Practical Neuroimaging in Stroke: A Case-Based Approach 9780750675376, 2009007679

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Practical Neuroimaging in Stroke: A Case-Based Approach Alejandro A. Rabinstein, M.D. Associate Professor of Neurology Department of Neurology Mayo Clinic Rochester, Minnesota

Steven J. Resnick, D.O. Department of Neurology Mount Sinai Medical Center Miami Beach, Florida Voluntary Assistant Professor Neurology Department University of Miami Miller School of Medicine Miami, Florida

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

PRACTICAL NEUROIMAGING IN STROKE: A CASE-BASED APPROACH Copyright © 2009 by Saunders, an imprint of Elsevier Inc.

ISBN: 978-0-7506-7537-6

All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocoping, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (⫹1) 215 239 3804 (US) or (⫹44) 1865 843830 (UK); fax: (⫹44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions.

Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. 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 the practitioner, relying on their own experience and knowledge of the patient, 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 Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher

Library of Congress Cataloging-in-Publication Data Rabinstein, Alejandro A. Practical neuroimaging in stroke : a case-based approach / Alejandro A. Rabinstein, Steven J. Resnick. -- 1st ed. p. ; cm. Includes bibliographical references and index. ISBN 978-0-7506-7537-6 1. Cerebrovascular disease--Imaging. I. Resnick, Steven J. II. Title. [DNLM: 1. Stroke--diagnosis. 2. Brain--blood supply. 3. Brain--pathology. 4. Diagnostic Imaging. WL 355 R116p 2009] RC388.5.R325 2009 616.8’1075--dc22 2009007679

Acquisitions Editor: Adrianne Brigido Developmental Editor: Joan Ryan Project Manager: Mary Stermel Design Direction: Karen O’Keefe Owens Marketing Manager: Courtney Ingram

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To my wife Carlota, my driving force, my guiding light, my safe harbor, and my destiny. To our children Hannah and Joshua, whose sweetness renews everyday the meaning of our lives. And to my father, who lives in me through his example. Alejandro A. Rabinstein To my beautiful wife, Elizabeth, and my boys, Jared, Koby, and Evan, without which none of this would have meaning. Elizabeth, thank you for always standing by my side and encouraging me. I love you more than words. I would also like to express gratitude and thanks to my loving parents, Jimmy and Lidia, for their guidance and support throughout my life. Steven J. Resnick

Contributors Sebastian Koch, M.D.

Steven J. Resnick, D.O.

Associate Professor of Clinical Neurology Department of Neurology University of Miami Miller School of Medicine Jackson Memorial Hospital Miami, Florida

Department of Neurology Mount Sinai Medical Center Miami Beach, Florida Voluntary Assistant Professor Neurology Department University of Miami Miller School of Medicine Miami, Florida

Nils Mueller-Kronast, M.D. Voluntary Clinical Assistant Professor of Medicine Indiana University School of Medicine Indianapolis, Indiana Director, NeuroInterventional Service Parkview Memorial Hospital Neurologist Fort Wayne Neurological Center President, Stroke Care Now Network Fort Wayne, Indiana

Alejandro A. Rabinstein, M.D. Associate Professor of Neurology Department of Neurology Mayo Clinic Rochester, Minnesota

Jose G. Romano, M.D. Associate Professor of Clinical Neurology Director, Cerebrovascular Division Department of Neurology University of Miami Miller School of Medicine Miami, Florida

Alexander Y. Zubkov, M.D., Ph.D. Director of Stroke Center Fairview Southdale Hospital Neurologist Minneapolis Clinic of Neurology Edina, Minnesota

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Preface We are convinced that Medicine is best taught case by case. We also believe that visual information has enormous didactic value and can anchor teaching messages expressed by words. With these two convictions in mind, we decided to pursue this project. Our goal was to design a practical book discussing the value of neuroimaging in the contemporary diagnosis and treatment of cerebrovascular diseases, one case at a time and image by image. This is a book written by clinicians for clinicians. The reader will not find detailed expositions on the technical aspects of neuroimaging modalities. There are several monographs authored by prominent neuroradiologists that are excellent resources for radiologists training in neurovascular imaging and great consultation material for trained radiology specialists. We hope neuroradiologists find our work enticing and the images appealing, but the book is addressed to clinicians interested in learning about how neuroimaging modalities can help them in their everyday management of stroke patients. We wanted the chapters to follow a straightforward pattern. They all start with a brief introduction to the general concepts of each topic. Then, concise case vignettes are presented including only the information most relevant to the educational messages of the images. The images themselves constitute the core of the chapters. They illustrate how they helped define diagnosis, guide management decisions, estimate prognosis, or sometimes serve as a means of therapeutic interventions. The diagnostic modalities shown throughout

the book are the ones we use in practice nowadays. The illustrations are followed by brief and eminently practical teaching messages, most often in the form of bullet points to maintain focus and emphasize conciseness. Extensive discussions were purposefully avoided to enhance the clarity of the text and preserve the power of the image-driven messages. Comprehensive and updated reference lists should serve as good resources for further quality reading on each subject. All images presented in this book are from patients we have treated. For us, these images are not just illustrative scans. They have real faces behind them. They bring back to our minds our successes and our failures. They remind us what our patients taught us. The discussion of the interpretation of the images reproduces the actual discussions we had at the bedside. The teaching messages we include in these chapters are the same ones we tried to convey to the trainees who shared with us the responsibility of caring for those patients. Composing this book was much harder than we expected. Finding the cases to provide graphic illustrations for all the major teaching messages we wanted to incorporate in the various chapters proved to be quite challenging. We kept working at it because we truly felt that the final product would fill an important gap on the otherwise crowded shelves of books concerning cerebrovascular diseases and be useful to the readers attending stroke patients. The work is finally done. We can only hope we fulfilled our goals. Alejandro A. Rabinstein, on behalf of all the authors

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Acknowledgements The majority of the patients included in this book were treated at Jackson Memorial Hospital (Miami, Florida, USA) and the medical campus of the University of Miami Miller School of Medicine. We want to acknowledge the continuous commitment of these two institutions to provide quality care to stroke patients.

We also want to thank Susan Pioli for her support to the original idea of this book and Adrianne Brigido, Joan Ryan, and Michael Troy for helping us bring the project to fruition.

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Chapter

1

Hypoxic-Ischemic Brain Damage Alejandro A. Rabinstein and Steven J. Resnick

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he brain is our most essential organ but also the most sensitive to oxygen deprivation. Diffuse hypoxia and ischemia result in global cerebral damage that follows a typical pattern defined by the selective vulnerability of brain regions. Irreversible injury occurs when systemic blood pressure drops below the minimal levels required for sustaining effective brain metabolism and energy production. Physiologically, this occurs when mean arterial pressure falls below the lower limit of cerebral autoregulation. Whereas moderately severe reductions in cerebral blood flow and oxygen supply result in depression or suppression of brain tissue metabolism, critically severe reductions cause irreversible disruption of cellular membranes (responsible for the development of cytotoxic edema) and cell death. The most characteristic example of hypoxic-ischemic brain damage is produced by cardiac arrest. Attempts to prognosticate outcome accurately after cardiac arrest have generated abundant research. Although clinical examination remains the preeminent tool to predict the chances of recovery after cardiac resuscitation, a number of electrophysiological and neuroimaging techniques provide valuable aid.1,2 This chapter summarizes the most important and useful features of neuroimaging in the diagnosis and prognosis of patients with global hypoxicischemic brain damage. Computed tomography (CT) scan has limited sensitivity to diagnose the extent of brain damage after a

diffuse hypoxic insult. Loss of the normal differentiation between cortical gray matter and subcortical white matter and effacement of the delineation of deep gray matter structures are the best known signs of global hypoxia on CT scan. They represent early stages of brain swelling, mostly due to cytotoxic edema. However, these findings may be subtle and difficult to recognize. Additionally, CT scans can be deceiving, showing little change in patients with severe hypoxic damage or presenting signs that may be confused with other conditions (i.e., pseudosubarachnoid hemorrhage).3–5 In patients who develop areas of infarction, CT scans may fail to reveal any focal hypodensities until 24 to 48 hours after the episode. In contrast, magnetic resonance imaging (MRI) scans are extremely useful to recognize the severity of structural damage even very shortly after a hypoxicischemic event. The prognostic usefulness of MRI scans is becoming increasingly well established. The advent of diffusion-weighted imaging (DWI) has added a new dimension to the role of MRI in the workup of patients with acute global brain hypoxia-ischemia. This sequence allows good visualization of laminar necrosis and other characteristic signs of hypoxic injury, and it offers reliable information of prognostic importance with unsurpassed promptness.5–11. Figure 1-1 summarizes the main radiological findings encountered in patients with severe hypoxic-ischemic brain damage. 1

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Hypoxic-Ischemic Brain Damage SUMMARY OF HYPOXIC-ISCHEMIC BRAIN DAMAGE Basal ganglia

Cerebral cortex

Sequence

CT

DWI

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T1 with Contrast

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Figure 1-1. Imaging findings in patients with hypoxic-ischemic brain damage affecting the basal ganglia and cerebral cortex. First row: Axial computed tomography (CT) of the basal ganglia showing symmetrical hypodensity in the caudate nuclei (left). Axial CT scans of the brain without contrast revealing linear hyperdensity outlining the cortex (right). Second row: Axial diffusion-weighted imagery (DWI) magnetic resonance imaging (MRI) scan demonstrates bilateral symmetrical hyperintensity within the stratiocapsular regions (left). Axial DWI MRIs show diffuse hyperintense signal change in the cerebral cortex indicating laminar necrosis (right). Third row: Axial T1-weighted MRI shows bilateral symmetrical hyperintense signals within the putamen bilaterally (left). Axial T1-weighted MRIs show bilateral areas of cortical hyperintensity representing laminar necrosis (right). Fourth row: Axial T1-weighted MRI with contrast discloses bilateral symmetrical enhancement in the external putamen bilaterally (left). Axial and sagittal T1-weighted MRI with contrast show linear enhancement outlining the cortex, predominantly located in the occipital lobes (right). Fifth row: Axial fluid-attenuated inversion recovery (FLAIR) MRI denoting bilateral symmetrical hyperintense signals in the lenticular nuclei (left). Examples of axial FLAIR MRI showing diffuse and focal cortical hyperintensities distributed throughout the cerebral cortex or preferentially in the medial occipital cortex (right).

Hypoxic-Ischemic Brain Damage

Case Vignette A 29-year-old, previously healthy man collapsed after a lightning strike. A bystander at the scene noted absence of pulse and audible heartbeat and performed basic cardiopulmonary resuscitation for nearly 15 minutes. On arrival, paramedics confirmed the diagnosis of cardiac arrest and initiated full advanced cardiac life support. Electrical defibrillation resulted in return of spontaneous circulation. Initial neurological examination at the hospital revealed that the patient was comatose but with intact brainstem reflexes. He had a Glasgow coma scale sum score of 4 and exhibited frequent

myoclonic jerks (myoclonic status). He subsequently failed to regain consciousness. Five days later, he was transferred to a tertiary care center. That day, an electroencephalogram (EEG) showed a very low-amplitude, slow (delta, occasional theta) background. A brain CT scan disclosed severe diffuse edema (Figure 1-2, upper row). A brain MRI performed 13 days after the insult displayed signs of extensive laminar necrosis (Figure 1-2, lower row). A second EEG was essentially unchanged almost 1 month after the arrest. He remained in vegetative state 2 months later.

Figure 1-2. Computed tomography (CT) scan of the brain showing effacement of the perimesencephalic cisterns (thin arrows) and areas of parenchymal low attenuation (thick arrows, upper left). Lower cut of the same CT scan reveals diffuse sulcal effacement with decreased differentiation between gray and white matter (upper right). T1-weighted magnetic resonance imaging scan showing high-intensity signals in the lenticular nuclei (arrows, lower left). Fluid-attenuated inversion recovery sequence disclosing hyperintense signal in the medial occipital cortices indicative of laminar necrosis (arrows, lower right).

