phase), central T1 and T2 hyperintensity is consistent with extracellular methemoglobin, while peripheral T1 and T2 low signal is consistent with hemosiderin. The rim is hypointense on the GRE image due to the superparamagnetic effects of hemosiderin. The hematoma is smaller due to retraction.

Figure 1.3. By convention, the most mature form of hemoglobin present defines the stage of hematoma evolution. The five stages of hemorrhage depicted in Fig. 1.1 are seen in the bottom row of Fig. 1.3. Each stage depicts the most mature form of hemoglobin present in the hematoma. They are not meant to imply homogeneity. The top row depicts intermediate stages of hematoma evolution between each step. In the intermediate stages, the most mature form of hemorrhage is seen at the periphery.

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PART I  Parenchymal Hemorrhage and Trauma

T1

T2

GRE

25 days

6 months

Figure 1.4. Parenchymal hemorrhage 25 days and 6 months after initial presentation. At 25 days (between early subacute to late subacute phase), there is a T1 hyperintense rim and central hypointensity consistent with methemoglobin surrounding deoxyhemoglobin. T2 signal intensity has evolved more rapidly, with near complete T2 hyperintensity, consistent with extracellular methemoglobin throughout the hematoma. At 6 months (between late subacute and chronic phases), hypointensity surrounds the encephalomalacic collapsing cavity on both T1 and T2 images consistent with hemosiderin as the most mature form of hemoglobin. The hematoma is much smaller due to retraction.

GRE

A

T2

B

T1 C+

C

CT

D

Figure 1.5. Chronic collapsed posthemorrhagic cavity. Axial magnetic resonance images (A–C) and computed tomography (CT) image (D) of the brain demonstrate hemosiderin within a thin collapsed T2 and T1 hypointense posthemorrhagic cavity barely visible on the CT image. GRE, Gradient echo.

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CHAPTER 1  Brain Parenchymal Hematoma Evolution

5

1

A

D

B

C

E

F

Figure 1.6. Sources of confusion—superimposed blood products of differing ages and hemorrhagic fluid levels. A patient on anticoagulation with a prior left frontal parenchymal hematoma and known subacute left frontal hemorrhagic cavity presents after an acute exacerbation. Coronal (A) and axial (B and C) computed tomography images at the time of the acute exacerbation demonstrate a hypodense left frontal hemorrhagic cavity with peripheral areas of hyperdense acute hemorrhage (arrows). There are also foci of acute subarachnoid hemorrhage (arrowheads). Axial T2 (D), axial T1 (E), and axial gradient echo (F) magnetic resonance imaging (MRI) images of the brain performed on the same day demonstrate a hemorrhagic fluid level within the subacute hemorrhagic cavity. Without the presence of an appropriate history, and considering the presence of multiple confounding factors, it would be difficult to predict the age of this hemorrhage based on the MRI signal characteristics alone.

SUGGESTED READING

Allkemper T, Tombach B, Schwindt W, et al. Acute and subacute intracerebral hemorrhages: comparison of MR imaging at 1.5 and 3.0 T–initial experience. Radiology. 2004;232(3):874–881. Aygun N, Masaryk TJ. Diagnostic imaging for intracerebral hemorrhage. Neurosurg Clin N Am. 2002;13(3):313–334, vi. Gomori JM, Grossman RI. Mechanisms responsible for the MR appearance and evolution of intracranial hemorrhage. Radiographics. 1988;8(3):427–440.

Kidwell CS, Wintermark M. Imaging of intracranial haemorrhage. Lancet Neurol. 2008;7(3):256–267. Parizel PM, Makkat S, Van Miert E, et al. Intracranial hemorrhage: principles of CT and MRI interpretation. Eur Radiol. 2001;11(9):1770–1783. Pfleger MJ, Hardee EP, Contant CF Jr, et al. Sensitivity and specificity of fluid-blood levels for coagulopathy in acute intracerebral hematomas. AJNR Am J Neuroradiol. 1994;15(2):217–223.

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Subdural Hemorrhage and Posttraumatic Hygroma Lindsay A.N. Duy, Juan E. Small

INTRODUCTION The accurate age determination of a subdural hemorrhage is one of the most common and basic assessments in the setting of head trauma. On computed tomography (CT), the classic descriptions of blood products within the subdural space relate to density changes which evolve over time. These changes reflect the evolution from acute blood to clot formation, clot retraction, clot lysis, and eventual resorption. Based on the density of the subdural collection, subdural hematomas (SDHs) are classically

subdivided into acute, subacute, and chronic SDHs. Although the process of estimation is generally straightforward in everyday clinical practice, several variations must be taken into account to avoid confusion. This confusion may be ameliorated by focusing first on the relevant anatomy and then on the different types of subdural collections, including both SDHs and subdural hygromas. An SDH is a typically crescent shaped extraaxial collection of blood within the innermost layer of the dura, designated the dural border cell layer (Fig. 2.1).

Bone Periosteal dura

Meningeal dura

Border cells Arachnoid barrier

Subarachnoid space Pia mater Brain

Figure 2.1. A subdural hematoma is a crescent-shaped extraaxial collection of blood within the innermost layer of the dura, as depicted in red at the bottom of the illustration. A magnified view of the meningeal layers between the inner table of the skull and the cerebral cortex is presented in the top of the illustration. The dura consists of several different layers of adherent cells. The innermost layer is the dural border cell layer. It is within this layer that subdural hematomas form.

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CHAPTER 2  Subdural Hemorrhage and Posttraumatic Hygroma

7

2 MV

MA

PA SS BV

DP

Figure 2.2. Dural vasculature. Both dural arteries and veins exist along the superior and inferior aspects of the dura. Although superficial meningeal arteries (MA) and veins (MV) are superficially located, a rich dural venous plexus (DP) likely involved in cerebrospinal fluid resorption is located within the inner portion of the dura. This dural plexus is most dense parasagittally. BV, Bridging vein; PA, penetrating arteriole extending to inner dural plexus; SS, superior sagittal sinus. (Modified from Mack J, Squier W, Eastman JT. Anatomy and development of the meninges: implications for subdural collections and CSF circulation. Pediatr Radiol. 2009;39:200–210.)

The fact that SDHs form within the innermost layer of the dura is of crucial importance for a conceptual understanding of the different types of subdural collections. This is because there is a rich venous plexus within this layer (Fig. 2.2). The small caliber of these vascular structures is beyond the resolution of our current imaging. Although there is still much that is unknown about its function, this venous plexus is thought to play a role in cerebrospinal fluid (CSF) resorption into the venous system.

SUBDURAL HEMATOMA EVOLUTION: OVERVIEW At its most basic, there are two types of traumatic subdural collections: SDH and subdural hygroma. An acute SDH represents acute blood products with or without clot formation. On CT imaging, an acute SDH often presents as a hyperdense subdural collection (Fig. 2.3). A subdural hygroma is the accumulation of clear or xanthochromic CSF within the subdural space. An acute subdural hygroma results from the acute accumulation of CSF within the dural border cell layer. This can result from an acute tear in both the arachnoid and the dural border cell layer, resulting in communication of these two spaces. Alternatively, this can also result from the acute impairment of CSF resorption (as often seen in the setting of subarachnoid hemorrhage), affecting the intradural venous plexus along the inner layer of the dura. On CT imaging, an acute subdural hygroma exists when a CSF isodense or nearly isodense subdural collection accumulates acutely (Fig. 2.4). Of course, the presence of a subdural hygroma and an SDH is not mutually exclusive. Varying degrees and combinations of clotted blood, unclotted blood, bloody CSF, and clear CSF can therefore be present within an acute subdural collection (Fig. 2.5). These varying degrees and combinations of clot, blood, and bloody CSF are what lead to the marked heterogeneity of patient imaging presentations (Fig. 2.6). The variable concentrations of either blood or CSF within a specific area of the acute subdural collection lead to different fluid properties and therefore different fluid behavior as time elapses. In

Figure 2.3. Acute subdural hematoma. A coronal image, performed after an acute fall several hours prior, demonstrates left tentorial, parafalcine, and right hemispheric hyperdense acute subdural hematomas (red arrows).

other words, many portions of these subdural collections are not simply “blood” or “hematoma.” It should be now readily apparent why the imaging characteristics of these collections generally do not conform to the magnetic resonance imaging (MRI) stages of hematoma evolution so firmly established for parenchymal hematomas (Fig. 2.7). Both SDHs and subdural hygromas can be either acute or chronic. SDHs are classified into acute, subacute, or chronic categories, depending on the amount of time elapsed since the time of injury. As previously noted, this determination is classically based on the density of the collection. At its most basic, the CT density of a simple SDH depends on the time interval between the bleeding episode and imaging (Fig. 2.8). Unfortunately, no uniformity exists as to the terminology and determination of these categories. For instance, categorization of an acute SDH may be considered for a collection less than a week old, the subacute category reserved for collections ranging in age from 1 to 3 weeks, and the chronic category reserved for a collection older than 3 weeks. A prerequisite for dating by this method is knowledge of the exact time of onset, which is frequently absent in routine clinical practice. Alternatively, acute SDH may be defined by blood products that are still clotted, subacute SDH reserved for collections in which the clot has lysed (generally 2 days to several days), and chronic SDH for collections older than 3 weeks. This method also leads to difficulties because the degree of clot formation can vary markedly, based on our previous discussion. Lastly, various patterns of subdural hemorrhage may be seen other than simply a collection of uniform density (Fig. 2.9). Perhaps the most important differentiating feature between acute and chronic SDHs is the formation of neomembranes encapsulating the hemorrhage. Intracranial reparative processes begin immediately after the acute separation of the dural border cell layer and formation of an SDH. There is proliferation of the dural border cell layer shortly after injury, fibroblast appearance within a day, formation of an outer membrane within a week, and formation of an inner membrane in approximately 3 weeks (Fig. 2.10).

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Presentation

A

1 day

B

1 month

C

Figure 2.4. Acute subdural hygroma. Axial computed tomography image conducted shortly after a motor vehicle accident (A) demonstrates hyperdense subarachnoid hemorrhage within the right sylvian fissure (white arrow). One day later (B), a hypodense collection consistent with an acute subdural hygroma is seen overlying the right frontal lobe (gray arrow). Complete resolution of the collection is evident 1 month later (C).

DURA

CLOT

BRAIN

Figure 2.5. Intraoperative photograph of craniotomy for evacuation of an acute subdural hematoma. Notice the large semisolid heterogeneous dark-red subdural blood clot (white arrow) between the overlying folded dura and the underlying brain. The semisolid gelatinous consistency of the acute subdural clot differs from that of the viscous fluid of the unclotted acute blood (black arrow) and from that of the less viscous bloody cerebrospinal fluid evident at the edge of the picture (gray arrow). (Courtesy Dr. Kavian Shahi.)

Figure 2.6. Axial noncontrast computed tomography image of acute subdural collections. Notice the space-occupying, masslike subdural blood clot (white arrow). The morphology and density of the clot differs from that of the more fluid-like morphology of acute only partially clotted hyperdense blood (black arrows) and even that of the bloody cerebrospinal fluid (CSF) (gray arrow). Notice the bloody CSF is intermediate in density between the hyperdense blood products and the fluid density CSF evident anteriorly between the hemispheres.

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A

B

C

D

Figure 2.7. Variable concentrations of blood and cerebrospinal fluid (CSF) in a subdural collection lead to differentiating imaging features of subdural hematoma and subdural CSF. Axial noncontrast computed tomography (CT) image of the brain (A) demonstrates right hemispheric and parafalcine subdural collections (orange arrows). Comparing coronal noncontrast CT (B) to coronal post contrast T1 (C) and coronal T2 magnetic resonance (D) images of the brain demonstrates to better advantage the differences between various portions of the right hemispheric subdural collection. In particular, on the coronal T2 image, the differences between the normal left-sided subarachnoid space (blue arrow), right-sided subdural hematoma (red arrow), right-sided subdural clot (orange arrow), and subdural CSF (yellow arrow) are readily evident.

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Presentation

2.5 weeks

A

B

4 weeks

C

Figure 2.8. Classic descriptions of acute, subacute, and chronic subdural hematoma density. A left tentorial hyperdense subdural hematoma is evident on an axial computed tomography image a few hours after head trauma (A, white arrow). At 2.5 weeks, heterogeneously isodense blood products are evident (B, white arrow). By 4 weeks, the hematoma is entirely hypodense as compared with the brain parenchyma (C, white arrow).