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As illustrated by this case, after an anoxic-ischemic event, CT may show signs of cerebral edema such as effacement of sulci, loss of differentiation between cortical gray matter and underlying white matter, blurring of the insular ribbon, and loss of distinction of the margins of the deep gray nuclei (particularly the lenticular nucleus). Watershed infarctions may be evident after the first 24 to 48 hours. In the most severe cases, CT scan may actually display reversal of the gray/white matter densities with relatively increased density of the thalami, brainstem, and cerebellum (“reversal sign”).12 This is associated with an ominous prognosis (Figure 1-3). Although CT scan may occasionally show early changes,13 it is most often normal hours after the insult and may remain unremarkable at later stages, even in patients with extensive neurological damage.5

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MRI is far more sensitive in the depiction of hypoxic-ischemic damage. It allows prompt and reliable identification of areas of laminar necrosis unrecognizable by CT scan.5 MRI findings, especially extensive cortical laminar necrosis and presence of changes in the brainstem and white matter, are associated with poor chances of recovery.5,7,11 Apart from cortical necrosis, MRI may exhibit changes in the cerebellum and basal ganglia, which may be present quite early. Cerebellar changes are often inconspicuous. Conversely, we have found an abnormal signal in the basal ganglia in the great majority of our patients, although the time of its appearance may vary. White matter abnormalities tend to manifest in the late subacute and chronic phases (after 10 days from the time of injury).6

ADDITIONAL EXAMPLES OF GLOBAL BRAIN EDEMA

Figure 1-3. Additional case illustrating the changes of severe of anoxic brain injury on computed tomography (CT) scan. A 55-year-old man had a cardiac arrest after surgery. CT scan 12 hours after the arrest shows effacement of the cortical sulci, loss of distinction of gray white matter junction, and slit-like lateral ventricles suggestive of diffuse cerebral edema (left). Higher cut displays multiple areas of decreased attenuation due to diffuse cerebral edema in a gyriform distribution over the hemispheric convexities (right).

Hypoxic-Ischemic Brain Damage

Cortical Laminar Necrosis ❖

Cortical laminar necrosis occurs because of the selective vulnerability of cortical layers 3, 4, and 5 to anoxia and ischemia. In addition to neurons, glial cells and blood are also damaged, resulting in a pan-necrosis. The selective vulnerability of gray matter may be due to higher metabolic demand and denser concentration of receptors for excitatory amino acids that are released after the anoxic-

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ischemic event, precipitating the mechanism of excitotoxicity. Early cytotoxic edema in these injured cells is responsible for the bright signals seen on DWI and the corresponding low apparent diffusion coefficient (ADC) values7,10,11 (Figures 1-4 and 1-5). The hyperintense signal observed on T1-weighted sequences is believed to be caused by the accumulation of denatured proteins in dying cells and does not represent presence of hemorrhage14,15(Figure 1-6).

Figure 1-4. Diffusion-weighted imaging sequence (left) and corresponding apparent diffusion coefficient maps (right) of a brain magnetic resonance image from a 51-year-old woman obtained 16 hours after resuscitation from prolonged cardiac arrest. Note restricted diffusion in the lenticular nuclei and throughout the cortex of both cerebral hemispheres. The patient remained comatose and expired 3 days later after withdrawal of life support.

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Hypoxic-Ischemic Brain Damage

Figure 1-5. Additional example of restricted diffusion affecting extensively the cortex of both cerebral hemispheres in a 58-year-old patient who underwent cardiopulmonary resuscitation after out-of hospital ventricular fibrillation. Images shown are diffusion-weighted imaging sequence (left) and apparent diffusion coefficient map (right) from a brain magnetic resonance image performed 46 hours after the cardiac arrest.

Figure 1-6. T1-weighted magnetic resonance imaging (MRI) scan showing patchy areas of cortical hyperintensity representing laminar necrosis (thin arrows). Also notice hyperintense signal in the putamen (thick arrows). This MRI scan was performed nearly 3 weeks after a cardiac arrest,

Hypoxic-Ischemic Brain Damage ❖

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Laminar necrosis may be identified within hours of the anoxic-ischemic event. In this acute phase (particularly the first 24 hours), DWI is far superior to conventional MRI sequences in its ability to distinguish cortical changes.6,7,11 ADC values are typically decreased to values ranging from 60% to 80% of normal.11 Cortical diffusion abnormalities are associated with poor outcome after cardiac arrest.16 T1 hyperintensities signaling laminar necrosis become evident after 2 weeks, peak at 1 to 3 months, and then fade slowly but can still be visible as late as 2 years after the insult. On fluid-attenuated inversion recovery (FLAIR), injured cortical areas are more prominently hyperintense between 1 month and 1 year after the event.14,15

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However, we have observed cortical changes on FLAIR within a few days of the anoxic insult (Figure 1-7). Affected cortex tends to appear isointense to slightly hyperintense on T2-weighted sequence. In our experience, this sequence offers limited value for the accurate diagnosis of laminar necrosis. Cortical enhancement is first seen after 2 weeks, peaks after 1 to 2 months, and is usually resolved after 6 months14,15 (Figure 1-8). Very severe cases of cortical necrosis can be visualized on CT scan, either in the form of gyriform high attenuation (likely caused by local hemorrhage) (Figure 1-9) or areas of cortical hypoattenuation (Figure 1-10).

Figure 1-7. Two cases of anoxic brain injury depicted on fluidattenuated inversion recovery (FLAIR) sequences. Upper row: FLAIR sequence of a brain magnetic resonance imaging (MRI) scan of a patient with persistent coma 6 days after being resuscitated from a cardiac arrest. It shows diffusely increased signal intensity in the insular, high frontal, parietal, and occipital cortex. The cortex also appears swollen in this relatively early stage. Lower row: Another example of cortical changes on FLAIR but in a later stage. This MRI was obtained 12 days after cardiac arrest. In addition to the high-intensity signal changes in the cortex, the lenticular nuclei also appear hyperintense bilaterally.

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Figure 1-8. Magnetic resonance imaging scan of the brain with gadolinium performed for prognostic purposes 1 month after cardiac arrest in a 45-year-old woman with limited recovery. She was fully incapacitated and was suspected to be cortically blind. Notice diffuse cortical enhancement predominantly involving the occipital and perirolandic cortical areas. The figure shows enhanced T1-weighted sequences with axial cuts (upper row), sagittal cut (lower left), and coronal cut (lower right).

Hypoxic-Ischemic Brain Damage

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Figure 1-9. This figure illustrates the changes caused by cortical laminar necrosis on computed tomography scan. Cortical edema (low attenuation) can be combined with small areas of hyperdensity (likely caused by hemorrhage or vascular congestion). These changes can be rather subtle as seen in the upper left (with magnified view on the upper right) or, less commonly, more manifest as shown in the lower row (arrowheads).

Figure 1-10. Computed tomography scan of the brain shows multifocal areas of severe cortical edema 3 days after cardiac arrest in a patient with persistent coma and myoclonic status. Basal ganglia also exhibit low attenuation.

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Hypoxic-Ischemic Brain Damage

Basal Ganglia Involvement ❖

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Changes in the deep gray nuclei are seen in most cases of anoxic-ischemic brain damage. Bilateral thalami, lenticular nuclei, and caudate nuclei may be involved. As exhibited by the illustrations, the distribution of lesions is not uniform across patients and may change over time in each patient (Figures 1-11 and 1-12). Lesions may be seen in association with cortical laminar changes or in isolation.

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Although signal changes are often present early, the time of appearance varies. The factors determining the timing and extent of these lesions remain to be established. Basal ganglia injury may be the anatomical substrate that accounts for the various adventitious movements frequently seen in survivors of cardiac arrest and other severe hypoxic-ischemic events.

Figure 1-11. Magnetic resonance imaging (MRI) scans showing evidence of basal ganglia involvement after anoxic insults. Upper row: Diffusion-weighted imagery sequence revealing restricted diffusion on bilateral putamen and caudate nuclei (left) and in the caudate nuclei and cortical areas (right). Lower row: T1-weighted sequence showing high-intensity signal in the putamen bilaterally (axial view on the left and coronal on the right). Note associated medial occipital changes on the axial cut.

Hypoxic-Ischemic Brain Damage

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Figure 1-12. Magnetic resonance imaging (MRI) scans showing evidence of basal ganglia involvement after cardiac arrest. Upper row: T2-weighted sequence displaying increased signal in lenticular nuclei, caudate nuclei, and throughout the cortical layer. Lower two rows: Various examples of anoxic changes affecting the basal ganglia on FLAIR. Notice that these changes may occur only in the deep structures (middle row) or may also involve cortical areas (lower row). The distribution of lesions in the basal ganglia may vary. See predominant putaminal involvement in the middle and lower images of the left column, combined caudate and lenticular involvement on the middle right, and predominant thalamic lesions in the lower right.

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Hypoxic-Ischemic Brain Damage

Watershed Infarctions ❖

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Watershed infarctions caused by a diffuse anoxicischemic insult appear to be more common in neonates and children. In adults, we have observed these lesions more often in patients who survive the event. In addition, watershed infarcts are not typically seen in conjunction with extensive laminar necrosis (Figure 1-13).

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It is tempting to hypothesize that watershed infarcts occur in cases of severe hypoperfusion without anoxia (as happens when they are caused by carotid occlusion or critical stenosis with systemic hypotension), whereas laminar necrosis results from anoxic injury.

Figure 1-13. Images demonstrate watershed infarctions after cardiac arrest. Upper row: Diffusionweighted imaging sequence showing restricted diffusion in internal and external watershed distributions 4 days after cardiac arrest in a pediatric patient. Lower row: Early changes already observed in the fluidattenuated inversion recovery sequence. Notice that the changes extend beyond typical watershed territory to affect larger areas of the frontal cortex on the right hemisphere.

Hypoxic-Ischemic Brain Damage

Vulnerable Cortical Areas: Perirolandic and Occipital Cortex ❖

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The perirolandic (Figure 1-14) and occipital cortex (Figure 1-15) are often involved to a greater extent than other cortical areas. In our experience, the medial occipital cortex is the area most commonly affected after anoxic-ischemic brain injury. The intense baseline metabolic demand of these regions may explain their selective vulnerability. Although it is commonly held that the hippocampi in the mesial temporal lobes are the cortical areas most susceptible to anoxia, radiological evidence of damage to these structures is seen much less com-

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monly after cardiac arrest than are lesions in the medial occipital lobes and perirolandic regions. However, it has been suggested that the damage to the hippocampus (along with the corpus callosum and white matter) may occur as a delayed manifestation of brain anoxia.17 Presence of diffusion abnormalities or T1 hyperintensity in these cortical areas in a patient with coma of unclear cause should be considered strongly supportive of the diagnosis of hypoxic-ischemic brain damage. Cerebellar lesions may be prominent in certain severe cases, and cerebellar ischemia is probably an extremely poor prognostic indicator (Figure 1-16).

Figure 1-14. This figure illustrates predominant anoxic changes in the perirolandic regions after cardiac arrest. Upper row: Restricted diffusion on diffusion-weighted imaging (left) and corresponding dark signal on the apparent diffusion coefficient map (right) in a 56-year-old man who sustained prolonged ventricular fibrillation-arrest 5 days before. Lower row: FLAIR sequence shows high-intensity signal outlining the perirolandic cortex (normal view on the left and magnified view on the right).

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Figure 1-15. Figure demonstrating predominant involvement of changes indicative of laminar necrosis in the occipital cortex (arrows). Diffusion-weighted imaging sequence is shown in the upper left and FLAIR sequence in the rest of the images. Notice selective involvement of medial occipital cortex and relative sparing of mesial temporal structures.

Figure 1-16. Evidence of cerebellar lesions after brain anoxia is seen in this magnetic resonance image of an 84-year-old woman who had prolonged respiratory arrest. Diffusion-weighted image showing extensive areas of restricted diffusion in both cerebellar hemispheres (left). T2-weighted sequence also shows high signal intensity in these regions (right).