Homogeneous

A

Heterogeneous

B

Layering

C

Figure 2.9. Different patterns of subdural density may be seen. An acute homogeneously hyperdense subdural hematoma (A, arrow) easily lends itself to a word description of its density. Other patterns of hemorrhage, including heterogeneous (B, arrow) and layering (C, arrow) collections, do not as easily conform to simply hyperdense, isodense, or hypodense categories. Estimating age based on density is therefore more challenging for complex collections.

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OM CSDH DURA

OM

DURA

A

B

IM IM IM BRAIN

C

D

Figure 2.10. Neomembranes encapsulate a chronic subdural hematoma. Operative photographs during craniotomy for chronic subdural hematoma evacuation demonstrate an outer membrane (OM) immediately under the reflected dura (A). After partial removal of the OM, the chronic subdural hematoma (CSDH) can be seen as heterogeneous old blood products (B). After removal of the chronic blood products, the inner membrane (IM) is evident (C). Only after incision of the IM can the brain be seen (D). (Courtesy Dr. Khalid Al-Kharazi.)

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Outer membrane

Chronic subdural hematoma

Inner membrane

Figure 2.11. Chronic subdural hematoma neomembrane neovascularization. Chronic subdural blood products are encapsulated within thick outer and thin inner neomembranes (blue area). Neovascularization (serpigionus red channels) predominantly involving the outer membrane accompanies neomembrane formation.

Neovascularization accompanies the formation of neomembranes and predominantly involves the outer membrane. Recurrent bleeding from these fragile vessels leads to acute on chronic hematoma expansion (Fig. 2.11). As the neomembrane matures in the context of multiple rebleeding episodes, various layers and septations may form (Fig. 2.12). Initially, the neomembranes are thin, although they occasionally may become quite thick over time or even calcify (Fig. 2.13). The risk of rebleeding diminishes markedly with a longstanding chronic subdural collection with this advanced degree of organization. In summary, multiple patterns of SDH may be encountered by the imaging interpreter. The patterns range from acute (acute SDH and acute subdural hygroma), to subacute (subacute SDH with resolving clot, as well as subacute subdural hygroma with xanthochromic CSF), to chronic (chronic SDH with or without septations) collections (Fig. 2.14).

SUBDURAL HEMATOMA EVOLUTION: IN GREATER DEPTH After one is equipped with the previously mentioned knowledge, the variations in the natural history of subdural collections are easier

to interpret. As noted previously, the variable concentrations of blood and/or CSF within a specific area of the acute hematoma lead to different fluid properties and therefore different fluid behavior over time (Fig. 2.15). In addition, the knowledge of the friable nature of the neovascularity along the outer neomembrane of a chronic SDH enables the imaging interpreter to more accurately identify the presence of an acute on chronic or subacute on chronic SDH (Fig. 2.16).

DIFFERENTIAL DIAGNOSIS Subdural hemorrhagic and CSF collections are common and therefore by far the most reasonable diagnostic consideration of an enlarged extraaxial space. However, other more rare diagnostic considerations mimicking an SDH should at times be entertained. These include prominent dural thickening which may appear alone as a hypodense extraaxial structure on CT (Fig. 2.17) or in combination with subdural hemorrhage (Fig. 2.18) and usually due to intracranial hypotension, subdural empyema (Fig. 2.19), and impaired CSF resorption related to metastatic disease (Fig. 2.20).

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A

B

C

D

E

F

Figure 2.12. Multiple patterns of septations may be seen within chronic subdural hematomas. (A–C) Schematics and (D–F) cases. A relatively simple chronic subdural hematoma has only inner and outer membranes (A). However, radial septation (B) and/or concentric septation (C) patterns can be encountered. Case D demonstrates a simple, homogeneous, chronic hypodense right-sided subdural collection with a single membrane delineating its inner border. Case E demonstrates a complex right hemispheric subdural collection with concurrent presence of concentric (green arrows) and radial septations (blue arrow). Case F demonstrates an acute on chronic right hemispheric subdural hemorrhage collection with clear delineation of a concentric septation (green arrows). ([A–C], Modified from Abecassis IJ, Kim LJ. Craniotomy for treatment of chronic subdural hematoma. Neurosurg Clin N Am. 2017;28[2]:229-237.)

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DURA OM

IM

A

CSDH

B

Figure 2.13. Craniotomy for resection of a chronic subdural hematoma (CSDH) with thick membranes. Directly underlying the dura, an operative photograph (A) demonstrates chronic blood clot (CSDH) enveloped by thick outer (OM) and inner membranes (IM). A photograph of the specimen resected en bloc (B) further demonstrates the marked thickness of the membranes. (Courtesy Dr. Victor Hugo Perez-Perez.)

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Figure 2.14. Multiple patterns of subdural collections may be encountered on imaging. (Modified from Lee K-S. History of chronic subdural hematoma. Korean J Neurotrauma. 2015;11[2]:27–34.)

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6 hours

A

12 hours

B

1 day

C

D

1 week

2 weeks

E

F

Figure 2.15. Serial axial computed tomography images performed on the same patient in Fig. 2.6 at presentation (A), 6-hour (B), 12-hour (C), 1-day (D), 1-week (E), and 2-week (F) intervals demonstrate different evolution patterns for different areas of variable blood and cerebrospinal fluid (CSF) concentrations within a subdural collection. The changes in morphology and density over time differ for the subdural blood clot (white arrow), the partially clotted acute hyperdense blood (black arrows), and the bloody CSF (gray arrow). Presentation

Figure 2.16. Natural history of acute/subacute on chronic subdural hematoma. Axial and coronal CT images of the brain conducted at presentation (A1–A3), 12 hours (B1–B2), 1 month (C1–C2), 2 12 months (D1–D2), and 3 months (E1–E2) demonstrate enlarging subdural collections. At presentation, small bilateral hyperdense subdural hematomas are evident overlying the frontal lobes (red arrows). Periodic interval increases in size are noted associated with different bouts of acute/subacute on chronic subdural hemorrhage evident at 1 month (green arrows), 2 12 months (orange arrows), and 3 months (yellow arrows).

A1

12 hours

1 month

2 ½ months

3 months

A2

B1

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D1

E1

A3

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C2

D2

E2

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Axial CT

A

Axial T1

C Coronal CT

B

Axial T1 C+

E Coronal T2

D

Coronal T1 C+

F

Figure 2.17. Dural thickening in a patient presenting with postural headaches. Axial computed tomography (CT) (A) and coronal CT (B) images demonstrate bilateral hemispheric extraaxial hypodensities (yellow arrows) mimicking subdural collections in a patient with a ventricular catheter in place (blue arrow). On axial T1 (C) and coronal T2 (D) images the bilateral extraaxial CT finding correlates with T1 hypointensity and T2 hyperintensity, again mimicking subdural collections (yellow arrows). However, this finding correlates with marked dural thickening and enhancement on postcontrast axial T1 (E) and coronal T1 (F) images, due to chronic intracranial hypotension. When a ventricular catheter is in place, dural thickening related to chronic overshunting should be considered.

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PART I  Parenchymal Hemorrhage and Trauma

Axial CT

A

Axial T1

C

Axial T1 C+

D

Coronal CT

B

Coronal T1 C+

E

Figure 2.18. Although generally benign, intracranial hypotension may be complicated by superimposed subdural hematomas. Computed tomography (CT) and magnetic resonance imaging images were obtained in a female presenting with a history of orthostatic headaches. A hyperdense acute subdural hematoma is evident on axial CT (A) and coronal CT (B) images (red oval). In addition, hypodense extraaxial spaces are noted overlying the bilateral hemispheres (red arrows). On axial T1 (C), the focal acute hematoma (red oval) is hyperintense. The more diffuse extraaxial collections (red arrows) are mildly hyperintense compared with cerebrospinal fluid, suggesting subacute to chronic subdural hematomas. On axial T1 postcontrast (D) and coronal T1 postcontrast (E) images, there is smooth dural thickening and enhancement consistent with intracranial hypotension (green arrows). The adjacent subacute to chronic subdural (orange arrows) and more acute subdural collection (red oval) do not enhance.

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1 am

8 pm

11:30 pm

2 days

4 days

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6 days

A1

B1

C1

D1

E1

F1

A2

B2

C2

D2

E2

F2

Figure 2.19. Subdural empyema. Elderly male with chronic nonhealing scalp ulcer presenting with shaking chills and confusion. A left-sided subdural collection (yellow arrows) is evident underlying an area of calvarial outer cortex irregular erosion (red arrows) at the site of the patient’s nonhealing scalp ulcer. Gradual enlargement of the subdural collection is evident over the course of 4 days (A1/A2, B1/B2, C1/C2, D1/D2, and E1/E2). A craniotomy was performed (F1/F2, green arrow) with evacuation of thick pus. Although the subdural collection is similar in appearance to a subdural hematoma, the different clinical context and presence of cortical erosion should point to subdural empyema. When present, the identification of abscess or parenchymal infection may be helpful differentiating imaging clues. Of note, notice in Fig. 2.1 at the beginning of this chapter how emissary veins drain both scalp and calvarium. It is via this route that infection can “skip” into the intracranial compartment without full-thickness skull involvement.

B

C

D

A Figure 2.20. Cranial metastasis with associated subdural hygroma. Positron emission tomography/computed tomography (A) demonstrates extensive metastatic disease. A right parietal subdural hygroma (orange arrows) underlying heterogeneous right parietal calvarial metastases on axial T2 (B), T1 (C), and T1 postcontrast (D) images (blue arrows). Presumably, neoplastic involvement of calvarial emissary veins and subsequent impaired cerebrospinal fluid resorption led to subdural hygroma formation.

SUGGESTED READING

Carroll JJ, Lavine SD, Meyers PM. Imaging of subdural hematomas. Neurosurg Clin N Am. 2017;28(2):179–203. Lee K-S. History of chronic subdural hematoma. Korean J Neurotrauma. 2015;11(2):27–34. Lee K-S, Bae W-K, Bae H-G, et al. The computed tomgraphic attenuation and the age of subdural hematomas. J Korean Med Sci. 1997;12:353–359. Web. Park H-R, Lee K-S, Shim J-J, et al. Multiple densities of the chronic subdural hematoma in CT scans. J Korean Neurosurg Soc. 2013;54(1):38. Print. Park S-H, Kang D-H, Park J, et al. Fibrinogen and D-dimer analysis of chronic subdural hematomas and computed tomography findings: a prospective study. Clin Neurol Neurosurg. 2011;113(4):272–276. Print. Reed D, Robertson WD, Graeb DA, et al. Acute subdural hematomas: atypical CT findings. AJNR Am J Neuroradiol. 1986;7(3):417–421. Print.

Scotti G, Terbrugge K, Melançon D, et al. Evaluation of the age of subdural hematomas by computerized tomography. J Neurosurg. 1977;47(3): 311–315. Print. Smith WP, Batnitzky S, Rengachary SS. Acute isodense subdural hematomas: a problem in anemic patients. AJR Am J Roentgenol. 1981;136(3):543–546. Print. Subramanian SK, Roszler MH, Gaudy B, et al. Significance of computed tomography mixed density in traumatic extra-axial hemorrhage. Neurol Res. 2002;24(2):125–128. Print. Tan S, Aronowitz P. Hematocrit effect in bilateral subdural hematomas. J Gen Intern Med. 2013;28(2):321. Print. Tanaka Y, Ohno K. Chronic subdural hematoma–an up-to-date concept. J Med Dent Sci. 2013;60:55–61. Web. Vezina G. Assessment of the nature and age of subdural collections in nonaccidental head injury with CT and MRI. Pediatr Radiol. 2009;39 (6):586–590. Yang W, Huang J. Chronic subdural hematoma: epidemiology and natural history. Neurosurg Clin N Am. 2017;28(2):205–210.

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Posterior Reversible Encephalopathy Syndrome Girish Bathla, Bruno Policeni

INTRODUCTION Posterior reversible encephalopathy syndrome (PRES) refers to a potentially reversible neurotoxic state occurring in association with vasogenic cerebral edema. Although the reported age range varies between 4 and 90 years, most affected patients are in their fourth or fifth decade of life. There is a female predominance, partly attributed to the underlying etiology. Clinically, PRES can present with a constellation of symptoms, with altered mental status (50%–80%) and seizures (60%–75%) being the most common, followed by headaches and visual disturbances. Occasionally, patients present with focal neurologic deficits, sensorimotor symptoms, or status epilepticus. These symptoms usually develop over several hours to a few days and are gradually progressive. PRES occurs more commonly in patients with eclampsia, organ transplantation, or hypertension. The association is perhaps strongest with eclampsia, with some authors reporting neuroimaging findings of PRES in up to 98% of these patients. Within the organ transplantation subgroup, the incidence is higher with myeloablative regimens and allogenic bone marrow transplants (7%–9%) when compared with patients receiving solid organ transplants (0.4%–6%). PRES can also accompany organ rejection or infection. Another common association is hypertension, which is seen in approximately 75% of patients and is usually moderate to severe (hypertensive encephalopathy). Other reported associations include sepsis, other infections, connective tissue disorders, autoimmune disorders, and chemotherapeutic agents such as cyclosporine, tacrolimus, and cisplatin.

EVOLUTION: OVERVIEW The pathogenesis of PRES remains controversial. The more widely accepted theory postulates failure of cerebral autoregulation in the setting of rapidly increasing blood pressure. Subsequent hyperperfusion and breakdown of the blood-brain barrier result in extravascular displacement of macromolecules and plasma and the appearance of vasogenic edema on neuroimaging. Because the posteriorly located regions within the brain have poor sympathetic innervation, they are more severely affected. The theory is supported by the frequent coexistence of hypertension in PRES. In addition, lowering of blood pressure results in both clinical and radiologic improvement. However, the theory fails to explain both the absence of underlying hypertension in up to 20% to 30% of patients and lack of positive correlation between cerebral edema and severity of hypertension. In fact, patients with more severe hypertension often have less vasogenic edema and arterial spasm. In addition, perfusion studies in patients with PRES demonstrate reduced cerebral blood volumes implying hypoperfusion, contrary to the theory that suggests hyperperfusion. Some authors therefore believe that PRES results from cerebral autoregulatory vasoconstriction precipitated by endothelial dysfunction from systemic conditions (Fig. 3.1). Subsequent hypoperfusion occurs and results in involvement of watershed territories on neuroimaging. The hypertension is felt to represent a compensatory reaction to reduced brain perfusion. This theory postulates upregulation of cytokines (tumor necrosis factor-α, interleukin-1, and interferon-γ), resulting in endothelial dysfunction, vasculopathy,

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and increased vascular permeability. These cytokines may provide a common pathway in various systemic conditions such as eclampsia, sepsis, other infections, autoimmune disorders, and organ transplant patients while also explaining the frequent association of these entities with PRES.

IMAGING APPEARANCE PRES most frequently appears as symmetric areas of parenchymal vasogenic edema that evolve over a period of days to weeks, becoming more prominent before eventually resolving in most cases (Fig. 3.2). Cortical and subcortical white matter involvement most frequently affects the occipital and parietal regions (98%), followed by the frontal lobe (68%), inferior temporal region (40%), and cerebellum (32%) (Fig. 3.3). Involvement of the deep white matter, basal ganglia, thalami, brainstem, and splenium is less common but occurs in approximately 10% to 20% of cases. Atypical patterns of involvement, with lesions predominantly localized to the brainstem (Fig. 3.4), posterior fossa (Fig. 3.5), or basal ganglia (Fig. 3.6), occasionally occur. In addition, involvement can be asymmetric and rarely even unilateral (Fig. 3.7). The varying distribution of parenchymal involvement can be broadly divided into four patterns, each seen in approximately 20% to 30% of cases. Patients with a holohemispheric border zone pattern typically show bilateral symmetric edema in the anterior cerebral artery–middle cerebral artery (ACA-MCA) and posterior cerebral artery–middle cerebral artery (PCA-MCA) territory border zones (Fig. 3.8). In the superior frontal sulcus border zone pattern, there is distinct frontal lobe involvement predominantly along the mid to posterior aspect of the superior frontal sulcus. In contrast to the holohemispheric pattern, the frontal pole is usually spared (Fig. 3.9). The parietal-occipital pattern manifests on imaging with predominant involvement of the parietal and occipital lobes along with variable temporal lobe involvement (Fig. 3.10). The partial or asymmetric expression pattern refers to cases that show incomplete or variable expression of the three primary patterns (Fig. 3.11). However, interestingly, the various patterns do not correlate with the presentations, clinical associations, or the course of the disease. Computed tomography (CT) may be normal (22%) or show nonspecific findings (33%). However, bilateral parenchymal hypodensities suggesting vasogenic edema secondary to PRES may be seen in up to 45% of cases (Fig. 3.12). On magnetic resonance imaging (MRI), involved regions manifest as areas of T1 and T2 prolongation. PRES lesions are most commonly characterized by facilitated diffusion due to vasogenic edema, with elevated signal on apparent diffusion coefficient (ADC) maps and variable signal on diffusion-weighted imaging (DWI) images because they have both diffusion and T2 weighting. PRES lesions can also have foci of restricted diffusion due to cytotoxic edema with low signal on ADC maps and increased signal on DWI images. In addition, because PRES can often present with seizures, patients may show coexisting postictal changes (Fig. 3.13). Gyriform contrast enhancement, implying breakdown of the blood-brain barrier, occurs in approximately 20% to 40% of cases (Fig. 3.14). The presence or absence of enhancement does not

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Figure 3.1. Posterior reversible encephalopathy syndrome pathophysiology illustration.

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PART II  Disorders of Cerebral Vascular Autoregulation

A

C

B

Figure 3.2. (A–C) Axial FLAIR images at the level of midbrain on days 1, 7, and 14 (A, B, and C, respectively) demonstrate patchy hyperintense regions in the bilateral posterior temporal and occipital subcortical white matter and overlying cortex (A) that are less prominent on follow-up imaging at 1 week (B) and show complete resolution at 2 weeks (C).

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Figure 3.3. Axial illustrations of the brain depict differential parenchymal involvement, which is most frequent in the occipital and parietal regions, followed by the frontal lobe, inferior temporal region, cerebellum, deep gray nuclei, and brainstem.

A

B

Figure 3.4. (A and B) Atypical posterior reversible encephalopathy syndrome. Axial T2-weighted image (A) and coronal FLAIR (B) images demonstrate confluent edema predominantly involving the brainstem with only minimal involvement of the periventricular white matter and left mesial temporal lobe.

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B

C

Figure 3.5. (A–C) Atypical posterior reversible encephalopathy syndrome (PRES). An axial FLAIR (A) image demonstrates edema in the left greater than right cerebellar hemispheres. A fat-saturated, gadolinium-enhanced T1-weighted (B) image at the same level reveals scattered punctate-enhancing foci. More cranially, an axial FLAIR image (C) demonstrates edema in the bilateral posterior temporal and occipital lobes commonly seen in PRES.

A

B

Figure 3.6. (A and B) Atypical posterior reversible encephalopathy syndrome. Axial FLAIR images demonstrate foci of edema involving the bilateral basal ganglia and deep white matter (A) as well as the bilateral paramedian frontal and parietal lobes (B). (Images courtesy Dr. Achint K. Singh, University of Texas Health Science Center, San Antonio, TX.)

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A

B

Figure 3.7. (A and B) Unilateral posterior reversible encephalopathy syndrome (PRES). Axial FLAIR images at the level of centrum semiovale (A) and midbrain (B) demonstrate patchy edema in the left frontal, parietal, posterior temporal, and occipital lobes in a patient with unilateral PRES.

A

C

B

Figure 3.8. (A–C) Holohemispheric posterior reversible encephalopathy syndrome. Coronal FLAIR images reveal presence of relatively symmetric edema in the anterior cerebral artery–middle cerebral artery (A and B) and posterior cerebral artery–middle cerebral artery (C) border zones. There is also edema in the cerebellar white matter and the bilateral mesial temporal lobes.

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A

B

Figure 3.9. (A and B) Superior frontal sulcus posterior reversible encephalopathy syndrome pattern. Axial FLAIR images reveal extensive relatively symmetric edema centered in the anterior cerebral artery–middle cerebral artery (A) and posterior cerebral artery–middle cerebral artery (B) border zones, with edema adjacent to the superior frontal sulci (A). More inferiorly, the involvement is predominantly posterior with sparing of the frontal poles (B). (Images courtesy Dr. Achint K. Singh, University of Texas Health Science Center, San Antonio, TX.)

A

B

Figure 3.10. (A and B) Dominant parieto-occipital posterior reversible encephalopathy syndrome pattern. Axial FLAIR images demonstrate extensive symmetric edema involving the bilateral parietal and occipital lobes. There is minimal involvement of the bilateral frontal lobes.

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Figure 3.11. (A and B) Partial expression posterior reversible encephalopathy syndrome. Axial FLAIR images reveal relatively symmetric edema involving the bilateral occipital lobes with sparing of the parietal lobes.

A

B

Figure 3.12. (A and B) Axial computed tomography images reveal relatively symmetric hypodensity in the bilateral parietal lobes in a patient with posterior reversible encephalopathy syndrome.

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A

C

B

D Figure 3.13. (A–D) Axial FLAIR (A and B) and DW (C and D) images in a patient with posterior reversible encephalopathy syndrome (PRES) who presented with seizures. Images A and C were obtained on day 1 and images B and D on day 4 of hospital admission. Images from the day of admission reveal symmetric regions of T2 prolongation in the bilateral occipital lobes, consistent with PRES. There is associated FLAIR hyperintensity (A) and restricted diffusion (C) involving the right thalamic pulvinar, consistent with coexisting postictal changes. Images from day 4 reveal partial resolution of the signal abnormalities involving the right thalamic pulvinar. Signal abnormalities involving the bilateral occipital lobes are slightly less prominent.

A

B

Figure 3.14. (A and B) Axial post contrast images reveal patchy gyriform enhancement and white matter hypodensity in the bilateral parietal lobes, corresponding to regions of T2 signal abnormality (not shown).

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A

B

Figure 3.15. (A and B) Conventional angiogram images following injection of the right internal carotid (A) and vertebral (B) arteries in a patient with posterior reversible encephalopathy syndrome. There is multifocal narrowing and irregularity of the distal anterior cerebral artery and middle cerebral artery branches (A), as well as of the basilar artery and distal posterior cerebral artery (PCA) branches. In addition, there is reduced parenchymal blush in the PCA territories compared with the posterior inferior cerebral artery territory.

A

B

Figure 3.16. Hemorrhagic PRES. (A and B) Axial noncontrast computed tomography image (A) in a patient with posterior reversible encephalopathy syndrome reveals focal intraparenchymal hemorrhage in the right posterior temporal occipital region, surrounded by vasogenic edema. Axial T2-weighted image at the same level (B) more clearly demonstrates edema in the bilateral posterior temporal occipital regions and basal ganglia. (Images courtesy Dr. Amit Agarwal, Penn State University College of Medicine, Hershey, PA.)

correlate with the overall extent of fluid-attenuated inversion recovery (FLAIR) abnormality, and it is unclear if enhancement portends poor outcome. Catheter, CT, or MR angiography may reveal vessel irregularity with focal areas of vasoconstriction and vasodilatation, resulting in a “string of pearls” appearance. Other reported findings include diffuse vasoconstriction, reduced capillary blush, and vessel pruning (Fig. 3.15). When present, the vasoconstriction most commonly involves second and third order branches and usually resolves on follow-up imaging as the clinical status of the patient improves. Interestingly, the vasospasm is often less prominent in severely hypertensive patients who also demonstrate significantly less vasogenic edema.

On perfusion studies with CT, MR, and Tc-99m hexamethylpropyleneamine oxime (HMPAO) SPECT, regions affected by PRES are hypoperfused with respect to the normal brain, a finding that argues against the more popular hyperperfusion theory. The relative cerebral blood volume (rCBV) in affected regions is reduced in up to 86% of patients with PRES.

COMPLICATIONS 1. Intracranial hemorrhage (ICH) can occur in 10% to 25% of cases and is often intraparenchymal and less commonly subarachnoid, although both may coexist (Fig. 3.16). ICH is more common in patients receiving anticoagulation and

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Figure 3.17. PRES complicated by cerebral infarction. (A–D) The axial computed tomography (CT) image (A, same patient as Fig. 3.14) reveals symmetric hypodensity in the bilateral parietal lobes in a patient with posterior reversible encephalopathy syndrome. There is corresponding hyperintensity on the axial T2-weighted image (B) and restricted diffusion on the DW image (C), more prominent on the left side. The follow-up CT image (D) obtained after 6 months reveals bilateral parietal encephalomalacia.