Hypoxic-Ischemic Brain Damage

False Radiological Signs: Pseudo-Subarachnoid Hemorrhage and False Middle Cerebral Artery Sign ❖

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False appearance of subarachnoid hemorrhage (SAH), or pseudo-SAH, may be seen in cases of advanced diffuse cerebral edema,3 including that caused by anoxia-ischemia4 (Figure 1-17, upper row). The most plausible explanation for the occurrence of this phenomenon is a combination of displacement of hypoattenuated cerebrospinal fluid, engorgement of pial compliance vessels, and edema in the adjacent cortex.3 As displayed in our cases, increased attenuation within the falx, tentorium, and, most remarkably, the basal cisterns is responsible for the possible misdiagnosis of SAH. This appearance may be particularly deceptive in patients with coma of unclear

Figure 1-17. False radiological signs in computed tomography scans after severe brain anoxia: pseudo-subarachnoid hemorrhage and false hyperdense middle cerebral artery sign. Pseudosubarachnoid hemorrhage thick arrows in the tentorium and sulci in the upper left panel and in the perimesencephalic cisterns in the upper right panel. Thin arrows mark examples of false hyperdense middle cerebral artery signs. Notice extensive brain swelling in all cases.

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etiology; in these patients, it may result in unnecessary testing. The pitfall of mistakenly diagnosing SAH in patients with global edema may be avoided by being aware of this possibility. When in doubt, it is useful to pay special attention to the attenuation values in the basal cisterns, because they are much lower in these false cases than those observed in true cases of SAH.3 As clearly shown by the images in Figure 1-17, patients with severe brain edema may also exhibit the false appearance of unilateral or, most often, bilateral middle cerebral artery (MCA) signs, which would suggest bilateral stroke rather than diffuse anoxia-ischemia. Close attention to the presence of signs of diffuse swelling beyond the boundaries of restricted arterial vascular territories helps avoid this misdiagnosis.

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Hypoxic-Ischemic Brain Damage

Early and Delayed White Matter Changes: Anoxic Leukoencephalopathy ❖

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White matter lesions typically become visible in the late subacute or chronic phase of evolution of anoxicischemic brain damage and worsen over time.6,18 (Figure 1-18). It has been suggested that this delayed leukoencephalopathy may be more common after prolonged

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hypoxemia combined with hypotension and acidosis,19 yet surprisingly little research addressing this form of leukoencephalopathy has been reported in the literature. Early white matter changes have been observed in some patients.20 The actual prevalence of this finding is unclear, but from our experience, it is probably quite low.

Figure 1-18. Seventy-year-old man with poor recovery 2 weeks after prolonged cardiorespiratory arrest complicated with renal failure and associated with severe acidosis. Mild initial improvement in alertness was followed by irreversible decline. Upper row: Axial diffusion-weighted imaging sequence shows patchy areas of bright signal within the white matter suggestive of anoxic leukoencephalopathy. These bright spots matched with low apparent diffusion coefficient (ADC) on the ADC map (not shown). Lower row: Axial FLAIR shows extensive white matter changes in the same patient.

Hypoxic-Ischemic Brain Damage

References 1. Levy DE, Caronna JJ, Singer BH, Lapinski RH, Frydman H, Plum F. Predicting outcome from hypoxic-ischemic coma. JAMA 1985; 253:1420–1426. 2. Maramattom BV, Wijdicks EF. Postresuscitation encephalopathy. Current views, management, and prognostication. Neurologist 2005; 11:234–243. 3. Given CA, Burdette JH, Elster AD, Williams DW III. Pseudo-subarachnoid hemorrhage: a potential imaging pitfall associated with diffuse cerebral edema. AJNR Am J Neuroradiol 2003; 24:254–256. 4. Phan TG, Wijdicks EF, Worrell GA, Fulgham JR. False subarachnoid hemorrhage in anoxic encephalopathy with brain swelling. J Neuroimaging 2000; 10:236–238. 5. Wijdicks EF, Campeau NG, Miller GM. MR imaging in comatose survivors of cardiac resuscitation. AJNR Am J Neuroradiol 2001; 22:1561–1565. 6. Arbelaez A, Castillo M, Mukherji SK. Diffusion-weighted MR imaging of global cerebral anoxia. AJNR Am J Neuroradiol 1999; 20:999–1007. 7. Els T, Kassubek J, Kubalek R, Klisch J. Diffusion-weighted MRI during early global cerebral hypoxia: a predictor for clinical outcome? Acta Neurol Scand 2004; 110:361–367. 8. Goto Y, Wataya T, Arakawa Y, Hojo M, Chin M, Yamagata S et al. [Magnetic resonance imaging findings of postresuscitation encephalopathy: sequential change and correlation with clinical outcome]. No To Shinkei 2001; 53:535–540. 9. Komiyama M, Nishikawa M, Yasui T. Cortical laminar necrosis in brain infarcts: chronological changes on MRI. Neuroradiology 1997. 39:474–479. 10. McKinney AM, Teksam M, Felice R, Casey SO, Cranford R, Truwit CL, et al. Diffusion-weighted imaging in the setting of diffuse cortical laminar necrosis and hypoxicischemic encephalopathy. AJNR Am J Neuroradiol 2004; 25:1659–1665.

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11. Lovblad KO, Wetzel SG, Somon T, Wilhelm K, Mehdizade A, Kelekis A, et al. Diffusion-weighted MRI in cortical ischaemia. Neuroradiology 2004; 46:175–182. 12. Han BK, Towbin RB, De Courten-Myers G, McLaurin RL, Ball WS Jr. Reversal sign on CT: effect of anoxic/ischemic cerebral injury in children. AJNR Am J Neuroradiol 1989; 10:1191–1198. 13. Tippin J, Adams HP Jr, Smoker WR. Early computed tomographic abnormalities following profound cerebral hypoxia. Arch Neurol 1984; 41:1098–1100. 14. Komiyama M, Nakajima H, Nishikawa M, Yasui T. Serial MR observation of cortical laminar necrosis caused by brain infarction. Neuroradiology 1998; 40:771–777. 15. Siskas N, Lefkopoulos A, Ioannidis I, Charitandi A, Dimitriadis AS. Cortical laminar necrosis in brain infarcts: serial MRI. Neuroradiology 2003; 45:283–288. 16. Barrett KM, Freeman WD, Weindling SM, Brott TG, Broderick DF, Heckman MG, et al. Brain injury after cardiopulmonary arrest and its assessment with diffusionweighted magnetic resonance imaging. Mayo Clin Proc 2007; 82:828–835. 17. Konaka K, Miyashita K, Naritomi H. Changes in diffusionweighted magnetic resonance imaging findings in the acute and subacute phases of anoxic encephalopathy. J Stroke Cerebrovasc Dis 2007; 16:82–83. 18. Takahashi S, Higano S, Ishii K, Matsumoto K, Sakamoto K, Iwasaki Y, et al. Hypoxic brain damage: cortical laminar necrosis and delayed changes in white matter at sequential MR imaging. Radiology 1993; 189:449–456. 19. Ginsberg MD, Hedley-Whyte ET, Richardson EP Jr. Hypoxicischemic leukoencephalopathy in man. Arch Neurol 1976; 33:5–14. 20. Chalela JA, Wolf RL, Maldjian JA, Kasner SE. MRI identification of early white matter injury in anoxic-ischemic encephalopathy. Neurology 2001; 56:481–485.

Chapter

2

Clinical-Anatomical Syndromes of Ischemic Infarction Alejandro A. Rabinstein and Steven J. Resnick

I

schemic stroke can be defined as a sudden focal neurological deficit corresponding to a vascular distribution. Brain imaging techniques allow us to visualize lesions with great anatomical precision. However, optimal interpretation of the information provided by neuroimaging requires having detailed knowledge of the arterial anatomy (Figures 2-1 through 2-4) and the vascular territories of the brain (Figure 2-5). Brain imaging has also enhanced our understanding of clinical-anatomical correlations in patients with ischemic infarctions. Before the development of modern neuroimaging modalities, these correlations could only be established by necropsy studies. In fact, clinical research using radiological data has shown that localization based on classical semiological syndromes may often be incorrect. Similar clinical presentations may occur in patients with strokes in different territories and, con-

versely, infarctions in the same territory may produce dissimilar manifestations in different patients. Nonetheless, accurate diagnosis relies on the recognition of the brain lesion in a defined vascular territory. This chapter provides illustrations of ischemic infarctions in all major vascular territories and presents the most common clinical correlations. It is conceived as a practical and concise guide to the correct interpretation of brain imaging and not as a comprehensive anatomical or semiological monograph on this important topic. The reader should keep in mind that the variety of distribution of infarctions encountered in practice is enormous. The boundaries of arterial territories are far from invariable across patients, and anatomical variations in the constitution of the cerebral circulation and its interconnections are relatively common.

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Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-1. Anterior circulation, frontal view on conventional angiogram (top) and three-dimensional angiogram (bottom). ICA, internal carotid artery; ACA, anterior cerebral artery; MCA, middle cerebral artery.

Clinical-Anatomical Syndromes of Ischemic Infarction Contralateral callosomarginal branch

Posterior internal frontal branch Middle internal frontal branch

Paracentral lobule artery of ACA Inferior internal parietal branch

Anterior internal frontal branch

Superior internal parietal branch Anterior branch MCA

Callosomarginal branch of ACA

Prerolandic artery* Prefrontal*

Frontopolar branch ACA

Posterior parietal branch MCA

Rolandic artery*

Angular artery MCA

Orbital-frontal*

Temporo-occipital branch MCA

Pericallosal branch ACA

Anterior choroidal artery Supraclinoid segment ICA Cavernous segment ICA Presellar segment ICA Orbitofrontal branch ACA

ICA (horizontal petrous segment) ICA (vertical petrous segment) Ophthalmic artery (OA)

Anterior genu intracavernous segment ICA

ICA (cervical segment)

* = branches of the anterior (superior) division of MCA

Figure 2-2. Anterior circulation, lateral view on conventional angiogram (top) and three-dimensional angiogram (bottom). ICA, internal carotid artery; ACA, anterior cerebral artery; MCA, middle cerebral artery.

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Clinical-Anatomical Syndromes of Ischemic Infarction

Parieto-occipital branch of posterior cerebral artery

Posterior thalamoperforator

Calcarine artery of posterior cerebral artery Duplicated SCA Inferior temporal branch of posterior cerebral artery Basilar artery Pontine perforator SCA PICA Vertebral artery (intradural) Hemispheric branch (PICA)

AICA

Vertebral artery (extradural)

Vertebrobasilar junction

Occipital artery Anterior spinal artery

C1-anastomosis to occipital artery

Figure 2-3. Posterior circulation, frontal view on conventional angiogram (top) and three-dimensional angiogram (bottom). PICA, posterior-inferior cerebellar artery; AICA, anterior-inferior cerebellar artery; SCA, superior cerebellar artery.

Clinical-Anatomical Syndromes of Ischemic Infarction Splenial branch of posterior cerebral artery Lateral posterior choroidal artery Parieto-occipital branch of PCA

Thalamus blush Medial posterior choroidal artery

Calcarine artery of PCA

Posterior thalamoperforator Anterior thalamoperforator

SCA

Posterior communicating artery Temporal branch of posterior cerebral artery

Vernian branch of PICA

AICA Tousil

Vertebrobasilar junction

Hemispheric branch of PICA

PICA

Anterior spinal artery

Vertebral artery

Figure 2-4. Posterior circulation, lateral view on conventional angiogram (top) and three-dimensional angiogram (bottom). PICA, posterior-inferior cerebellar artery; AICA, anterior-inferior cerebellar artery; SCA, superior cerebellar artery; PCA, posterior cerebral artery.

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Clinical-Anatomical Syndromes of Ischemic Infarction

A

A

A M

M M

P

A P M

P

P

Figure 2-5. Arterial territories of the cerebral hemispheres. Coronal image is shown on the left, axial in the middle, and sagittal on the right. A ⫽ anterior cerebral artery territory, M ⫽ middle cerebral artery territory, P ⫽ posterior cerebral artery territory.

CAROTID BIFURCATION OCCLUSION Case Vignette A 61-year-old man with history of coronary artery disease, previous myocardial infarction, and multiple vascular risk factors presented to the emergency department with global aphasia and right hemiplegia for more than 6 hours. On examination, he was drowsy and exhibited forced left gaze deviation, right hemianopia, right flaccid hemiplegia involving the arm and the leg to similar degree, and absent response to pain on the right side. Diffusion-weighted imagery (DWI) of the brain revealed a large area of ischemia in the left hemisphere, including the territories of the anterior and middle cerebral arteries (Figure 2-6).

Fluid-attenuated inversion recovery (FLAIR) sequence showed no parenchymal hyperintensity but disclosed extensive hyperintense signal in the left middle cerebral artery consistent with fresh thrombus (Figure 2-7). Magnetic resonance angiography (MRA) of the intracranial circulation confirmed the presence of a left carotid terminus occlusion (Figure 2-7). The patient was subsequently diagnosed with acute myocardial infarction and a left ventricular mural thrombus. His neurological condition deteriorated over the following 48 hours, and he expired after care was restricted to palliative measures.

Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-6. Diffusion weighted imaging (left) and apparent diffusion coefficient map (right) of the brain magnetic resonance imaging show extensive areas of restricted diffusion—indicative of cellular edema—in the territories of the left anterior and middle cerebral arteries.

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Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-7. Fluid-attenuated inversion recovery magnetic resonance imaging showing hyperintense signal (top row, arrow) in the left middle cerebral artery extending from the top of the intracranial carotid artery caused by acute thromboembolism; regular (left) and enhanced views (right). Hyperintense signal is also seen in the left anterior cerebral artery (lower left panel, arrowhead). Magnetic resonance angiogram of the intracranial circulation confirms the diagnosis of left carotid terminus occlusion (lower right panel).

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Occlusion of the carotid bifurcation (carotid terminus or carotid T) typically results in infarction on the anterior cerebral and middle cerebral artery territories, including the deep structures perfused by the lenticulostriate branches (Figure 2-8). Patients often present with depressed level of consciousness, forced gaze deviation toward the side of the infarction, contralateral homonymous hemianopia, dense contralateral hemiparesis or hemiplegia (face, arm, and leg), and contralateral sensory loss. Aphasia is present when the infarction affects the dominant hemisphere and neglect when the nondominant side is affected. Decreased alertness and profound leg weakness are the most useful clinical signs to differentiate a carotid T occlusion from the more common middle cerebral artery stroke.

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An intravascular hyperdensity at the level of the carotid bifurcation may often be seen on CT scan. Thin-section computed tomography (CT) scans1 and T2* gradient echo magnetic resonance (MR) sequence2 may reveal intra-arterial thrombus with greater sensitivity. Early recognition of this massive stroke is essential because mortality is the rule unless prompt recanalization may be achieved (Figure 2-9). Although intravenous thrombolysis may occasionally be successful, most experts prefer to pursue intra-arterial treatment (pharmacological thrombolysis or mechanical embolectomy) given the large size of the clot responsible for the vascular occlusion.3,4

Clinical-Anatomical Syndromes of Ischemic Infarction TOP OF THE CAROTID ARTERY TERRITORY STROKE (“CAROTID T”)

Figure 2-8. Multiple ascending cuts of a brain magnetic resonance imaging (diffusion-weighted imagery sequence) illustrating the distribution of ischemia in a patient with carotid terminus occlusion.

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Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-9. Fifty-eight-year-old man presenting with right carotid T occlusion who expired on the third day after hospitalization. Admission computed tomography scan is shown in the upper row, and magnetic resonance imaging (MRI) obtained a few hours later is displayed in the middle (diffusion weighted imaging on the left and apparent diffusion coefficient map on the right), and lower (T2-weighted MRI) rows.

Clinical-Anatomical Syndromes of Ischemic Infarction

MIDDLE CEREBRAL ARTERY OCCLUSION ❖

The clinical manifestations of middle cerebral artery (MCA) strokes can vary broadly, depending on the precise location of the vessel occlusion and the strength of the collateral circulation. Proximal

MIDDLE CEREBRAL ARTERY (MCA) TERRITORY STROKE INVOLVING DEEP TERRITORY

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occlusion of the horizontal (M1) segment of the MCA typically results in infarction of the lenticular nucleus and internal capsule (Figure 2-10), whereas more distal M1 occlusions spare these deep structures (Figure 2-11).

MIDDLE CEREBRAL ARTERY (MCA) TERRITORY STROKE SPARING OF DEEP TERRITORY

Figure 2-10. Ischemic infarction of the middle cerebral artery

Figure 2-11. Ischemic infarction of the middle cerebral artery

territory from proximal occlusion of the horizontal (M1) segment of the vessel. Note that the infarction involves the basal ganglia and internal capsule because the occlusion is proximal to the takeoff of the lenticulostriate braches.

territory from distal occlusion of the horizontal (M1) segment of the vessel. Note that the infarction spares the basal ganglia and internal capsule because the occlusion is distal to the takeoff of the lenticulostriate braches.

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Clinical-Anatomical Syndromes of Ischemic Infarction

The MCA supplies most of the cortical convexity, putamen, upper portion of the globus pallidus, posterior head and whole body of the caudate, large parts of the internal capsule (all but the lowest area of the posterior limb, and often the genu and the posterior-superior aspect of the anterior limb), external capsule, capsula extrema, claustrum, and substantia innominata. Figure 2-12 illustrates the topographical patterns of MCA infarction. The MCA is divided in four segments (see Figures 2-1 and 2-2). The M1 or horizontal segment is a single stem that give rise to the penetrating lenticulostriate branches. It branches into two (or occasionally three) M2 or insular segments as it enters the Sylvian fissure. The M3 or opercular segments ascend following the curvature of the operculum. The M4 or cortical segments travel along the sulci and gyri of the cerebral convexity.

Case Vignette A 65-year-old man with history of hypertension presented with acute global aphasia and right flaccid hemiplegia involving the lower face, the arm, and, to a lesser degree, the leg. He also had a dense right visual field deficit and profound right sensory loss. Magnetic resonance imaging (MRI) with DWI revealed extensive ischemia in the territory of the left MCA (Figure 2-13). T2* sequence disclosed a hypointense signal in the left MCA indicative of acute vessel thrombosis and MRA confirmed the left M1 occlusion (Figure 2-14). Atrial fibrillation was noted on cardiac telemetry. Over the following 48 hours, the patient developed fatal brain swelling (see Figure 2-14).

Clinical-Anatomical Syndromes of Ischemic Infarction MIDDLE CEREBRAL ARTERY (MCA) STROKE PATTERNS

Territorial

Cortical branch

Deep territory

Internal borderzone

Superficial perforator

External borderzone

Figure 2-12. Topographical patterns of middle cerebral artery infarction.

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Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-13. Brain magnetic resonance imaging showing acute infarction of the left middle cerebral artery territory (diffusion-weighted imaging on the left and matching apparent diffusion coefficient on the right). Note sparing of the deep territory indicating distal M1 occlusion.

Clinical-Anatomical Syndromes of Ischemic Infarction

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Figure 2-14. T2* sequence demonstrates acute thrombus in the distal part of the M1 segment of the left middle cerebral artery (MCA) (upper left, arrow). Fluid-attenuated inversion recovery sequence depicts the extension of the infarction (upper right); notice hyperintense vessel signal in sulcal braches (arrowhead). Intracranial magnetic resonance angiography confirmed the distal MCA occlusion (lower left). Computed tomography scan 2 days later shows massive progression of ischemic brain swelling (lower right).

Territorial MCA Infarction ❖

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The largest MCA infarctions (territorial infarctions) result from proximal occlusion of the proximal M1 segment and absence of enough collateral flow to limit the extent of the infarction. Patients characteristically present with preserved level of consciousness, gaze deviation or strong preference toward the side of the infarction, contralateral homonymous visual field deficit, and contralateral hemiparesis/hemiplegia (leg weakness is caused by involvement of deep capsular fibers) and hemi-hypoesthesia/anesthesia. Aphasia and hemineglect occur in dominant and nondominant infarctions, respectively (see later discussion for more details on deficits of cortical function). Hyperdense MCA sign may be seen on the initial CT scan. Its presence is associated with less chances of recanalization after thrombolysis5,6 and worse likelihood of favorable recovery.5–7 Still, intravenous thrombolysis remains the standard of care for patients with MCA stroke presenting within 3 hours of symptom onset regardless of the presence of this radiological sign.6 Although preferential use of intra-arterial interventions has been advocated by some groups, the benefits of this approach are thus far unproved.8

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Occlusions of the distal M1 (horizontal) segment of the MCA produce large infarctions involving the cortex and subcortical white matter but sparing the striatocapsular structures perfused by the lenticulostriate branches (Figure 2-11). Patients present with facial-brachial weakness (relative leg sparing), which tends to be less severe and recover better than in cases of proximal M1 occlusion. Hemisensory loss usually follows a similar distribution. Contralateral homonymous hemianopsia and transient deviation of the eyes and head toward the side of the infarction are also characteristically present. Complete cortical infarctions of the MCA on the dominant hemisphere cause global aphasia and ideomotor apraxia (Figure 2-13). Extensive cortical infarctions of the MCA on the nondominant hemisphere manifest with a combination of contralateral visuospatial neglect, anosognosia, motor impersistence, dressing and constructional apraxia, and occasionally sensory aprosodia. Acute confusion, often with pronounced agitation, may predominate upon presentation (Figure 2-15). Cortical infarctions may have a patchy appearance when some cortical regions are saved by collateral circulation (Figure 2-16).

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Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-15. A 54-year-old woman presented to the emergency department with mild confusion, left visual field impairment, left hemiparesis, and left-sided neglect. Computed tomography scan of the brain (upper row) shows early low attenuation changes in the right middle cerebral artery (MCA) distribution, sparing the deep structures. The acute right MCA infarction was subsequently confirmed by magnetic resonance imaging (diffusionweighted imaging sequence shown, lower left). Intracranial magnetic resonance angiography displayed the occlusion of the right MCA responsible for the ischemic stroke (lower right).

Figure 2-16. Patchy infarction of the right middle cerebral artery territory shown on diffusion-weighted imaging. Although the patient had an occluded right M1 segment, the infarction is discontinuous likely because of preservation of part of the cortex of the arterial territory by perfusion through collateral flow.

Deep Middle Cerebral Artery Infarction ❖

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Deep infarctions in the territory of the MCA are caused by occlusion of lenticulostriate branches. These vessels perfuse the anterior limb, genu, and anterior segment of the posterior limb of the internal capsule (especially its rostral portion); the corona radiata adjacent to the body of the lateral ventricle;

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the body and upper half of the head of the caudate nucleus, lentiform nucleus, and external capsule. The anatomical pattern of lenticulostriate arteries is highly variable. Most often, there are two medial and four or five lateral main lenticulostriate branches, all of which arise most commonly from the dorsal aspect of the MCA horizontal trunk.9

Clinical-Anatomical Syndromes of Ischemic Infarction

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Lateral branches are generally larger and longer than the medial. Ramifications of these arteries generate an average of more than 20 penetrating vessels.9 Often multiple small branches originate from a single common stem. Deep infarctions are classified as lacunar, when they measure less than 15 mm in maximal diameter on axial cuts, or striatocapsular when they are larger (usually ⬎20 mm in greatest diameter) (Figure 2-17).10,11 Lacunar infarctions are typically produced by occlusion of a single penetrating artery, whereas striatocapsular infarctions characteristically occur when multiple penetrating branches are occluded. However, this is far from a rule, because infarctions clearly larger than lacunes may originate from occlusion of a common lenticulostriate stem that gives rise to two or more smaller penetrating branches.10,12

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Deep infarctions in the MCA territory often present with lacunar syndromes (pure motor, sensorimotor, dysarthria-clumsy hand). Deficits may be more restricted and result in brachiocrural or brachiofacial syndromes. Manifestations traditionally associated with cortical lesions may occur in larger infarctions of the upper internal capsule or even the external capsule, including aphasia, hemineglect, and apraxia. Similarly, subinsular infarctions may present with signs indistinguishable from the anterior opercular syndrome (loss of voluntary control of facial, lingual, pharyngeal, and masticatory muscles, resulting in severe dysarthria and dysphagia). Also, extrapyramidal signs have been noted in patients with putaminal ischemia,13 and abulia, akinesia, and, more rarely, chorea have been reported in association with caudate infarctions.14

Figure 2-17. Examples of deep infarctions in the middle cerebral artery (MCA) territory. The case displayed in the top row is unusual because of concomitant involvement of the head of the caudate—typically perfused by the recurrent artery of Heubner, most often a branch of the anterior cerebral artery—and the lenticular nucleus (diffusion-weighted imaging [DWI] on upper left and matching apparent diffusion coefficient map on the upper right). The case portrayed in the lower row illustrates extension of the infarction into the paraventricular corona radiata (DWI is shown). These cases serve to highlight the various anatomical presentations that can be seen with deep infarctions in the MCA territory.