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Figure 3.18. Border-zone infarcts. (A and B) Axial FLAIR (A) and DWI (B) at the level of centrum semiovale show abnormal hyperintense FLAIR signal involving the anterior cerebral artery–middle cerebral artery and middle cerebral artery–posterior cerebral artery border zones, with corresponding areas of restricted diffusion, consistent with infarctions.

in patients who have undergone allogenic bone marrow transplantation. 2. Cerebral infarction, characterized by restricted diffusion, occurs in 10% to 30% of cases. When present, it is often associated with incomplete clinical recovery (Fig. 3.17). 3. Cerebral herniation can occur, especially in cases with severe posterior fossa involvement.

MIMICS AND DIFFERENTIAL DIAGNOSIS PRES may be mimicked both clinically and radiologically by a myriad of conditions that present with encephalopathic

features and demonstrate vasogenic or even cytotoxic edema on neuroimaging. Cerebral ischemia secondary to hypoperfusion may present with involvement of the border zone vascular territories, mimicking PRES (Fig. 3.18). Lesions typically show more extensive areas of restricted diffusion, a clinical state predisposing to hypoperfusion is present, and the patients rarely present with seizures. Occasionally, acute disseminated encephalomyelitis (ADEM) can mimic PRES (Fig. 3.19). Lesions usually have elevated diffusion but can also have restricted diffusion. Patchy contrast enhancement can also occur. In contradistinction to PRES, ADEM is typically not symmetric, is frequently preceded by a viral illness, and can

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CHAPTER 3  Posterior Reversible Encephalopathy Syndrome

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C Figure 3.19. (A–C) Acute disseminated encephalomyelitis. Axial FLAIR (A), DWI (B), and postcontrast (C) images reveal abnormal areas of T2 prolongation involving the vascular border zones bilaterally (A) with incomplete rims of restricted diffusion (B) and faint enhancement in some of the lesions (C).

be accompanied by an inflammatory cerebrospinal fluid (CSF) profile. The presence of reversible cerebral angiographic abnormalities and reversible brain edema brain associated with both PRES and reversible cerebral vasoconstriction syndrome (RCVS) suggests an overlapping pathophysiology. In addition to multifocal vascular narrowing and transient edema, patients with RCVS may present with border zone cerebral infarctions, subarachnoid hemorrhage, and/or parenchymal hemorrhage (Fig. 3.20). RCVS often affects young and middle-aged females and typically follows exposure to sympathomimetic or recreational drugs. Other known triggers include eclampsia, binge drinking, and strenuous physical activity.

Postictal changes may be mistaken for PRES. There is often extensive cortical involvement, and the lesions are typically unilateral. The pulvinar of the thalamus and the hippocampus are often affected. In addition, involved regions show hyperperfusion, unlike PRES, which shows hypoperfusion. Other conditions producing vasogenic edema such as venous sinus thrombosis, inflammatory or infectious vasculitides, autoimmune disorders, and metabolic conditions such as uremic encephalopathy may mimic PRES. These entities are rare, and the clinical history often leads to the correct diagnosis.

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Figure 3.20. (A and B) Reversible cerebral vasoconstriction syndrome. Computed tomography angiography, axial MIP images, in a patient with cocaine exposure, performed at presentation (A) and after 3 months (B). The initial image (A) demonstrates marked luminal irregularity and segments of vasoconstriction involving the bilateral middle cerebral artery (MCA) and proximal anterior cerebral artery (ACA) vessels, worst in the left MCA. The follow-up image (B) shows interval resolution of the vasculopathy.

SUGGESTED READING

Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol. 2008;29:447–455. Bartynski WS, Boardman JF. Distinct imaging patterns and lesion distribution in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol. 2007;28:1320–1327. Bartynski WS. Posterior reversible encephalopathy syndrome. Part 1. Fundamental imaging and clinical features. AJNR Am J Neuroradiol. 2008;29:1036–1042. Bartynski WS. Posterior reversible encephalopathy syndrome. Part 2. Controversies surrounding pathophysiology of vasogenic edema. AJNR Am J Neuroradiol. 2008;29:1043–1049.

Bathla G, Hegde AN. MRI and CT appearances in metabolic encephalopathies due to systemic diseases in adults. Clin Radiol. 2013;68:545–554. Fugate JE, Rabinstein AA. Posterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions. Lancet Neurol. 2015 Jul 13; pii: S1474-4422(15)00111-8. doi:10.1016/S1474-4422(15)00111-8. [Epub ahead of print]. Legriel S, Pico F, Azoulay E. Understanding Posterior Reversible Encephalopathy Syndrome. Annual update in intensive care and emergency medicine 2011. New York: Springer Berlin Heidelberg; 2011:631–653. McKinney AM, Short J, Truwit CL, et al. Posterior reversible encephalopathy syndrome: incidence of atypical regions of involvement and imaging findings. AJR Am J Roentgenol. 2007;189:904–912.

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Cerebral Amyloid Angiopathy Mara Kunst

INTRODUCTION Cerebral amyloid angiopathy (CAA) is a microangiopathy defined by progressive deposition of beta amyloid (Aβ) in the walls of distal cortical and leptomeningeal vessels. The resulting small vessel damage can result in hemorrhage, infarction, and/or chronic hypoperfusion, the sequela of which produce a spectrum of characteristic neuroimaging findings. Although both hereditary and sporadic forms exist, in this chapter, we will focus on sporadic CAA, which is most commonly found in older individuals and is associated with Alzheimer dementia (AD).

EPIDEMIOLOGY, PATHOLOGY, AND CLINICAL PRESENTATION CAA is a frequent neuropathologic finding and fairly common clinical entity in the elderly. Population studies estimate the presence of CAA in approximately 30% of individuals older than 60 years and approximately 55% of patients with dementia.1 The most severe complication of CAA is hemorrhage. Approximately 20% of spontaneous intracranial hemorrhage in the elderly is attributable to CAA.2

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CHAPTER 4  Cerebral Amyloid Angiopathy

CAA results from impaired perivascular lymphatic drainage and failure of elimination of Aβ from the brain with age and AD.3–6 Aβ is derived from proteolysis of the amyloid precursor protein, an integral membrane protein found in many tissues but concentrated in the synapses of neurons. Different proteolytic enzymes produce Aβ of varying lengths, solubility, and aggregation capabilities.7,8 Under normal conditions, all forms diffuse through the narrow extracellular spaces of the brain parenchyma before entering the bulk flow lymphatic drainage pathways located in the basement membranes of distal cortical and leptomeningeal arterioles and capillaries.9 These peripheral vessels seem particularly prone to Aβ deposition due to the basic composition of the arterial wall and absence of alternative perivascular lymphatic drainage pathways.10 Age and certain genetic factors contribute to changes in the basement membrane and hardening of the arterial walls, which disrupts this drainage.4,11 In this setting, the longer, insoluble form of Aβ (Aβ42), which tends to aggregate more easily, is more readily deposited in the brain parenchyma, contributing to the formation of senile plaques and AD. The shorter, soluble form (Aβ40), which does not aggregate as easily, can still diffuse through the extracellular matrix but is not easily cleared by the cerebral lymphatics and becomes deposited in the basement membrane,3–9,11 laying the foundation for CAA. As disease progresses and Aβ accumulates, it disrupts the basement membrane, erodes smooth muscle, and eventually replaces the entire vessel wall, extending into the adventitia (Fig. 4.1).12 Severe CAA is often accompanied pathologically by obliterative intimal changes, hyaline degeneration, microaneurysmal dilation, and fibrinoid necrosis.13 The resulting vasculopathy is the basis for CAA pathology, leading to development of acute and chronic hemorrhage, ischemia, and chronic hypoperfusion, any or all of which can be reflected in the computed tomography (CT) and magnetic resonance imaging (MRI).14

CLINICAL AND IMAGING FEATURES Overview Patients with CAA are frequently asymptomatic, particularly in the early stages. As disease progresses, there can be tremendous overlap with other diseases commonly afflicting the elderly, such as transient ischemic attacks (TIAs), other acute neurologic deficits, and dementia. Individual patient presentation and progression is extremely varied, in part due to how different CAA risk factors affect the process of perivascular clearance. For instance, the ApoE4 genotype alters the biochemical composition of the basement membrane, whereas midlife hypertension alters the biochemical forces on the arterial wall.15 Whether alone or combined, these mechanisms make the vessel wall more susceptible to Aβ deposition. Delineation of individual risk factors to predict potential hemorrhage and progression to ischemia or dementia are the subject of continued research.8,12 Although definitive diagnosis of CAA still relies on brain biopsy, there has been a trend toward more definitive diagnosis with imaging.8 The Boston criteria were developed in the mid-1990s as a tool to both improve and standardize the diagnosis of CAA and have been refined since then (Box 4.1).16,17

In Greater Depth The Boston criteria rely heavily on the hemorrhagic manifestations of CAA, which are most characteristic of the disease, and include lobar hemorrhages, cerebral microbleeds (also called petechial microhemorrhages), and cortical superficial siderosis (cSS). However, nonhemorrhagic manifestations of the disease may predominate in individual patients, underscoring the radiologist’s role in arriving at the diagnosis. These include white matter changes, cortical

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microinfarcts, MRI visible perivascular spaces, and CAA-related inflammation (Fig. 4.2).

Hemorrhagic Manifestations of Cerebral Amyloid Angiopathy The most clinically devastating manifestation of CAA is spontaneous lobar intracerebral hemorrhage (ICH). The lobar predominance is due the underlying Aβ deposition pattern that favors cortical vessels over those in the deep gray or white matter or the brainstems. CAA-related ICHs tend to cluster in the posterior cortical regions and also affect the cerebellar hemispheres.18 Because of their superficial location, CAA-related ICHs more readily dissect into the subarachnoid spaces and less so into the ventricles.14 Cerebral microbleeds (CMs) are very common in CAA and therefore one of the diagnostic markers of the Boston criteria. Their imaging signature on MRI arises from perivascular hemosiderin deposition in CAA-affected vessels, which gets concentrated in macrophages.19 The paramagnetic properties of this deposited hemosiderin result in local inhomogeneities in the magnetic field, resulting in loss of signal on T2* gradient echo and susceptibilityweighted imaging. Although most papers define CMs as having a size of approximately 5 mm (range 2–10 mm), it cannot be overemphasized that size and number detected vary dramatically with imaging technique.20,21 CAA-related CMs are, like CAA-related ICHs, lobar in distribution, with a predilection for the posterior brain regions, thereby distinguishing themselves from the more central CMs of hypertension. When strictly lobar, they strongly predict CAA pathology in a hospital setting. However, in the general population, this correlation does not appear as strong.21 CAA-related CMs appear to be spatially correlated with areas of amyloid deposition in positron emission tomography (PET) using the amyloid radioligand Pittsburgh Compound B (PiB PET).22 Overall, they represent a relatively easily assessable biomarker for disease severity22 and possibly progression.23 cSS is another key hemorrhagic feature of CAA. It describes a specific imaging pattern of linear signal loss along the gyral surface of the cerebral convexities.24 cSS is a common finding in patients with symptomatic probable or definite CAA, found in 40% to 60% of cases.25 Although the exact pathophysiologic mechanism is not known, observational data indicate that the cSS most likely represents the hemosiderin residues from acute convexity subarachnoid hemorrhage resulting from rupture of CAA-laden cortical or leptomeningeal vessels.24 CAA-related cSS is a predictor of future spontaneous ICH,26 with potential implications for antithrombotic therapies.24

Nonhemorrhagic Manifestations of Cerebral Amyloid Angiopathy CAA is closely associated with the presence and severity of white matter hyperintensities (WMHs) of presumed vascular origin. These lesions are hyperintense on T2 or fluid-attenuated inversion recovery (FLAIR) sequences and located in the periventricular and subcortical white matter. In CAA patients, these WMHs are more severe than those in healthy older adults or patients with AD.27 CAA-related WMHs appear to predominate in the posterior (parietooccipital) brain regions27 and are shown to correlate with higher concentrations of Aβ deposition on PiB PET.28 Based on Aβ’s observed effects on vessel wall structure and function, WMHs in CAA most likely arise from some mix of acute ischemic and chronic hypoperfusion.14 Cerebral microinfarcts are tiny infarcts, in the millimeter to submillimeter range, which are frequently only visible on microscopic tissue examination. Diffusion-weighted imaging lesions are detected in approximately 15% of patients with CAA and ICH,29,30 and chronic cortical infarcts are seen in up to 100% of CAA patients on ultra-high-field MRI.31 Although

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Figure 4.1. Cerebral amyloid angiopathy (CAA) pathology. Amyloid precursor protein (APP) in neurons breaks down into beta amyloid (Aβ)40 and Aβ42. The longer form (Aβ42) cannot diffuse into the cerebral vasculature and gets deposited in the brain parenchyma, contributing to senile plaques and Alzheimer disease. The shorter form (Aβ40) can diffuse into the vessel walls, where clearance should occur through the perilymphatic drainage pathways. As vessels are damaged by atherosclerosis, CAA cannot be readily cleared and begins to deposit, eventually breaking down the vessels walls.