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Clinical-Anatomical Syndromes of Ischemic Infarction

Superficial Divisional Middle Cerebral Artery Infarction ❖

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Occlusions of the superior (or anterior) M2 branch most commonly cause infarctions involving the extensive cortical and subcortical regions of the frontal lobe convexity and the anterior parietal lobe (Figure 2-18). Both the precentral and postcentral gyri are usually affected. Clinical manifestations are contralateral hemiparesis and hemisensory loss, predominantly faciobrachial. Conjugate eye deviation or gaze preference toward the side of the infarction occurs often, but visual fields tend to be spared. Nonfluent aphasia with oral apraxia and severe dysarthria are frequently disabling deficits in patients with dominant infarctions. Depression is also a common feature in these patients. Acute confusional state, contralateral hemi-inattention, visual perceptual impairment, aprosodia, and anosognosia are prevailing neuropsychological disturbances in infarctions of the nondominant hemisphere. Superior division MCA infarctions may be caused by large artery atherothrombosis or cardiac embolism; the former mechanism probably predominates.15 Occlusion of the inferior (or posterior) M2 branch produces infarction involving the parietal and temporal lobes (Figure 2-19).

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The most common clinical manifestations include contralateral sensory and visual field deficits. Variable degrees of hypoesthesia with tactile extinction upon double simultaneous stimulation and homonymous hemianopia or superior quadrantanopia are the most characteristic features. Weakness, when present, is usually mild and transient. Fluent (Wernicke’s) aphasia occurs with infarctions of the dominant hemisphere. Hemineglect, constructional dyspraxia and other visual–perceptual difficulties, and sensory aprosody are encountered in patients with nondominant infarctions. Acute confusional state, often associated with agitated delirium, may predominate in right-sided infarctions of the inferior M2 division.16 It is important to keep this diagnosis in mind when evaluating any patient presenting with acute confusion and agitation, because detailed neurological examination may be difficult in these cases, and sensory, visual, and perceptual deficits may be easily missed. Infarctions of the inferior division of the MCA are predominantly caused by cardiac embolism.15,16 Carotid artery disease is rarely a cause of infarctions in this vascular distribution.

Clinical-Anatomical Syndromes of Ischemic Infarction

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Figure 2-18. Superior division middle cerebral artery stroke. Diffusion-weighted imaging and apparent diffusion coefficient map shown in the upper row. Fluid-attenuated inversion recovery sequence displayed on the lower left. Conventional angiogram (lateral view, lower right) demonstrates the absence of filling of the occluded superior M2 branch.

Figure 2-19. Inferior division left middle cerebral artery infarction. Diffusion-weighted imaging sequence is shown.

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Clinical-Anatomical Syndromes of Ischemic Infarction

Superficial Cortical Infarctions ❖

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Insular infarctions rarely occur in isolation, but insular involvement is seen in close to half of patients with nonlacunar infarctions of the MCA territory (Figure 2-20). Damage to the insular cortex is most frequently found with large MCA infarctions and proximal M1 occlusions.17 Insular infarctions have received considerable attention because they have been consistently associated with increased likelihood of cardiac arrhythmias, myocardial injury, and adverse outcome including sudden cardiac death.18–20 Left20 and right-sided18,19 infarctions have been associated with worse cardiac outcomes in different studies. Hence, the degree of lateralization in the control of autonomic cardiac function in humans remains to be fully elucidated.

Figure 2-20. Examples of middle cerebral artery infarction with involvement of the insular cortex. Upper row: Early computed tomography scan (left) with a hyperdense vessel sign in the Sylvian fissure (arrow) and loss of differentiation of the right insular ribbon and underlying anatomical boundaries. Diffusion-weighted imagery (DWI) sequence of magnetic resonance imaging (MRI) (right) allows recognition of the extension of the ischemic area. Lower row: DWI sequence of MRI (left) showing a restricted area of ischemia in the right insular region. MRA (right) shows a flow gap in the distal M1 segment (arrowhead) with reduced filling of M2 branches.

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It has been reported that MCA infarctions involving the insular territory may be more prone to growth.21 The nature of this phenomenon deserves further exploration. Other cortical branch infarctions may be caused by occlusion of M3 branches (Figure 2-12) and may present with distinctive clinical syndromes. Some common examples of localizing clinical features encountered in practice are shown in Table 2-1. These cortical infarctions are typically caused by embolism (from arterial or, probably most often, cardiac sources). Occasionally cortical branch infarctions represent the only sequelae in patients who present with severe hemispheric deficits but later improve dramatically. These cases of “spectacular shrinking deficits” are thought to result from fragmentation of a large embolus that initially occludes the ICA bifurcation or proximal M1 segment.22,23

Clinical-Anatomical Syndromes of Ischemic Infarction

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TABLE 2-1. Clinical features of MCA branch infarctions. Brain region

Arterial branches

Distinctive features

Additional signs

Precentral

Precentral, prefrontal, orbitofrontal

Motor impersistence Contralateral limb-kinetic apraxia

Contralateral fasciobrachial weakness (predominantly proximal or distal brachial weakness) and transcortical motor aphasia

Perirolandic

Central (rolandic)

Distal arm paresis (with distal branch occlusion)

Facial weakness and sensory loss (with proximal occlusions)

Postcentral

Anterior parietal

Conduction aphasia (left) Ideomotor apraxia Acute hemiconcern* (right, rare) Opercular cheiro-oral syndrome† (rare)

Hemisensory loss Hemineglect (right) Constructional dyspraxia (right)

Angular

Angular (often posterior parietal and posterior temporal also involved)

Gerstmann’s syndrome‡ (left) Balint’s syndrome§ (bilateral)

Contralateral visual field deficits Transcortical sensory aphasia (left) Visual perceptual deficits (right)

Temporal

Temporo-occipital, posterior temporal, middle temporal, anterior temporal, temporopolar

Abnormal musical perception (mostly right) Cortical deafness (bilateral) Pure word deafness (left)

Fluent aphasia (left) Contralateral superior quadrantanopsia Left visual neglect and extinction (right) Agitated confusion (right)

* Patients focus on left hemibody, often rubbing, pinching, pressing, or lifting the left arm with the right one. This neurobehavioral disturbance is short-lasting, typically resolving after the first few days. † Patients lose voluntary control of facial, lingual, pharyngeal, and masticatory muscles, which results in severe dysarthria and dysphagia. ‡ Dysgraphia, acalculia, right-left disorientation, and finger agnosia. § Optic ataxia, peripheral visual inattention, and gaze apraxia (severe deficits of smooth pursuit and all saccades except for vestibular quick phases).

Hemispheric Border-Zone Infarctions ❖

External border-zone infarctions affect the “watershed” areas between the superficial anterior cerebral artery and MCA territories, and the superficial MCA and posterior cerebral artery (PCA) territories (Figures 2-12 and 2-21).

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These cortically based infarctions may be single or multiple simultaneous, in one or both hemispheres. They typically result from severe hemodynamic failure, often from a combination of ipsilateral vascular stenosis and a drop in systemic blood pressure.

Figure 2-21. Example of fairly extensive acute external border-zone infarctions in patients who had developed severe hypotension during emergency cardiovascular surgery and who had preexistent bilateral carotid artery stenosis.

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Clinical-Anatomical Syndromes of Ischemic Infarction

Clinical presentation varies according to the precise location and extension of the ischemic damage. Severe cases may mimic territorial infarctions of the MCA. More characteristically, patients manifest acute transcortical (often mixed) aphasia or conduction aphasia associated with variable degrees of hemiparesis and homonymous visual field deficits. Balint’s syndrome is usually due to bilateral damage to the watershed region between MCA and PCA. It consists of visual disorientation, spasms of fixation (apraxia of gaze), optic ataxia, and simultagnosia with peripheral vision inattention. Internal border-zone infarctions involve deep frontal white matter between the anterior cere-

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bral artery (ACA) and MCA, often bilaterally (Figures 2-12 and 2-22). This pattern of ischemia is caused by severe systemic hypotension or prolonged hypoxemia, and it is most commonly seen after cardiopulmonary arrest.24 It may also be encountered after prolonged, complicated cardiac surgery.25 The classical clinical picture is characterized by proximal or complete bilateral brachial paralysis with preservation of leg movements, often described as “man-in-the-barrel syndrome.”24 Also, profound hypoperfusion may induce ischemic lesions between the deep and superficial branches of the MCA. In those cases, variable degrees of hemiparesis tend to be the predominant clinical manifestation.

Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-22. Three examples of internal border-zone infarctions. Notice the variable distributions of the lesions (unilateral or bilateral, confluent or patchy, purely internal or combined with areas of ischemia in the external border-zone region). Systemic hypotension was the mechanism of infarction in all these cases. Upper row: Diffusion-weighted imaging (DWI) sequence on the left and fluid-attenuated inversion recovery on the right. Middle row: DWI and matching apparent diffusion coefficient map. Lower row: DWI at two levels.

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Clinical-Anatomical Syndromes of Ischemic Infarction

ANTERIOR CEREBRAL ARTERY OCCLUSION ❖

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ANTERIOR CEREBRAL ARTERY (ACA) TERRITORY STROKE

The ACA supplies the entire medial surface of the frontal and parietal lobes, the basal aspect of the frontal lobes, the head and body of the corpus callosum, and various deep structures including components of the olfactory pathway, cingulum, and the anterior portions of the diencephalon (hypothalamic nuclei) and head of the caudate nucleus (irrigated by the recurrent artery of Heubner) (Figure 2-23). The ACA is typically divided into precommunicating (A1 segment) and postcomunicating portions (distal ACA, A2–A5 segments) by the anterior communicating artery (see Figure 2-1). Anatomical variations are often present, including unilateral A1 segment hypoplasia (“threadlike” in 6%–8%, absent in 0.2%–2%, and hypoplastic in 6%–10%), multiple anterior communicating arteries (up to 40% in necropsies); unpaired or azygous ACA (1%–5%); and various anomalies in distal branching.26–28 These variations affect the ability of collateral circulation to compensate for ischemia in the event of a stroke (e.g., patients with poor cross-flow through the anterior communicating artery will suffer greater ischemic damage to the frontal lobe ipsilateral to a carotid occlusion). Additionally, anomalies in the anterior communicating artery region are associated with increased frequency of saccular aneurysm.29

Figure 2-23. Multiple ascending cuts of a brain magnetic resonance imaging (diffusion-weighted imaging sequence) illustrating the distribution of ischemia in a patient with proximal left anterior cerebral artery occlusion.

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Case Vignette A 65-year-old man presented to the hospital with acute onset of left crural paresis. He had suffered a myocardial infarction 2 weeks before and was taking aspirin and clopidogrel for secondary prevention of coronary events. Examination revealed left leg weakness predominantly involving the proximal flexor muscles and

associated with hyperreflexia. MRI demonstrated acute infarction in the right ACA distribution (Figure 2-24). Echocardiogram disclosed a mural thrombus overlying a hypokinetic segment of the left ventricle. The patient was anticoagulated and recovered well with physical therapy.

Figure 2-24. Diffusion-weighted imaging sequence of magnetic resonance imaging showing an acute right anterior cerebral artery infarction.

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Semiological presentations vary substantially among patients with ACA infarctions. Motor and neurobehavioral manifestations dominate the clinical picture. Weakness involves predominantly the contralateral leg (hemiparesis with crural predominance), but isolated leg weakness (crural monoparesis) is relatively rare. Leg weakness is more pronounced distally, and tone is flaccid the first few days and spastic later. Even if severe initially, patients usually achieve favorable recovery. Bilateral ACA infarction should be considered among the causes of acute paraparesis. Damage to the medial frontal lobe involving the supplementary motor area may produce motor neglect, with decreased utilization of the contralateral limbs. Caudate ischemia manifests with contralateral bradykinesis, clumsiness, and motor perseveration.30 Sensory deficits are milder and mostly affect integrative functions (discriminative and proprioceptive sensations). Neurobehavioral manifestations are variable and complex. They include expressions of callosal discon-

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nection, such as left ideomotor apraxia, agraphia, and tactile anomia. Antegrade amnesia occurs often and may be disabling. Severe abulia is a characteristic feature, but it is only persistent in cases of bilateral infarctions. Akinetic mutism may be caused by lesions affecting the anteromedial frontal lobes, and it may resemble coma.31 Speech subsequently recovers, but milder disturbances may subsist.32 Alien-hand phenomena may be seen in patients with damage to the medial frontal lobe, corpus callosum, or both. Pathological grasping, sucking, and other frontal release signs; urinary incontinence; and gait apraxia may occur after unilateral ACA infarctions but are more common with bilateral frontal damage. ACA infarctions, often bilateral, are most commonly seen as a consequence of severe vasospasm following rupture of an anterior communicating artery aneurysm (Figure 2-25). In the remainder of the cases, cardiac embolism (as illustrated in our vignette) and ICA atherosclerosis are the most frequent mechanisms. Intrinsic disease of the ACA is uncommon.

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Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-25. A 46-year-old woman with subarachnoid hemorrhage from rupture of an anterior communicating artery aneurysm developed severe, symptomatic vasospasm 5 days after the bleeding causing extensive ischemia in the territories of anterior cerebral artery. Diffusion-weighted imaging sequence of the magnetic resonance imaging is shown on the left and conventional angiogram confirming severe vasospasm (arrow) is displayed on the right.

ANTERIOR CHOROIDAL ARTERY OCCLUSION ❖

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The anterior choroidal artery (AChA) arises from the supraclinoid ICA. It consistently supplies the optic tract, lateral geniculate body, posterior limb of the internal capsule, cerebral peduncle, and the choroid plexus. However, its area of perfusion may be larger and include the middle portion of the medial temporal lobe, medial globus pallidus, lateral thalamus, and the posterior paraventricular corona radiata region (Figure 2-26). Most AChA infarctions are small (⬍20 mm) and often manifest clinically as lacunar syndromes.33 Pure motor and ataxia-hemiparesis syndromes predominate. Sometimes the latter is associated with hypesthesia. AChA infarcts may also be larger and resemble territorial infarctions. The most common syndrome consists of contralateral homonymous hemianopia (with a spared “beaked” segment), hemiplegia, and

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hypesthesia.34,35 Neuropsychological and perceptual deficits may also be found but are less characteristic. Large AChA infarctions are often deceiving. They can exhibit unexpected manifestations, such as ipsilateral ptosis with or without other signs of Horner’s syndrome, impaired vertical eye movements, and contralateral adventitious movements. These large infarctions with complex clinical manifestations may exhibit a stuttering presentation, which represents a formidable diagnostic challenge for the clinician. Brain imaging becomes invaluable for correct localization in these cases. Small AChA strokes share the pathophysiology of other small penetrating artery infarctions. Meanwhile, large AChA infarcts are most often related to large vessel atherothrombosis or cardiac embolism.35 Surgical treatment of anterior choroidal artery aneurysm carries a high risk of disabling ischemic complications.36

Clinical-Anatomical Syndromes of Ischemic Infarction

45

Figure 2-26. A 59-year-old man with history of hypertension, hyperlipidemia, and insulin-requiring diabetes mellitus presented to the hospital with recurrent episodes of dysarthria and left hemiparesis lasting between 5 and 20 minutes. The latest spell began as the patient was entering the magnetic resonance imaging (MRI) scanner, and the deficits failed to resolve. On examination, the patient had a dense left hemianopia, dysarthria and moderate left hemiparesis involving face, arm, and leg. MRI showed restricted diffusion in the territory of the right anterior choroidal artery (medial temporal lobe, superior peduncle, and posterior limb of the internal capsule).

POSTERIOR CEREBRAL ARTERY OCCLUSION ❖

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The PCAs supply the midbrain, thalami, lateral geniculate bodies, posterior portion of the choroid plexus, occipital lobes, inferior and medial aspects of the temporal lobes, and posterior-inferior areas of the parietal lobes. This territory is illustrated in Figure 2-27. The PCAs constitute the terminal branches of the basilar artery. However, persistence of the fetal origin of the PCA from the internal carotid artery is seen in approximately 10% to 30% of individuals.37,38 In these patients, the PCA continues a large posterior communicating artery and does not join the basilar artery. Rarely, this variation is present bilaterally. The PCAs are also conventionally divided in segments: the P1 segment (mesencephalic or precommunicating) extends from the PCA origin on the top of the basilar to the union with the posterior communicating artery, the P2 segment (ambient or postcommunicating) spans from the posterior communicating artery junction until the posterior midbrain. The main branches of these two proximal PCA segments are the central perforating branches (thalamoperforating, thalamogeniculate, and peduncular arteries), posterior choroidal vessels (medial posterior and lateral posterior choroidal arteries), anterior and posterior temporal arteries, and

splenial branches to the posterior aspect of the corpus callosum. The distal PCA segments are the short P3 segment (quadrigeminal), extending within the perimesencephalic cistern from the posterior midbrain to the calcarine fissure, and the terminal P4 segment (calcarine or cortical). The latter gives origin to several cortical branches, including the inferior temporal arteries (anterior, middle, and posterior), the parietooccipital artery, and the calcarine artery itself. The PCA trajectory and branches are shown in Figures 2-3 and 2-4.

Case Vignette A 68-year-old woman with a history of atrial fibrillation on chronic anticoagulation presented to the hospital with acute behavioral changes, visual disturbances, and right hemiparesis. On examination, she was somnolent, had poor short-term recollection, dense right hemianopia, mild right hemiparesis, and profound right hypoesthesia. Her INR was subtherapeutic because the patient had recently stopped taking warfarin for a dental procedure, and she had opted not to replace it with subcutaneous lowmolecular-weight heparin. MRI of her brain showed a large left PCA infarction and MRA disclosed proximal occlusion of this vessel (Figure 2-28). Despite some functional recovery over the following 6 months, her visual and cognitive disturbances remained disabling.

46

Clinical-Anatomical Syndromes of Ischemic Infarction POSTERIOR CEREBRAL ARTERY (PCA) TERRITORY STROKE

Figure 2-27. Multiple ascending cuts of a brain magnetic resonance imaging (diffusion-weighted imaging sequence) illustrating the distribution of ischemia in a patient with infarction of the left posterior cerebral artery territory.

Clinical-Anatomical Syndromes of Ischemic Infarction

47

Figure 2-28. Fluid-attenuated inversion recovery magnetic resonance imaging and angiography of the brain showing a large left posterior cerebral artery infarction from embolic occlusion of the P1 segment. Notice thalamic involvement because the occlusion was proximal to the takeoff of the perforating thalamic branches.

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Proximal occlusion of a PCA may produce severe neurological deficits including decreased level of consciousness (from mesencephalic and diencephalic involvement), profound disturbances of visual perception, antegrade amnesia, ophthalmoparesis (from damage to the upper midbrain), hemiplegia (typically from peduncular ischemia), hemihypoesthesia, and hemianopia.39 In the acute setting, large PCA infarctions may be clinically indistinguishable from MCA strokes.15 Thus brain imaging is essential to make the correct diagnosis and direct further evaluations. PCA occlusions distal to the origin of penetrating arteries irrigating the midbrain and thalamus are much more benign, often presenting with isolated contralateral visual field deficits (Figure 2-29). Visual field deficits from PCA infarctions present remarkable variability. They result from damage to the lateral geniculate nuclei, visual radiations, and

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calcarine cortex. Table 2-2 lists the most common visual field disturbances found in practice. Macular sparing is often encountered in unilateral strokes, presumably thanks to collateral circulation from the MCA perfusing the occipital pole. However, preservation of central vision also requires sparing of the visual radiations connected to the occipital pole. More complex visual disturbances are characteristic of PCA infarctions and have important localizing value. Visual agnosia, prosopagnosia, color dysnomia and dyschromatopsia, and aberrations of visual perception, such as palinopsia and micropsia, can occur. Anton syndrome is defined by the patient’s denial of cortical blindness. Sensory manifestations are caused by thalamic injury. Hypoesthesia or anesthesia are the most frequent abnormalities; numbness and paresthesias are the most common complaints. Déjerine-Roussy

48

Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-29. Another example of a left posterior cerebral artery infarction (computed tomography scan shown on the left and diffusion-weighted imagery on the right). Notice in his case that there is a large occipital infarction but with no thalamic involvement because the site of the vascular occlusion was distal to the takeoff of the perforating thalamic branches.

TABLE 2-2. Visual field disturbance caused by PCA infarction. Bilateral PCA infarction Cortical blindness Bilateral altitudinal hemianopia Unilateral PCA infarction Macular sparing hemianopia Temporal crescent paring hemianopia

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Quadrantanopia Isolated macular hemianopia (rare)

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syndrome is relatively infrequent but distinctive; it consists of severe paroxysmal pain in the hypoesthetic side contralateral to a thalamic lesion caused by a thalamogeniculate branch occlusion. It is typically seen in conjunction with rapidly resolving hemiparesis, choreiform movements, dystonic hand posture, and ataxia. Patients with left PCA infarctions may experience incapacitating neurocognitive disorders. Alexia without agraphia (from infarction of the splenium

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of the corpus callosum and related connecting hemispheric fibers) is best known, but alexia with agraphia may also occur (when the infarction extends toward the angular gyrus). Anomic aphasia may be produced by left temporo-occipital strokes. Severe memory impairment can be caused by ischemia of the mesial temporal structures or the thalamus. Left PCA stroke may be responsible for single stroke dementia.40 Topographical disorientation and some constructional apraxia may be seen after right PCA infarctions (Figure 2-30). Midbrain ischemia may express with ipsilateral or bilateral ophthalmoparesis (III nerve palsy, abnormal vertical eye movements) and contralateral hemiplegia (Figure 2-31). Bilateral thalamic infarctions may result in initial alterations in the level of consciousness and subsequent cognitive (predominantly antegrade memory) and sensory sequelae (Figure 2-32). Embolism from a cardiac or an arterial (aortic arch, vertebral artery origin) source is the most common mechanism of PCA stroke. Intrinsic atherosclerosis of the PCA is much less common but must be investigated in cases of pure PCA ischemia.

Clinical-Anatomical Syndromes of Ischemic Infarction

49

Figure 2-30. A 64-year-old woman with atrial fibrillation who was brought to the emergency department by her daughter after she was found acutely confused and unable to find her way in her own house. Examination revealed confusion with mild agitation, topographical disorientation, and constructional and dressing apraxia. She also had a left visual field deficit. Magnetic resonance imaging of the brain confirmed the clinical suspicion that the patient had an acute infarction of the right posterior cerebral artery territory (diffusion-weighted imagery and matching apparent diffusion coefficient shown in the upper row, fluid-attenuated inversion recovery sequence shown in the lower row).

Figure 2-31. Patient with left midbrain and small occipital lobe infarction from embolic proximal posterior cerebral artery occlusion.

50

Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-32. Bilateral thalamic infarction secondary to top of the basilar embolism with spontaneous recanalization. Patient presented with sudden coma, and although he recovered alertness, he remained cognitively disabled.

VERTEBROBASILAR DISEASE ❖

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Occlusion of the basilar artery represents the most dreaded form of ischemic stroke. At its worst, it causes massive fatal infarction involving the brainstem, cerebellum, the occipital and posterior temporal lobes, and the thalami (Figure 2-33). However, these catastrophic results may at times be avoided by prompt recognition of early signs of vertebrobasilar ischemia. The normal vascular anatomy of the vertebrobasilar system is shown in Figures 2-3 and 2-4. The vertebral artery is typically divided in four segments: the V1 segment extends from the vessel origin to its entrance into the vertebral foramen of the fifth or sixth cervical vertebra; the V2 or intraforaminal segment transverses the vertebral foramina of C6 to C2; the V3 segment emerges from the C2 foramen and turns to circle the posterior arch of the atlas; the V4 or intradural segment begins as the vessels pierces the dura and ends at the vertebrobasilar junction (at the pontomedullary level).