commonly associated with other hemorrhagic and nonhemorrhagic manifestations of CAA, there is evidence of that the cortical microinfarcts independently contribute to cognitive impairment and brain atrophy,32,33 making them a promising target of research. Perivascular spaces in the centrum semiovale identified on MRI were recently shown to be associated with PiB PET cerebrovascular Aβ burden.34 Their appearance is thought to reflect obstructed

perivascular lymphatic drainage channels resulting from progressive Aβ deposition,35 and their presence is a proposed marker for CAA (Fig. 4.3).36 CAA-related inflammation is a more rapidly progressive CAA disease manifestation. It is a meningoencephalitis presenting with subacute mental status and behavioral changes, headaches, seizures, and occasional focal neurologic deficits, with pathologic evidence of CAA-related inflammation.14,15,37,38 Characteristic MRI findings

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CHAPTER 4  Cerebral Amyloid Angiopathy

BOX 4.1  Diagnostic Criteria for Cerebral Amyloid Angiopathy DEFINITE CAA Full postmortem examination, demonstrating: • Lobar, cortical, or corticosubcortical hemorrhage • Severe CAA with vasculopathy • Absence of other diagnostic lesion PROBABLE CAA WITH SUPPORTING PATHOLOGY Clinical data and pathologic tissues demonstrating: • Lobar, cortical, or corticosubcortical hemorrhage • Some degree of CAA in specimen • Absence of other diagnostic lesion PROBABLE CAA Clinical data and MRI or CT demonstrating: • Multiple hemorrhage restricted to lobar, cortical or corticosubcortical regions • Age >55 years • Absence of other cause of hemorrhage POSSIBLE CAA Clinical data and MRI or CT demonstrating: • Single lobar, cortical, or corticosubcortical regions • Age >55 years • Absence of other cause of hemorrhage CAA, Cerebral amyloid angiopathy; CT, computed tomography; MRI, magnetic resonance imaging.

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include unifocal or multifocal WMHs, typically asymmetric and extending to the subcortical U-fibers, with variable leptomeningeal enhancement. Blood-sensitive sequences may demonstrate any or all of the hemorrhagic CAA imaging manifestations, helping to differentiate this from other causes of meningoencephalitis (Fig. 4.4).39 CAA-related inflammation responds readily to immunosuppressive therapy, such as high-dose steroids or cyclophosphamide, underscoring the necessity of early and accurate recognition. The combination of the previous insults and their cumulative effect on brain connectivity is thought to underlie the mechanism by which CAA pathology contributes to atrophy and dementia (Fig. 4.5).40–42

DIFFERENTIAL DIAGNOSIS Lobar parenchymal hemorrhage carries a broad differential, with leading causes being hypertension, trauma, bleeding diathesis, CAA, illicit drug use, and vascular malformations. Less frequent causes include vasculitis, ruptured cerebral aneurysms, and hemorrhagic tumors. History, physical exam, and lab values frequently allow for distinction of these etiologies. Computed tomographic angiography (CTA) is helpful for excluding aneurysms, vascular malformations, and vasculitis, whereas contrast-enhanced MRI helps to exclude hemorrhagic tumors. The diagnostic dilemma arises when a patient receives an MRI for work-up of nonemergent causes, including dementia, TIAs, or mental status changes. Several disease entities can produce CMs and/or WHMs that can mimic those of CAA, including chronic hypertension, multiple cavernous malformations, disseminated intravascular coagulation, fat embolism, and hemorrhagic metastases (Fig. 4.6). Although a peripheral distribution of CMs is supportive of CAA over chronic hypertension, there can be broad overlap with other disease entities, particularly when CAA is in the early stages. Familiarity with the constellation of hemorrhagic and nonhemorrhagic manifestations of CAA is critical in arriving at the correct diagnosis.

RISK FACTORS AND TREATMENT

Figure 4.2. Manifestations of cerebral amyloid angiopathy. (1) Cortical microinfarcts, (2) superficial siderosis, (3) lobar hemorrhage, (4) cerebral microbleeds, (5) white matter hyperintensities of presumed vascular origin, and (6) enlarged perivascular spaces.

Immunotherapies using Aβ-selective antibodies have shown a reduction in Aβ deposition, reportedly through Aβ neutralization and lymphatic clearance.43 Other potential therapies are aimed at preventing Aβ production or protecting small vessels from its toxic effects. Although promising, these therapies are still in the experimental stages. To date, there is no disease-specific CAA treatment. Effective management of CAA patients is centered on the prevention of incident or recurrent hemorrhage, while simultaneously decreasing risk of stroke.44 A common approach is to avoid antithrombotic therapies as much as possible to decrease risk of ICH occurrence and severity.44 Preliminary evidence has also suggested a link between aspirin and increased ICH recurrence.45,46 However, the systematic discontinuation of antiplatelet agents remains controversial because these agents may help to prevent other vascular events.47,48 Although CAA-related ICHs are not thought to be pathophysiologically linked to hypertension, control of blood pressure to within the normal range is recommended by the recently updated American Heart Association Guidelines.14,49 Strict blood pressure control has been shown to decrease CAA-related ICH recurrence by up to 77%.14,50,51 Although lipid-lowering medications play a significant role in prevention of vascular events, the use of statins has been linked to an increased risk of ICH, making their specific use controversial.

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Figure 4.3. Manifestations of cerebral amyloid angiopathy in three patients: Images A, B, and C refer to patient 1: (A and B) Susceptibilityweighted imaging (SWI) shows right frontal superficial siderosis (red arrow), cortical microhemorrhages (blue arrow indicates one in the right frontal lobe), and the residua of a left inferior parietal remote lobar hemorrhage (green arrow); (C) T2-weighted image shows prominent perivascular spaces (yellow oval) in the left centrum semiovale. Images D and E refer to patient 2: (D) SWI image shows right posterior temporal occipital superficial siderosis (red arrow); (E) T1-weighted image shows subacute right frontal lobar hemorrhage. Images F, G, and H refer to patient 3: (F) SWI image shows cortical microhemorrhages (blue arrow indicates one in the right frontal lobe) and residua of left inferior parietal lobar hemorrhage (green arrow); (G) FLAIR image shows prominent white matter hyperintensities (red star); and (H) diffusion-weighted imaging shows right frontal cortical infarct (white arrow).

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Patient with acute presentation at level of ventricles.

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Patient with acute presentation at level of centrum semiovale.

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Patient baseline exam one year earlier.

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Figure 4.4. Inflammatory cerebral amyloid angiopathy (CAA) and progression. An 86-year-old male presents with left facial and arm numbness and slurred speech over several days. Axial FLAIR images (A and D) show right frontal and parietal confluent FLAIR hyperintense signal extending to the subcortical region (red stars). SWI images (B and E) show prominent multifocal superficial siderosis (red arrows indicate right frontal components). Diffusion-weighted image (C) shows a right frontal cortical infarct (white arrow). Gadolinium-enhanced T1-weighted image (F) shows leptomeningeal enhancement in the central sulcus (yellow arrow). All of these findings support acute inflammatory CAA. (G and H) Axial FLAIR images in the same patient obtained 1 year earlier show white matter hyperintensities of CAA (red stars) without superimposed inflammatory changes. The patient had small subdural hematomas at that time.

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Figure 4.5. Cerebral amyloid angiopathy (CAA) progression to dementia. Aβ, Beta amyloid.

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Figure 4.6. Patterns of hemorrhage. (A and B) Cerebral amyloid angiopathy. Axial gradient echo sequences (GRE) images in two patients showing classic peripheral predominant cerebral microbleeds, superficial siderosis, and hemosiderin staining of remote lobar hemorrhage. (C and D) Hypertensive vasculopathy. Axial GRE images in one patient showing microhemorrhages in a central distribution, particularly in the pons, cerebellum, and basal ganglia. (E and F) Multiple cavernous malformations. Axial GRE image (E) shows randomly distributed foci of susceptibility artifact. Axial T2 image (F) shows a right frontal lesion with a T2 hyperintense, lobulated center (arrow), consistent with an underlying cavernous malformation. (G and H) Coagulopathy. Axial GRE images show innumerable microhemorrhages distributed throughout the brain, without associated acute infarcts in this patient with sepsis and disseminated intravascular coagulopathy. (I and J) Fat embolism syndrome. Axial GRE (I) images show innumerable microhemorrhages distributed throughout the brain. Axial DWI (J) shows innumerable punctate acute infarctions in this patient with fat embolism due to a long bone fracture. (K and L) Hemorrhagic metastases. Axial GRE image (K) reveals multiple areas of susceptibility artifact varying in size. Axial postcontrast T1-weighted image (L) shows ring enhancement in a left occipital lesion (arrow), consistent with a metastasis in this patient with lung cancer.

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REFERENCES

1. Keage HA, Carare RO, Friedland RP, et al. Population studies of sporadic cerebral amyloid angiopathy and dementia: a systematic review. BMC Neurol. 2009;9:3. 2. Meretoja A, Strbian D, Putaala J, et al. SMASH-U: a proposal for etiologic classification of intracerebral hemorrhage. Stroke. 2012;43(10):2592–2597. 3. Carare RO, Hawkes CA, Jeffrey M, et al. Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy. Neuropathol Appl Neurobiol. 2013;39(6): 593–611. 4. Hawkes CA, Jayakody N, Johnston DA, et al. Failure of perivascular drainage of β-amyloid in cerebral amyloid angiopathy. Brain Pathol. 2014;24(4):396–403. 5. Roberts KF, Elbert DL, Kasten TP, et al. Amyloid-β efflux from the central nervous system into the plasma. Ann Neurol. 2014;76(6): 837–844. 6. Maki T, Okamoto Y, Carare RO, et al. Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid. Ann Clin Transl Neurol. 2014;1(8):519–533. 7. Prelli F, Castaño E, Glenner GG, et al. Differences between vascular and plaque core amyloid in Alzheimer’s disease. J Neurochem. 1988;51(2):648–651. 8. Thal DR, Walter J, Saido TC, et al. Neuropathology and biochemistry of Aβ and its aggregates in Alzheimer’s disease. Acta Neuropathol. 2015;129(2):167–182. doi:10.1007/s00401-014-1375-y. [Epub 2014 Dec 23]. 9. Weller RO, Massey A, Newman TA, et al. Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. Am J Pathol. 1998;153(3):725–733. 10. Thal DR, Ghebremedhin E, Orantes M, et al. Vascular pathology in Alzheimer disease: correlation of cerebral amyloid angiopathy and arteriosclerosis/lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol. 2003;62:1287–1301. 11. Hawkes CA, Härtig W, Kacza J, et al. Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. Acta Neuropathol. 2011;121(4):431–443. 12. Keable A, Fenna K, Yuen HM, et al. Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy. Biochim Biophys Acta. 2016;1862(5):1037–1046. 13. Vonsattel JP, Myers RH, Hedley-Whyte ET, et al. cerebral amyloid angiopathy without and with cerebral hemorrhages: a comparative histological study. Ann Neurol. 1991;30(5):637–649. 14. Boulouis G, Charidimou A, Greenberg SM. Sporadic Cerebral Amyloid Angiopathy: Pathophysiology, Neuroimaging Features, and Clinical Implications. Semin Neurol. 2016;36(3):233–243. 15. Kinnecom C, Lev MH, Wendell L, et al. Course of cerebral amyloid angiopathy-related inflammation. Neurology. 2007;68(17): 1411–1416. 16. Knudsen KA, Rosand J, Karluk D, et al. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001;56(4):537–539. 17. Martinez-Ramirez S, Romero JR, Shoamanesh A, et al. Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage. Alzheimers Dement. 2015;11(12):1480–1488. 18. Rosand J, Muzikansky A, Kumar A, et al. Spatial clustering of hemorrhages in probable cerebral amyloid angiopathy. Ann Neurol. 2005;58(3):459–462. 19. Xavier-Neto J, dos Santos AA, Rola FH. Acute hypervolaemia increases gastroduodenal resistance to the flow of liquid in the rat. Gut. 1990;31(9):1006–1010. 20. Shams S, Martola J, Cavallin L, et al. SWI or T2*: which MRI sequence to use in the detection of cerebral microbleeds? The Karolinska Imaging Dementia Study. AJNR Am J Neuroradiol. 2015;36(6):1089–1095. doi:10.3174/ajnr.A4248. [Epub 2015 Feb 19]. 21. Wardlaw JM, Smith EE, Biessels GJ, et al. STandards for ReportIng Vascular changes on nEuroimaging (STRIVE v1). Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12(8): 822–838. 22. Dierksen GA, Skehan ME, Khan MA, et al. Spatial relation between microbleeds and amyloid deposits in amyloid angiopathy. Ann Neurol. 2010;68(4):545–548.

23. Gurol ME, Dierksen G, Betensky R, et al. Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy. Neurology. 2012;79(4):320–326. 24. Charidimou A, Linn J, Vernooij MW, et al. Cortical superficial siderosis: detection and clinical significance in cerebral amyloid angiopathy and related conditions. Brain. 2015;138(Pt 8):2126–2139. 25. Charidimou A, Jäger RH, Fox Z, et al. Prevalence and mechanisms of cortical superficial siderosis in cerebral amyloid angiopathy. Neurology. 2013;81(7):626–632. 26. Linn J, Wollenweber FA, Lummel N, et al. Superficial siderosis is a warning sign for future intracranial hemorrhage. J Neurol. 2013;260(1):176–181. 27. Reijmer YD, van Veluw SJ, Greenberg SM. Ischemic brain injury in cerebral amyloid angiopathy. J Cereb Blood Flow Metab. 2016;36(1):40–54. 28. Gurol ME, Viswanathan A, Gidicsin C, et al. Cerebral amyloid angiopathy burden associated with leukoaraiosis: a positron emission tomography/magnetic resonance imaging study. Ann Neurol. 2013;73(4):529–536. 29. Auriel E, Gurol ME, Ayres A, et al. Characteristic distributions of intracerebral hemorrhage-associated diffusion-weighted lesions. Neurology. 2012;79(24):2335–2341. 30. Kimberly WT, Gilson A, Rost NS, et al. Silent ischemic infarcts are associated with hemorrhage burden in cerebral amyloid angiopathy. Neurology. 2009;72(14):1230–1235. 31. van Veluw SJ, Jolink WMT, Hendrikse J, et al. Cortical microinfarcts on 7T MRI in patients with spontaneous intracerebral hemorrhage. J Cereb Blood Flow Metab. 2014;34(7):1104–1106. 32. Launer LJ, Hughes TM, White LR. Microinfarcts, brain atrophy, and cognitive function: the Honolulu Asia Aging Study Autopsy Study. Ann Neurol. 2011;70(5):774–780. 33. van Veluw SJ, Hilal S, Kuijf HJ, et al. Cortical microinfarcts on 3T MRI: clinical correlates in memory-clinic patients. Alzheimers Dement J Alzheimers Assoc. 2015;11(12):1500–1509. 34. Ramirez J, Berezuk C, McNeely AA, et al. Visible Virchow-Robin spaces on magnetic resonance imaging ofAlzheimer’s disease patients and normal elderly from the Sunnybrook Dementia Study. J Alzheimers Dis. 2015;43(2):415–424. 35. Arbel-Ornath M, Hudry E, Eikermann-Haerter K, et al. Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models. Acta Neuropathol. 2013;126(3):353–364. 36. Charidimou A, Jaunmuktane Z, Baron JC, et al. White matter perivascular spaces: an MRI marker in pathology-proven cerebral amyloid angiopathy? Neurology. 2014;82(1):57–62. doi:10.1212/01. wnl.0000438225.02729.04. [Epub 2013 Nov 27]. 37. Eng JA, Frosch MP, Choi K, et al. Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol. 2004;55(2):250–256. 38. Chung KK, Anderson NE, Hutchinson D, et al. Cerebral amyloid angiopathy related inflammation: three case reports and a review. J Neurol Neurosurg Psychiatry. 2011;82(1):20–26. 39. Auriel E, Charidimou A, Gurol ME, et al. Validation of clinicoradiological criteria for the diagnosis of cerebral amyloid angiopathy– related inflammation. JAMA Neurol. 2015;1–6. 40. Reijmer YD, Fotiadis P, Martinez-Ramirez S, et al. Structural network alterations and neurological dysfunction in cerebral amyloid angiopathy. Brain. 2015;138(Pt 1):179–188. 41. Benedictus MR, Hochart A, Rossi C, et al. Prognostic Factors for Cognitive Decline After Intracerebral Hemorrhage. Stroke. 2015;46(10):2773–2778. 42. Yamada M. Cerebral Amyloid Angiopathy: Emerging Concepts. J Stroke. 2015;17(1):17–30. 43. Bales KR, O’Neill SM, Pozdnyakov N, et al. Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity. Brain. 2016;139(Pt 2):563–577. 44. Hofmeijer J, Kappelle LJ, Klijn CJM. Antithrombotic treatment andintracerebral haemorrhage: between Scylla and Charybdis. Pract Neurol. 2015;15(4):250–256. 45. Biffi A, Halpin A, Towfighi A, et al. Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy. Neurology. 2010;75(8):693–698. 46. Falcone GJ, Rosand J. Aspirin should be discontinued after lobar intracerebral hemorrhage. Stroke. 2014;45(10):3151–3152. 47. Flynn RWV, MacDonald TM, Murray GD, et al. Prescribing antiplatelet medicine and subsequent events after intracerebral hemorrhage. Stroke. 2010;41(11):2606–2611.

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48. Al-Shahi Salman R, Dennis MS. Antiplatelet therapy may be continued after intracerebral hemorrhage. Stroke. 2014;45(10):3149–3150. 49. Hemphill JC III, Greenberg SM, Anderson CS, et al; American Heart Association Stroke Council; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/ American Stroke Association. Stroke. 2015;46(7):2032–2060. 50. Schiffrin EL. Blood pressure lowering in PROGRESS (Perindopril Protection Against Recurrent Stroke Study) and white matter

hyperintensities: should this progress matter to patients? Circulation. 2005;112(11):1525–1526. 51. Dufouil C, Chalmers J, Coskun O, et al; PROGRESS MRI Substudy Investigators. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation. 2005;112(11): 1644–1650.

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CHAPTER 4  Cerebral Amyloid Angiopathy

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Wernicke Encephalopathy Aaron B. Paul

INTRODUCTION Wernicke encephalopathy (WE) was first described in 1881 by Carl Wernicke as a “superior acute hemorrhagic polioencephalitis.”1 WE is now recognized as a complication of thiamine (vitamin B1) deficiency and results in the following clinical triad: mental confusion, gait ataxia, and ocular dysfunction. Diagnosing WE is straightforward when a known alcoholic demonstrates all of these symptoms. Unfortunately, this occurs in a minority of patients. One study investigating 245 patients over a 10-year period discovered that only 33% of patients demonstrated the complete triad. Consequently, WE is believed to be underdiagnosed.2 The most common symptoms of WE are mental status abnormalities (82%), ocular dysfunction (29%), ataxia (23%), and polyneuropathy (11%).3 Mental status abnormalities include disorientation, indifference, and inattentiveness, with impaired learning and memory.3 Ocular abnormalities include nystagmus, bilateral cranial nerve VI palsies, and conjugate gaze palsies.4 Ataxia affects both stance and gait and is secondary to a combination of polyneuropathy, cerebellar involvement, and vestibular dysfunction.5 Korsakoff syndrome is a memory disturbance with amnesia and confabulation that may develop if the thiamine deficiency is left untreated.6 WE can be identified at autopsy in 0.4% to 2.8% of the population.7 Aside from alcoholism, WE has been reported in a variety of conditions that disrupt thiamine absorption. Examples include following gastrointestinal surgery, prolonged vomiting, chemotherapy, systemic infections, noninfectious disease, and dietary imabalances.4 Thiamine is needed for a variety of cellular processes including the maintenance of membrane osmotic gradients and glucose metabolism.4 With insufficient dietary intake, the human body’s stores become depleted in approximately 1 month.8 At histopathology, both vasogenic and cytotoxic edema can be identified, along with swelling of astrocytes and oligodendrocytes, proliferation of microglia, necrosis, demyelination, vascular proliferation, petechial hemorrhage, and disruption of the blood-brain barrier.9 The intravenous administration of thiamine is the treatment for WE. Importantly, glucose should never be administered without thiamine because doing so can precipitate or worsen WE.

WERNICKE ENCEPHALOPATHY IMAGING EVOLUTION: OVERVIEW Optimal management of WE depends on a timely and accurate diagnosis. However, the diagnosis can be missed due to the disease’s occasionally subtle imaging findings, its temporal evolution, and the challenge of perceiving symmetric involvement of brain anatomy. Fortunately, characteristic imaging features within the appropriate clinical context can be used to confidently diagnose WE. WE can be conceptually organized into early and late stages (Fig. 5.1). Early WE begins with symmetric T2/FLAIR hyperintensity involving the thalami, mammillary bodies, hypothalamus, walls of the third ventricle, tectal plate, and periaqueductal gray matter. Contrast enhancement of the mammillary bodies can also be seen, is more common in alcoholic patients,10 and may be the only imaging finding.11 Contrast should therefore be administered when clinical suspicion is high (Fig. 5.2). In late WE, mammillary body atrophy and enlargement of the third ventricle are seen (Fig. 5.3). Cases demonstrating subtle T2/FLAIR hyperintensity isolated to the mammillary bodies and periaqueductal gray matter without involvement of the walls of the third ventricle or thalami, and without enhancement are less conclusive. Table 5.1 contrasts the differences in the imaging findings of early versus late WE.

WERNICKE ENCEPHALOPATHY IMAGING VARIANTS There are important imaging variants of WE that are essential for an expert understanding. Symmetric T2 hyperintensity can also involve the cerebral cortex, fornix, splenium, caudate nuclei, red nuclei, cranial nerve nuclei, cerebellum, vermis, and dentate nuclei.12–17 These imaging variants may occur in conjunction with the more typical WE imaging findings, and therefore their presence should not necessarily suggest a superimposed process (Fig. 5.4).

DIFFERENTIAL DIAGNOSIS The most important differential diagnoses for WE can be divided into the following four categories: ischemic, infectious-inflammatory, toxic, and metabolic. Ischemic considerations include artery of Percheron infarction, top of the basilar infarction, and deep cerebral vein thrombosis.

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A

B

C

D Figure 5.1. Wernicke encephalopathy (WE) temporal evolution. Early WE (A and B) demonstrates signal abnormality involving the thalami, mammillary bodies, walls of the third ventricle, tectal plate, and periaqueductal gray. Late WE (C and D) demonstrates mammillary body atrophy and enlargement of the third ventricle.

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CHAPTER 5  Wernicke Encephalopathy

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D

E

F

Figure 5.2. Early Wernicke encephalopathy. Middle-aged female with history of depression and alcoholism presents with catatonia after overdosing on Seroquel. Her mental status was noted to dramatically improve with IV thiamine. Axial FLAIR (A to D) images demonstrate hyperintensity involving the thalami (yellow arrow), walls of the third ventricle (black arrow), periaqueductal gray matter (gray arrow), tectal plate (orange arrow), and hypothalamus (green arrow). Axial (E) and sagittal (F) contrast-enhanced T1-weighted images show enhancement of the mammillary bodies (red arrows).

A

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Figure 5.3. Late Wernicke encephalopathy. Middle-aged male with a two-decade history of alcoholism requiring multiple hospitalizations. Coronal T1 (A) and sagittal T1 (B) images demonstrate enlargement of the third ventricle (gray arrow) and atrophy of the mammillary bodies (red arrow).