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Asymmetry in the vertebral arteries is commonly seen. Left vertebral artery dominance is present in nearly 45% of people, and in close to 25% the right vertebral artery is larger. Hence, true vertebral artery codominance is encountered in less than one third of the general population. Hypoplastic vertebral arteries, sometimes ending after the origin of the posterior-inferior cerebellar artery, are less frequent but certainly not rare.41 Infarctions at different levels are caused by different mechanisms:42 ❖ Proximal territory infarctions (i.e., involving the medulla and lower cerebellum) are caused by embolism from the heart or atherosclerosis of the extracranial vertebral arteries or by hypoperfusion related to severe intracranial vertebral occlusive lesions. ❖ Middle territory infarctions (i.e., involving pons and anterior cerebellum) are typically due to intrinsic basilar artery disease. ❖ Distal territory infarctions (i.e., involving midbrain, superior cerebellum and posterior cerebral artery territories) are mostly embolic from cardiac or vertebral artery sources.

Clinical-Anatomical Syndromes of Ischemic Infarction VERTEBRAL-BASILAR ARTERY TERRITORY STROKE

Figure 2-33. Computed tomography scan of the brain showing a massive infarction in the vertebrobasilar territory.

51

52

Clinical-Anatomical Syndromes of Ischemic Infarction

Case Vignette A 64-year-old woman was found unresponsive in her bathroom by her husband. She was intubated by the paramedics and transported to our emergency department. On arrival, she was comatose and breathing at a rate of 40 to 45 per minute. She was tachycardic and hypertensive. Her pupils were slightly anisocoric (3.5 mm on the left and 3 mm on the right), and responses to light were minimal on the left and absent on the right. Corneal and oculocephalic reflexes were preserved. Best motor responses to pain were in the form of withdrawal. DWI showed restricted diffusion in the

midcerebellum and mesencephalon (Figure 2-34). A hyperintense signal in the basilar artery indicative of acute thrombosis was visualized on FLAIR. Conventional angiography confirmed occlusion of the basilar trunk. She underwent successful basilar recanalization by intraarterial thrombolysis combined with mechanical disruption of the clot. Despite reperfusion, the patient failed to improve neurologically. Repeat MRI showed established infarction throughout the midbrain. Patient expired shortly after her family requested withdrawal of artificial life support.

Clinical-Anatomical Syndromes of Ischemic Infarction

53

Figure 2-34. First row: Diffusion-weighted imaging showing acute brainstem and cerebellar ischemia. Second row: T1-weighted imaging and fluid-attenuated inversion recovery (FLAIR) sequences revealing a hyperintense basilar artery, indicative of acute basilar artery thrombosis. Third row: Conventional angiogram confirming occlusion of the mid to distal basilar artery (left) with subsequent recanalization following intra-arterial thrombolysis (right). Fourth row: Repeat FLAIR disclosing extensive pontomesencephalic infarction.

54 ❖

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Clinical-Anatomical Syndromes of Ischemic Infarction

Early signs of vertebrobasilar ischemia can be subtle and possibly deceiving. Fluctuations with remissions and relapses of symptoms may precede frank progression and irreversible development of severe deficits. Table 2-3 presents a list of common signs that should raise the suspicion of basilar occlusive disease. Diagnostic imaging modalities other than angiography have limited value in the acute setting. CT scan has poor sensitivity in the posterior fossa but,

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TABLE 2-3. Signs suspicious for basilar artery occlusion. Combination of ophthalmoplegia with motor, sensory, or coordination deficits Crossed motor or sensory findings Acute ataxia with inability to walk Sequential appearance of bilateral Babinski signs* Sequential appearance of bilateral weakness Acute reduction in the level of consciousness * It can also be seen in patients with incipient craniocaudal herniation from massive supratentorial infarctions.

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at times, may reveal a hyperdense clot in the basilar artery (Figure 2-35). MRI with DWI demonstrates the extension of the ischemic damage (Figure 2-36). The clinical suspicion of acute symptoms from occlusive basilar artery disease is a medical emergency. If the patient is outside the therapeutic window for intravenous thrombolysis but deemed salvageable, it is advisable to perform catheter angiography without delay to confirm the diagnosis and allow endovascular treatment. The pattern of acute multiple brain infarctions in the posterior circulation on MRI-DWI is frequently associated with vertebrobasilar atherothrombotic disease.43 The top of the basilar syndrome (or rostral basilar artery syndrome) is characterized by sudden loss of consciousness, sometimes preceded by acute vertigo, ataxia, and diplopia. It is the manifestation of rostral brainstem, occipitotemporal, and thalamic ischemia (Figure 2-37). The area of infarction may also involve the superior cerebellum. Upon awakening, patients may exhibit drowsiness, agitation, disordered visual perception, and oculomotor dysfunction. Motor deficits are typically absent. The mechanism of the stroke is almost invariably embolic (from a cardiac or proximal arterial source).44

Figure 2-35. A 72-year-old man was brought comatose to the emergency department. He had been found unresponsive at home by his wife in the middle of the night, and paramedics had intubated him upon their arrival. On examination he had anisocoria, absence of corneal reflex on one side, asymmetric oculocephalic reflexes, and bilateral extensor posturing to pain. Computed tomography scan performed nearly 8 hours after the patient had last been seen showed a hyperdense basilar artery sign (left, arrow). Catheter angiography confirmed the suspected occlusion of the basilar artery at its middle segment (right, arrow). Although the basilar artery was recanalized following endovascular therapy (mechanical embolectomy combined with intra-arterial thrombolysis), the patient failed to improve, and the family requested withdrawal of life support measures 2 days later.

Clinical-Anatomical Syndromes of Ischemic Infarction

55

Figure 2-36. This example illustrates the value of magnetic resonance imaging (MRI) in revealing the extension of ischemia in patients with basilar artery occlusion. Notice the computed tomography scan (upper left) does not allow clear recognition of brainstem infarction, which is easily visualized on diffusion weighted imaging (upper right) and, to a considerably lesser degree, on fluid-attenuated inversion recovery (lower left). MRI can be combined with magnetic resonance angiography to define the vascular occlusion (lower right).

56

Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-37. A patient with occlusion of the top of the basilar artery causing infarctions in mesencephalon, bilateral thalami, and bilateral occipital lobes. The mechanism of the stroke was cardiac embolism. Diffusion-weighted imaging is shown in the upper row, fluid-attenuated inversion recovery in the lower left, and magnetic resonance angiography in the lower right. Short arrows indicate areas of ischemia and long arrow signals the top of the embolic occlusion of the basilar top.

CEREBELLAR INFARCTIONS ❖

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The cerebellum is normally irrigated by three pairs of long circumferential arteries: the posterior inferior, anterior inferior, and superior cerebellar arteries (PICA, AICA, and SCA). Anatomical variations affecting these vessels are not uncommon. Pure territorial cerebellar infarctions are most often caused by embolism. The coexistence of cerebellar infarction and brainstem ischemia constitutes an indication to study the vertebrobasilar circulation for possible atherothrombotic disease.

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Imaging with MRI is useful to delineate the true extent of the infarction and recognize the presence of brainstem involvement. MRI, especially DWI, often discloses multiple areas of cerebellar ischemia.45–49 Multiple small cerebellar infarctions are frequently associated with atherosclerotic vertebrobasilar disease.48,49 Mass effect from large cerebellar infarctions can produce rapid herniation. Serial CT scans are valuable aids to serial neurological examinations for the timely diagnosis of cerebellar swelling.

Clinical-Anatomical Syndromes of Ischemic Infarction

Posterior Inferior Cerebellar Artery Infarction Case Vignette A 38-year-old woman presented with severe neck and posterior head pain, dizziness, gait imbalance, and right-hand clumsiness. Her examination predominantly demonstrated right appendicular ataxia. Brain imaging disclosed a large right PICA stroke with incipient mass effect (Figure 2-38). Vascular imaging revealed a right vertebral artery occlusion, most likely due to dissection. The patient was carefully monitored in the stroke unit, and as she developed mild confusion and restlessness, repeat imaging was performed showing worsening swelling with displacement of the fourth ventricle, effacement of the subarachnoid cisterns, distortion of the brainstem, and dilatation of the temporal horn of the right lateral ventricle. The patient immediately underwent suboccipital craniectomy. She improved substantially after surgery and achieved good functional recovery over the ensuing 6 months.

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The PICA originates from the V4 segment of the vertebral artery. It typically has a medial and a lateral branch. Anatomical variations include a common PICA-AICA trunk, both PICAs arising from a single trunk, and extradural origin of the vessel in one or both sides. It supplies the dorsal and caudal regions of the cerebellum and the dorsal tegmentum of the medulla. As illustrated in the presented case, typical initial clinical manifestations are headache, vomiting,

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57

vertigo, and ataxia (ipsilateral lateropulsion with inability to walk, ipsilateral dysmetria and dysdiadocokinesis). The elements of Wallenberg’s syndrome may be present in cases involving the dorsolateral medulla. As swelling progresses, patients may exhibit behavioral changes (confusion, agitation) followed by depressed level of consciousness as obstructive hydrocephalus develops. Compression of adjacent cranial nerve and brainstem structures is manifested by ipsilateral facial palsy, ophthalmoparesis (including ipsilateral VI nerve dysfunction), and contralateral hemiparesis. When examining brain imaging scans, it is important to focus on the degree of distortion and shift of the IV ventricle, effacement of the quadrigeminal cistern, brainstem deformity, evidence of hydrocephalus, and signs of upward herniation. Presence of these findings predicts neurological deterioration.50,51 Infarct volume appears to have lesser prognostic worth.50 Decompressive suboccipital craniectomy is indicated in patients with a declining level of consciousness.52 However, because clinical decline occurs quickly in these patients, it is reasonable to consider preemptive surgery in patients with incipient clinical signs of swelling or radiological features predictive of deterioration. Embolism from the heart or a proximal arterial source is the most common mechanism of PICA strokes.53 Prognosis depends on the extent of the infarction. Favorable recovery is possible after timely decompressive surgery.52

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Clinical-Anatomical Syndromes of Ischemic Infarction

Figure 2-38. Diffusion-weighted imagery and apparent diffusion coefficient map (upper row) and fluidattenuated inversion recovery (middle left) of the magnetic resonance imaging obtained on admission demonstrating a large area of acute infarction in the right posterior inferior cerebellar artery territory. Computed tomography (CT) scan 36 hours later showed worsening of swelling with brainstem compression (middle right) and obstructive hydrocephalus (lower left). CT scan after suboccipital craniectomy revealed adequate decompression of the posterior fossa (lower right).

Clinical-Anatomical Syndromes of Ischemic Infarction

Anterior Inferior Cerebellar Artery Infarction ❖

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The AICA stems from the inferior third of the basilar artery. Its size is often inversely correlated with the size of the PICA on the same side. As already mentioned, a common PICA-AICA arising from the distal vertebral or proximal basilar arteries is a normal anatomical variation. It supplies a small region of the anterior and medial cerebellum, typically restricted to the middle cerebellar peduncle and the flocculus, and the inferior lateral portion of the pontine tegmentum (Figure 2-39). The classical clinical picture is characterized by multiple cranial nerve deficits on the side of the occlusion, which may include facial hypoesthesia, facial weakness, abducens palsy, vestibular syndrome, hear-

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59

ing loss, and occasionally tinnitus. Contralateral hemiparesis, incoordination, and decreased pain and temperature sensations are also fairly common.54 AICA infarctions are small and difficult to visualize on CT scan. MRI with DWI offers much better sensitivity for the detection of AICA strokes. It also demonstrates coexistent areas of ischemia; in fact, the combination of PICA and AICA infarctions has been noted to be frequent when patients are examined with MRI-DWI.45 Complications from swelling do not occur unless other arterial distributions are involved. The most common mechanism of ischemia is vertebrobasilar atherothrombosis.45,53 Pure AICA infarctions have relatively good prognosis.45

Figure 2-39. Examples of anterior inferior cerebellar artery (AICA) territory infarctions due to basilar artery disease. The case shown in the upper row illustrates a right AICA infarction on diffusion-weighted imaging (left) with associated pontine ischemia from concomitant compromise of a paramedian penetrating branch; the image on the right is from the fluid-attenuated inversion recovery (FLAIR) sequence displaying a hyperintense basilar artery sign from acute thrombosis of this vessel (arrow). The case shown in the lower row illustrates bilateral AICA infarctions on FLAIR (arrowheads) caused by basilar atherosclerosis visible on magnetic resonance angiography (right, arrow).