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Artery of Percheron infarction typically produces T2 hyperintensity and restricted diffusion in the bilateral thalami and may also extend into the midbrain18 (Fig. 5.5). Top of the basilar infarction involves these areas, as well as the bilateral posterior cerebral artery (PCA) distributions. Deep cerebral vein thrombosis results in T2 hyperintensity with increased and/or decreased diffusion in the bilateral thalami and basal ganglia, often with associated hemorrhage. The involvement of a distinctive vascular territory, as well as the clinical history and presentation, help to differentiate these diagnoses from WE. Infectious-inflammatory considerations include acute disseminated encephalomyelitis (ADEM), Creutzfeldt-Jakob disease, and West Nile virus. ADEM typically involves the deep gray nuclei TABLE 5.1  Summary of Wernicke Encephalopathy (WE) Evolution Pattern Early WE FLAIR hyperintensity Enhancement Atrophy

Late WE

Yes Yes No

No No Yes

and white matter with multifocal T2 hyperintense lesions and enhancement along the leading edge of inflammation.19 CreutzfeldtJakob disease produces T2 and diffusion-weighted imaging (DWI) hyperintensity (with variable signal on apparent diffusion coefficient [ADC] maps) in the basal ganglia, thalami, and cerebral cortex. West Nile virus involves the basal ganglia and thalami with T2 hyperintensity.20 The clinical history, presentation, and distribution of findings help to differentiate these diagnoses from WE. Toxic considerations include carbon monoxide, heroin, and metronidazole-induced encephalopathy. Mild carbon monoxide poisoning results in T2 hyperintensity in the globi pallidi. More severe poisoning results in T2 hyperintensity in the remainder of the deep gray nuclei and cortex. Heroin results in a toxic leukoencephalopathy with T2 hyperintensity predominantly involving the posterior limbs of the internal capsules extending superiorly into the perirolandic white matter and inferiorly into the pontine corticospinal tracts with relative sparing of the subcortical U-fibers.21 Metronidazole-induced encephalopathy involves the dentate nuclei, vestibular nuclei, and tegmentum with T2 hyperintensity and less frequently involves the corpus callosum, midbrain, pons, and medulla (Fig. 5.6).22 The clinical history, presentation, and distribution of findings again help to differentiate these diagnoses from WE.

A

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D

E

F

Figure 5.4. Atypical Wernicke encephalopathy. Middle-aged female found down. Axial FLAIR images (A to F) demonstrate atypical FLAIR hyperintensity involving the bilateral frontal cerebral cortex (blue arrow) and fornices (green arrow), in addition to the more typical involvement of the thalami (orange arrow), walls of the third ventricle (red arrow), periaqueductal gray matter (yellow arrow), tectal plate (gray arrow), and hypothalamus (black arrow).

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D

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D

Figure 5.5. Artery of Percheron infarction. Middle-aged male presents with sudden onset of unresponsiveness. Axial FLAIR (A and B) images demonstrate bilateral hyperintense thalamic lesions (yellow arrow) extending into the rostral midbrain (blue arrow). The lesions have restricted diffusion (hyperintense on DWI [C] and hypointense on apparent diffusion coefficient map [D], typical of acute to subacute infarctions).

Figure 5.6. Metronidazole-induced encephalopathy. Elderly male with a history of recurrent Clostridium difficile infection on a 6-month course of metronidazole presents with dysmetria and dysarthria. Axial FLAIR (A to C) and Axial T2 (D) images demonstrate abnormal signal involving the splenium of the corpus callosum (gray arrow), superior colliculi (red arrow), dentate nuclei (black arrow), and inferior olivary nuclei (orange arrow).

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Central pontine myelinosis is the most important metabolic consideration. Central pontine myelinosis results in T2 hyperintensity and restricted diffusion in the central pons and less frequently involves the corpus callosum, midbrain, and medulla.23 The classic pontine involvement and imaging configuration help to differentiate this entity. REFERENCES

1. Wernicke C. Die Akute Hämorrhagische Polioencephalitis Superior. Lehrbuch der Gehirnkrankheiten für Ärzte und Studierende. Vol. II. Kassel: Fischer Verlag; 1881:229–242. 2. Victor M, Adams RA, Collins GH. The Wernicke-Korsakoff Syndrome and Related Disorders due to Alcoholism and Malnutrition. Philadelphia: FA Davis; 1989. 3. Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernickekorsakoff complex: a retrospective analysis of 131 cases diagnosed at necropsy. J Neurol Neurosurg Psychiatry. 1986;49:341. 4. Zuccoli G, Pipitone N. Neuroimaging findings in acute Wernicke’s encephalopathy: review of the literature. AJR Am J Roentgenol. 2009;192(2):501–508. 5. Ghez C. Vestibular paresis: a clinical feature of Wernicke’s disease. J Neurol Neurosurg Psychiatry. 1969;32:134. 6. Kopelman, Thomson AD, Guerrini I, et al. The Korsakoff syndrome: clinical aspects, psychology and treatment. Alcohol Alcohol. 2009;44(2):148–154. 7. Harper C, Fornes P, Duyckaerts C, et al. An international perspective on the prevalence of the Wernicke-Korsakoff syndrome. Metab Brain Dis. 1995;10:17. 8. Zuccoli G, Siddiqui N, Cravo I, et al. Neuroimaging findings in alcohol-related encephalopathies. AJR Am J Roentgenol. 2010;195(6): 1378–1384. 9. Gui QP, Zhao WQ, Wang LN. Wernicke’s Encephalopathy in nonalcoholic patients: clinical and pathologic features of three cases and literature reviewed. Neuropathology. 2006;26(3):231–235. 10. Zuccoli G, Gallucci M, Capellades J, et al. Wernicke encephalopathy: MR findings at clinical presentation in twenty-six alcoholic and nonalcoholic patients. AJNR Am J Neuroradiol. 2007;28: 1328–1331.

11. Konno Y, Kanoto M, Hosoya T, et al. Clinical significance of mammillary body enhancement in wernicke encephalopathy: report of 2 cases and review of the literature. Magn Reson Med Sci. 2014;13(2):123–126. [Epub 2014 Apr 28]. 12. Bae SJ, Lee HK, Lee JH, et al. Wernicke’s encephalopathy: atypical manifestation at MR imaging. AJNR Am J Neuroradiol. 2001;22:1480–1482. 13. Zuccoli G, Motti L. Atypical Wernicke’s encephalopathy showing lesions in the cranial nerve nuclei and cerebellum. J Neuroimaging. 2008;18:194–197. 14. Lapergue B, Klein I, Olivot JM, et al. Diffusion weighted imaging of cerebellar lesions in Wernicke’s encephalopathy. J Neuroradiol. 2006;33:126–128. 15. Liu YT, Fuh JL, Lirng JF, et al. Correlation of magnetic resonance images with neuropathology in acute Wernicke’s encephalopathy. Clin Neurol Neurosurg. 2006;108:682–687. 16. Murata T, Fujito T, Kimura H, et al. Serial MRI and (1)H-MRS of Wernicke’s encephalopathy: report of a case with remarkable cerebellar lesions on MRI. Psychiatry Res. 2001;108:49–55. 17. Thomas AG, Koumellis P, Dineen RA. The fornix in health and disease: an imaging review. Radiographics. 2011;31(4):1107–1121. 18. Matheus MG, Castillo M. Imaging of acute bilateral paramedian thalamic and mesencephalic infarcts. AJNR Am J Neuroradiol. 2003;24(10):2005–2008. 19. Matheus MG, Castillo M. Imaging of acute bilateral paramedian thalamic and mesencephalic infarcts. AJNR Am J Neuroradiol. 2003;24(10):2005–2008. 20. Ali M, Safriel Y, Sohi J, et al. West Nile virus infection: MR imaging findings in the nervous system. AJNR Am J Neuroradiol. 2005;26(2):289–297. 21. Hagel J, Andrews G, Vertinsky T, et al. “Chasing the dragon”–imaging of heroin inhalation leukoencephalopathy. Can Assoc Radiol J. 2005;56(4):199–203. 22. Roy U, Panwar A, Pandit A, et al. Clinical and neuroradiological spectrum of metronidazole induced encephalopathy: our experience and the review of literature. J Clin Diagn Res. 2016;10(6):[Epub 2016 Jun]. 23. Alleman AM. Osmotic demyelination syndrome: central pontine myelinolysis and extrapontine myelinolysis. Semin Ultrasound CT MR. 2014;35(2):153–159. [Epub 2013 Sep 28].

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Central Pontine Myelinolysis Juan E. Small, Daniel L. Noujaim, Arwa O. Badeeb

INTRODUCTION Central pontine myelinolysis (CPM) was originally described by Adams and colleagues in 1959. He first detailed the entity in a group of malnourished and alcoholic patients. Further studies and advancement in medicine have shown that CPM most commonly results from the rapid correction of serum sodium in hyponatremic patients. The pathophysiology of CPM is currently not fully understood. However, it has been shown that CPM results from the physiologic imbalance of osmoles within the brain. Many other conditions associated with disorders of solute metabolism, including inappropriate antidiuretic hormone secretion syndrome, malnutrition, psychogenic polydipsia, liver transplantation, and dialysis disequilibrium syndrome, share the common finding of alterations in cellular volume control. The imaging findings of CPM correspond to locations within the brain (in this case the pons) that are most susceptible to osmotic stress, as do the findings

of extrapontine myelinolysis (EPM). Together, CPM and EPM constitute the osmotic demyelination syndromes (ODSs). The central pons is the most commonly identified site of involvement in ODSs. A necropsy series of 58 cases identified isolated central pontine involvement in 50% of cases. The other 50% of cases had either central pontine with extrapontine (30%) or isolated extrapontine (20%) involvement (Fig. 6.1). Histologic sites of EPM have been described within the cerebellum, lateral geniculate body, external capsule, extreme capsule, hippocampus, putamen, cerebral cortex/subcortex, thalamus, and caudate, in descending order of frequency. Importantly, extrapontine involvement is usually symmetric. Myelinolysis results in preservation of local neurons and axons in the effected sites without an inflammatory reaction, as evident by paucity of lymphocytes on histologic specimens. These findings help to differentiate myelinolysis from multiple sclerosis or infarction. Histologic specimens have also demonstrated splitting and

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CHAPTER 6  Central Pontine Myelinolysis

vacuolization of myelin sheaths, which are subsequently taken up by macrophages.

IMAGING PATTERN Classically, CPM demonstrates T2 hyperintensity within the central pons, with peripheral pontine sparing, as well as sparing of the corticospinal tracts. This results in a “trident” or “bat wing” appearance on axial images (Fig. 6.2). EPM also causes T2 hyperintensity but in typically symmetric extrapontine locations (listed previously) (Fig. 6.3).

47

Conventional CT and MR imaging findings typically lag behind the clinical manifestations of CPM. Although CT may show late low-attenuation changes in the central pons in some cases, serial MR imaging is the most appropriate method to evaluate patients with clinically suspected CPM. One case series of two patients proposes that T2 hyperintensity in extrapontine locations may predate central pontine T2 hyperintensity in some patients.

TEMPORAL EVOLUTION: OVERVIEW Variable imaging features may be evident in osmotic demyelination, depending on when the process is imaged. In particular, the acute, subacute, and chronic imaging characteristics differ. Furthermore, some variable imaging features, including the diffusion-weighted imaging (DWI) and postcontrast imaging characteristics, may be present or absent according to phase.

Acute Phase

Figure 6.1. Relative proportions of central pontine myelinolysis (CPM), extrapontine myelinolysis (EPM), and CMP with EPM. (From: Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry. 2004;75[suppl 3]:iii22–iii28.)

A

B

Figure 6.2. Central pontine myelinolysis—axial and coronal T2-weighted images show T2 hyperintense signal involving the central pons with peripheral pontine sparing (red circle) and sparing of the corticospinal tracts (blue arrows). This pattern of involvement results in a T2 “bat wing” or “trident” appearance on axial imaging.

A

B

Several reports have suggested that DWI images might facilitate the early diagnosis of CPM. However, the exact frequency and onset in time of the appearance of these abnormal findings in relation to symptoms is still unclear. When present, DWI signal hyperintensity may begin to appear within 24 to 72 hours after onset of symptoms. ADC signal varies from hypointensity (restricted diffusion) when intramyelinolytic cytotoxic edema predominates to hyperintensity if vasogenic edema related to myelin destruction predominates. These competing processes result in variable DWI and ADC signal profiles that may differ between patients and may differ during the course of the disease in an individual patient as the balance of cytotoxic and vasogenic processes shifts. Several case reports, such as that of Ruzek et al., have shown that early DWI changes are a common finding in CPM/EPM. However, others have reported that these signal changes may not regularly precede tissue changes described on conventional MRI sequences. One report suggests that DWI can be normal in the acute stage of CPM, even within 1 week after the onset of symptoms. Graff-Radford et al. reported that 21% of their patients showed no abnormalities on early MRI; however, all patients had characteristic pontine signal abnormality on T2-weighted images on repeat imaging. This finding is in agreement with a more recent report that early MRIs were normal in 25% of cases. Early in the diagnosis of CPM/EPM, faint hyperintensity on T2-weighted and fluid-attenuated inversion recovery (FLAIR) imaging in characteristic locations may be the only finding. T1-weighted images usually show normal to hypointense T1 signal. Postcontrast enhancement due to blood-brain barrier disruption may also occur at this stage.

C

Figure 6.3. Central pontine and extrapontine myelinolysis—axial FLAIR images at the level of the pons (A) and basal ganglia (B and C) demonstrating classic central pontine pattern of involvement, as well as multiple symmetric sites of extrapontine involvement including the basal ganglia, thalami, and external capsules in a patient with history of alcohol abuse presenting with hyponatremia.

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Subacute Phase Multiple case reports, such as that of Cramer et al., show development of increasing T2 hyperintensity within the central pontine region a week after the development of symptoms, with variable expansion of the pons. DWI images may still show increased signal with corresponding decreased signal on the ADC map. Alternatively, follow-up imaging may show normalized or elevated ADC values, suggesting the disappearance of cytotoxic edema in the later phases despite persistent increased signal on T2-weighted images due to vasogenic edema and/or gliosis. Similarly, enhancement should resolve in the subacute period.

Chronic Phase Usually, the degree and extent of pontine hyperintensity on T2-weighted images decrease a few weeks after the onset of symptoms. Case reports have shown that the milder the signal on T2-weighted images beyond the subacute phase, the better the long-term outcome. The classic configuration of “trident” or “bat wing” pontine T2 hyperintense signal abnormality with sparing of the corticospinal tracts and peripheral pons persists, although the lesion is smaller in size compared with initial imaging due to volume loss. Corresponding T1 hypointensity without enhancement typically also persists. These findings are summarized in Table 6.1, as well as in two MRI cases of CPM (Figs. 6.4 and 6.5).

MIMICS AND DIFFERENTIAL DIAGNOSIS 1. Chronic ischemic changes from microangiopathic disease: These lesions may involve a similar location as CPM but typically do

FLAIR

T2

DWI

ADC

not have restricted diffusion and do not spare the corticospinal tracts. In addition, this entity almost always has associated supratentorial white matter changes (Fig. 6.6). 2. Acute pontine infarct, acute disseminated encephalomyelitis, and demyelination: These lesions may have a similar appearance to CPM but typically are asymmetric and may not spare the peripheral pons and corticospinal tracts (Fig. 6.7). 3. Paraneoplastic processes: These lesions are rare; however, they may be central in the pons and effect extrapontine sites. These lesions will typically resolve with treatment of the associated primary cancer (Fig. 6.8). 4. Brainstem hemorrhage: These hemorrhages demonstrate signal characteristics and evolution as described in the hemorrhage chapter (see Chapter 1) and usually produce susceptibility effects consistent with blood products (Fig. 6.9). 5. Gliomas: typically seen in the pediatric population, with marked pontine expansion that engulfs the basilar artery.

TABLE 6.1  Summary of Central Pontine Myelinolysis Evolution on Imaging MR Sequence

Acute CPM

Subacute CPM

DWI ADC T2/FLAIR T1

↑ ↓ ↑ ↓

↑↑ ↓ or—or ↑ ↑↑ ↓↓

or — or—or ↑ or — or —

Chronic CPM — ↑ ↑ ↓

ADC, Apparent diffusion coefficient; CPM, central pontine myelinolysis; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery.

T1

T1 postcontrast At presentation

4 days later

1 month later

3 months later

9 months later Figure 6.4. Mental status change following orthotopic liver transplant. T2 and FLAIR images demonstrate an initial increase in abnormal signal between presentation and the 4-day follow-up study with progressive decrease in signal and size of abnormality involving the central pons over time (red box). Diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) images demonstrates mildly restricted diffusion early that is replaced by T2 “shine-through” effect in later stages (green box). In addition, active wallerian degeneration is seen to involve the middle cerebellar peduncles at 9-month follow-up related to pontocerebellar disconnection. T1 and T1 postcontrast images demonstrate subtle earlyphase enhancement that resolves in later stages (blue box). There is progressive decrease in size of T1 hypointensity corresponding to sites of T2 signal abnormality in the later stages suggesting volume loss.

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Figure 6.5. Acute and chronic phases of central pontine myelinolysis. Left to right: Axial FLAIR, T2, diffusion, apparent diffusion coefficient (ADC), T1, T1 postcontrast. There is “trident” T2 hyperintensity and T1 hypointensity sparing the peripheral pons and corticospinal tracts. There is subtle DWI hyperintensity with ADC hyperintensity at presentation. Six months later, there is diminished T2 and ADC hyperintensity and T1 hypointensity, pontine volume loss, and resolved DWI hyperintensity. No contrast enhancement is seen at either time point.

A

A

B

Figure 6.6. Small vessel microangiopathic changes of the pons. (A) Axial T2 and (B) axial FLAIR. Chronic microangiopathic changes involving the central pons in an asymptomatic patient. Supratentorial chronic microangiopathic changes were also seen. Note involvement of the corticospinal tracts.

B

Figure 6.7. Acute pontine infarct (A) axial DWI and (B) axial ADC. The patient presented with acute left-sided weakness and slurred speech. An acute right paramedian pontine infarct demonstrates restricted diffusion on DWI and ADC images. Note asymmetry of the lesion compared with central pontine myelinolysis.

Figure 6.8. Paraneoplastic encephalopathy patient with a history of ovarian carcinoma presenting with encephalopathy with marked improvement in mental status following chemotherapy. (Row 1) At presentation, central pontine T2 hyperintense signal with restricted diffusion and T1 hypointensity. The “trident” or “bat wing” morphology of central pontine myelinolysis is absent, although the corticospinal tracts are spared. (Row 2) At 1-month follow-up, there is slight increase in extent of the T2 abnormality within the central pons with peripheral restricted diffusion and central T2 “shinethrough” effect. No enhancement is seen. (Row 3) At 2.5-month follow-up, there is decrease in the size of the T2 hyperintense lesion. Restricted diffusion and T1 hypointensity have resolved. There is a small focus of elevated diffusion (hyperintense on the ADC map). No enhancement is seen. (Row 4) At 4-month follow-up, the T2 hyperintense lesion is smaller in the anterior posterior dimension but longer in the transverse dimension. There is increased facilitated diffusion. No abnormality is identified on T1-weighted images, and there is no abnormal enhancement.

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Figure 6.9. Acute pontine hemorrhage—CT shows hyperdense acute hemorrhage in the central pons. The hemorrhage is mildly hypointense on T1 and markedly hypointense on FLAIR and T2-weighted images, consistent with deoxyhemoglobin. Mild surrounding hyperintense edema is seen on FLAIR and T2-weighted images. There is no abnormal enhancement to suggest an underlying mass lesion. Deoxyhemoglobin causes local susceptibility effects, which results in low signal on DWI. There is also a more chronic hemorrhage with hemosiderin (T1 and T2 hypointense with susceptibility and no surrounding edema) in the medial left cerebellum.

SUGGESTED READING

Adams RD, Victor M, Mancall EL. Central pontine myelinolysis, a hitherto undescribed disease occurring in alcoholic and malnourished patients. AMA Arch Neurol Psychiatry. 1959;81(2):154–172. Alleman AM. Osmotic demyelination syndrome: central pontine myelinolysis and extrapontine myelinolysis. Semin Ultrasound CT MR. 2014;35(2):153–159. Chu K, Kang DW, Ko SB, et al. Case report: diffusion-weighted MR findings of central pontine and extrapontine myelinolysis. Acta Neurol Scand. 2001;104(6):385–388. Cramer SC, Stegbauer KC, Schneider A. Case report: decreased diffusion in central pontine myelinolysis. AJNR Am J Neuroradiol. 2001;22(8):1476–1479. Förster A, Nölte I, Wenz H, et al. Value of diffusion-weighted imaging in central pontine and extrapontine myelinolysis. Neuroradiology. 2013;55(1):49–56. Graff-Radford J, Fugate JE, Kaufmann TJ, et al. Clinical and radiologic correlations of central pontine myelinolysis syndrome. Mayo Clin Proc. 2011;86(11):1063–1067.

Kang SY, Ma HI, Lim YM, et al. Normal diffusion-weighted MRI during the acute stage of central pontine myelinolysis. Int J Neurosci. 2012;122(8):477–479. Martin RJ. Central pontine and extrapontine myelinolysis: the osmotic demyelination syndromes. J Neurol Neurosurg Psychiatry. 2004;75(suppl 3):iii22–iii28. Ruzek KA, Campeau NG, Miller GM. Case report, early diagnosis of central pontine myelinolysis with diffusion-weighted imaging. AJNR Am J Neuroradiol. 2004;25(2):210–213. Venkatanarasimha N, Mukonoweshuro W, Jones J. AJR teaching file: symmetric demyelination. AJR Am J Roentgenol. 2008;191(3 suppl):S34–S36. Yuh WT, Simonson TM, D’Alessandro MP, et al. Temporal changes of MR findings in central pontine myelinolysis. AJNR Am J Neuroradiol. 1995;16(4 suppl):975–977.

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PART IV  Metabolic Disorders

7

Herpes Simplex Encephalitis Gene M. Weinstein, Juan E. Small

INTRODUCTION Herpes simplex encephalitis (HSE) is the most common cause of fatal sporadic encephalitis worldwide. In adults and older children, most cases of HSE are caused by the herpes simplex virus 1 (HSV-1) virus. Patients initially present with nonspecific neurologic signs, including altered mental status, focal cranial nerve defects, hemiparesis, dysphagia, aphasia, ataxia, and seizures, usually with accompanying fevers.1 Symptoms of

encephalopathy then progress with devastating results; the mortality rate exceeds 70% without treatment, with only 11% of survivors returning to baseline function.2 Acyclovir has been the mainstay of treatment for HSE, and the estimated mortality reduction is 70% to 28%.3 The percent of survivors who return to normal function is also higher among acyclovir-treated cohorts.4 Delayed initiation of acyclovir therapy is directly associated with poorer outcome.5 Thus early recognition of HSE and aggressive

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CHAPTER 7  Herpes Simplex Encephalitis

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7

A

B

Figure 7.1. Typical MRI features of herpes simplex encephalitis. (A) On presentation there may be unilateral or bilateral asymmetric involvement of limbic system structures, including the temporal lobes, insulae, and cingulate gyri. Restricted diffusion, representing areas of necrosis, is a characteristic feature but not always present. Extensive FLAIR hyperintensity is typically seen. Areas of enhancement or hemorrhage are sometimes seen. (B) Follow-up imaging after several months shows parenchymal volume loss and some residual FLAIR hyperintensity in the regions most severely affected.

empiric treatment with acyclovir is vital to improve morbidity and mortality.

TEMPORAL EVOLUTION: OVERVIEW The HSV enters the brain via the cranial nerves. Clinical presentation is usually with an acute onset of encephalopathy, with fever being present in almost all cases. Recruitment of local inflammatory responses leads to cytotoxic edema, presenting as restricted diffusion, which is the most apparent imaging finding in the early stage. The initial site of HSE involvement is usually the medial temporal lobes, either unilaterally or bilaterally (in which case it is often asymmetric; Fig. 7.1). HSE has a strong predilection for the limbic system6 and spreads along these pathways to involve the contralateral medial temporal lobe, anterior temporal lobe, parahippocampal gyrus, amygdala, orbitofrontal gyri, mammillary bodies, insula, and fornix. The thalamus, parietal lobes, and occipital lobes may occasionally also be affected. The basal ganglia and brainstem are characteristically spared. As the disease progresses the restricted diffusion normalizes and T2/FLAIR signal increases. Hemorrhage and enhancement can be variably present on imaging, but generally do not impact prognosis. However, fulminant hemorrhagic necrosis of the affected areas leads to a high mortality rate. Survivors often have long-term sequela, manifesting as regional parenchymal volume loss and encephalomalacia on follow-up imaging. A small subset of patients has recurrence of symptoms that is felt to be immune mediated.

TEMPORAL EVOLUTION: IN GREATER DEPTH It is unclear whether HSE is caused by reactivation of a latent HSV-1 infection or if it represents a primary infection. Latent HSV-1 remains in the trigeminal ganglia of asymptomatic patients after the acute illness subsides,7 and it is postulated that the encephalitis is a result of reactivation of the latent virus.8 An

alternative theory is that HSE is a primary infection in which the virus travels to the brain either through the trigeminal nerves or olfactory tracts. The latter is supported by studies demonstrating that in at least half of cases of HSE the strain of the virus identified is different from the one responsible for herpes labialis in that individual,9 as well as studies demonstrating that the percent of HSE patients that provide a history of herpes labialis is not higher than in the general population.10 Regardless of the timing of inoculation, the most widely accepted theory is that the virus gains access to the central nervous system via the cranial nerves, either through the olfactory or trigeminal nerves. Once the virus breaches the brain parenchyma, it triggers an immune reaction that may itself contribute to cell death and tissue destruction. Clinically, HSE presents with nonspecific neurologic findings of an acute (