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Clinical-Anatomical Syndromes of Ischemic Infarction

Superior Cerebellar Artery Infarction ❖

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The SCAs arise from the distal third of the basilar artery shortly before it culminates in its bifurcation giving rise to the PCAs. They are the most constant major cerebellar vessels. They supply the ventral and rostral vermis and paraventral areas, the anterior-superior aspects of the cerebellar hemispheres (including the dentate, intermediate, and fastigial nuclei and most of the deep cerebellar white matter), and the superior cerebellar peduncles. SCAs also provide branches to the tectum of the midbrain and the dorsolateral tegmentum of the upper pons (Figure 2-40). Pure SCA strokes manifest with dysarthria, nystagmus, and axial and ipsilateral appendicular ataxia.55

Figure 2-40. Patient with paroxysmal atrial fibrillation who presented with sudden onset of dysarthria, dysbasia, and right dysmetria. Magnetic resonance imaging disclosed an acute right superior cerebellar artery (SCA) infarction as shown on diffusion-weighted imagery (upper row) and fluid-attenuated inversion recovery (lower left) sequences. These images illustrate the usual territory perfused by the SCA. Magnetic resonance angiography (lower right) shows the absence of the right SCA; notice clear visualization of the left SCA (arrow).

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SCA-territory ischemia may be part of the rostral basilar artery syndrome (discussed earlier).56 MRI scans have shown that SCA infarctions are often multiple, with several lesions in the SCA territory (one or both sides) or other cerebellar territories.46,47 They may remain clinically unnoticed, particularly when they occur in the context of other embolic infarctions in more eloquent areas. Complications from swelling are infrequent after SCA strokes. Most SCA infarctions are due to embolism from a cardiac source or proximal vertebrobasilar atherothrombosis.46 Prognosis is benign in isolated SCA strokes, especially if partial. However, bilateral SCA infarctions and infarctions extending into the upper brainstem may be fatal or disabling.57

Clinical-Anatomical Syndromes of Ischemic Infarction

Cerebellar Border-Zone Infarctions ❖

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Infarctions involving the boundary zones between arterial territories are relatively frequent in the cerebellum, but their identification is only possible using MRI scans. Figure 2-41 illustrates relatively large bilateral infarctions between PICA and SCA territories induced by a major fall in perfusion pressure.

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However, border-zone cerebellar infarctions tend to be small and multiple.48,49,58 They are commonly associated with advanced vertebrobasilar atherosclerosis, likely resulting in microembolism.43,48,49,58 Thus their presence should be considered an indication to pursue noninvasive vascular imaging of the posterior circulation.

Figure 2-41. Patient with postoperative stroke following profound intraoperative hypotension blood loss and hypotension. Diffusion-weighted imaging (DWI; left) and fluid-attenuated inversion recovery (FLAIR; right) sequences display bilateral cerebellar infarctions in border-zone distribution. Notice relative apparent discrepancy between the area of restricted diffusion on DWI and the regions with increased signal intensity due to established infarction on FLAIR. This difference is not uncommonly seen in patients with ischemia because of hemodynamic insufficiency and may be due to the presence of areas of subcritical ischemia, which appear bright on DWI.

BRAINSTEM INFARCTIONS ❖

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The perfusion of the brainstem is supplied by three pairs of vessels: two paramedian branches, two short circumferential branches, and two long circumferential branches. Occlusions of these branches at different levels give rise to specific syndromes, which are anatomically purer in their classic descriptions than typically

found in practice. In fact, the increasing use of MRI has disclosed that symptoms and signs of traditional syndromes often overlap.

Medullary Infarctions The main ischemic medullary syndromes are illustrated in Figure 2-42.

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Clinical-Anatomical Syndromes of Ischemic Infarction MEDULLA ANATOMY MEDULLA ANATOMY

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LATERAL MEDULLARY SYNDROME (Wallenberg syndrome)

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1 = Vertebral artery 2 = Pyramid (corticospinal tract) 3 = Medial lemniscus 4 = Spinothalamic tract 5 = Medial longitudinal fasiculus 6 = Inferior cerebellar peduncle 7 = Hypoglossal nuclei 8 = Spinal tract of V 9 = Reticulospinal fibers (sympathetic) 10 = Vagus nerve White lines = hypoglossal nerve

CONTRALATERAL loss of pain and temperature of the body Damage to lateral spinothalamic tract (#3) IPSILATERAL loss of pain and temperature of the face Damage to spinal tract of V (#8) IPSILATERAL Horner’s syndrome Damage to reticulospinal fibers (#9) IPSILATERAL pharangeal and vocal cord paralysis Damage to vagus nerve (#10) IPSILATERAL cerebellar signs and symptoms MEDIAL MEDULLARY SYNDROME (Alternating hypoglossal hemiplegia)

CONTRALATERAL hemiplegia Damage to pyramid of the medulla (#2) CONTRALATERAL loss of position and vibration of the body Damage to medial lemniscus (#3) IPSILATERAL tongue paresis and atrophy Damage to hypoglossal nerve (white dotted line)

Figure 2-42. Medullary anatomy and main medullary stroke syndromes.

Case Vignette A 75-year-old man was admitted with sudden onset of dysphagia, dysarthria, and gait imbalance. He had longstanding history of hypertension and poorly controlled type 2 diabetes. On examination, he had left miosis and ptosis, dysarthria, difficulty swallowing his saliva, left ataxia, and decreased sensation to pain and temperature on the right side. He developed uncontrollable hiccups in the emergency department. CT scan was not informative, but DWI demonstrated a left lateral

Figure 2-43. Diffusion-weighted imaging sequence of magnetic resonance imaging showing an acute left lateral medullary infarction. Notice coexistent left cerebellar ischemia in the posterior inferior cerebellar artery territory.

medullary infarction with associated ischemia of the left cerebellum (Figure 2-43). The PICA was not seen on noninvasive angiogram and considered to be occluded. Irregularities in other intracranial vessels indicated widespread intracranial atherosclerosis. The patient required temporary placement of a percutaneous gastrostomy tube for safe feeding but subsequently made a favorable recovery with moderate residual dysarthria and ataxia.

Clinical-Anatomical Syndromes of Ischemic Infarction

Wallenberg’s Syndrome ❖

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The triad of Horner’s syndrome, ipsilateral ataxia, and contralateral hypalgesia is most useful in the identification of lateral medullary infarction.59 Facial weakness and ocular symptoms are frequent and do not necessarily imply that the infarction extends beyond the lateral medulla60 (although presence of those signs often indicates extension up to the pontomedullary junction).61 When Wallenberg’s syndrome is suspected, the ipsilateral vertebral artery must be investigated because occlusion of this vessel is often responsible for the infarction.61 Vertebral atherothrombosis is by far the most common mechanism.61 Vertebral dissection has been found responsible in some cases.61,62 Other

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mechanisms, including cardiac embolism, are relatively rare. MRI with DWI is sensitive for the detection of small medullary infarctions in the acute and subacute phases.63 Combined with MRA, this imaging modality may confirm the diagnosis of medullary stroke, delineate the extent of the ischemia, and determine the status of the parent vertebral artery. Associated cerebellar ischemia is commonly identified on MRI but may remain undetected by CT scan.61,64

Pontine Infarctions The main ischemic pontine syndromes are illistrated in Figure 2-44.

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Clinical-Anatomical Syndromes of Ischemic Infarction ANATOMY OF THE LOWER PONS

ANATOMY OF THE MID-PONS

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1 = Basilar artery 2 = Corticospinal fibers Corticobulbar fibers Corticopontine fibers 3 = Medial longitudinal fasciculus (MLF) 4 = Facial nerve (black arrow) 5 = Vestibulocochlear nerve (white arrow) 6 = Middle cerebellar peduncle/Brachium Pontis 7 = Medial leminiscus 8 = Spinothalamic tract 9 = Facial nucleus

Pontine syndrome

Millard Gubler syndrome

Pure motor hemiparesis, Dysarthria clumsy hand, Ataxic hemiparesis

Locked-in syndrome

Diffusion weighted imaging

1 = Basilar artery 2 = Corticospinal fibers Corticobulbar fibers Corticopontine fibers 3 = Medial longitudinal fasciculus (MLF) 4 = Facial nucleus with nerve (black arrow) 5 = Abducens nucleus with nerve (white arrow) 6 = Fourth ventricle 7 = Medial leminiscus 8 = Spinothalamic tract 9 = Internal carotid artery

Nuclei/Tracts damaged

Clinical signs and symptoms

Corticospinal tract Cranial nerve VI Cranial nerve VII

Contralateral hemiparesis Ipsilateral lateral rectus paresis Ipsilateral peripheral facial paresis

Basis pontis = Corticospinal tract

Contralateral hemiparesis

Bilateral basis pontis Bilateral cranial VI-fasicular

Quadraplegia

Bilateral corticobulbar

Impairment of horizontal eye movement Aphonia

Figure 2-44. Pontine anatomy and main pontine stroke syndromes.

Clinical-Anatomical Syndromes of Ischemic Infarction

Case Vignette A 63-year-old man developed acute onset of slurred speech, gait imbalance, left-sided weakness, and horizontal diplopia. Initially he did not seek medical attention because “he did not like doctors who always found something wrong with him,” but after more than 12 hours of persistent deficits, his family convinced him to go to the hospital. On examination, he had mild dysarthria, right abducens palsy, right facial weakness, left arm and leg weakness, and mild axial and right appendicular ataxia. CT scan showed an area of possible hypoattenuation of the right pons, which was subsequently confirmed by MRI with DWI (Figure 2-45). MRA of the

intracranial vessels disclosed atherosclerotic midbasilar stenosis (see Figure 2-45), which was likely the culprit for the pontine stroke by occluding a paramedian penetrating branch. During the hospitalization the patient was diagnosed with hypertension, diabetes mellitus, and hyperlipidemia. He was discharged on antiplatelet therapy, a statin, an angiotensin-converting enzyme (ACE) inhibitor, and an oral hypoglycemic agent. He achieved fair functional recovery with the help of intensive physical and occupational therapy. He remained compliant with the medications and has not had recurrent symptoms of posterior circulation ischemia.

Figure 2-45. Magnetic resonance imaging of the brain showing an acute right pontine infarction as noted on diffusion-weighted imagery/apparent diffusion coefficient (upper row) and T2-weighted sequence (lower left). The mechanism responsible for the stroke was basilar artery atherosclerosis, as seen on the magnetic resonance angiography (lower right, arrow).

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Clinical-Anatomical Syndromes of Ischemic Infarction

Pontine infarctions are better visualized by MRI, because streak artifact through this region often compromises the sensitivity of CT scan. The most typical clinical manifestations of pontine infarctions include oculomotor palsy (sometimes associated with internuclear ophthalmoplegia or one-and-a-half syndrome), contralateral motor and sensory deficits, and ataxia. Vestibular disorder ipsilateral to the infarction may also occur. The dysarthria may be extremely disabling, and the most severe cases may present with anarthria. MRI is much superior to CT scan in the distinction between lacunar infarctions, confined to the depth of the pontine parenchyma (although the boundaries of lacunar infarctions may be more difficult to define on DWI), and larger infarctions reaching

ANATOMY OF THE MIDBRAIN

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the surface of the pons, of which paramedian infarctions are the most common. Identification of paramedian pontine infarctions should prompt evaluation of the basilar artery, because they are often caused by atherothrombosis of this vessel, as illustrated by our case.65 High-resolution MRI may detect basilar artery plaques near or at the origin of the paramedian penetrating arteries in patients with apparently normal MRA (because the basilar artery luminal diameter is maintained by vascular remodeling).66

Midbrain Infarctions The main ischemic midbrain syndromes are illustrated in Figure 2-46.

WEBER SYNDROME

1

1 2

2 3

3 4

5

4

CONTRALATERAL hemiplegia Damage to corticospinal and corticobulbar tract (#1) IPSILATERAL oculomotor paresis Damage to oculomotor nucleus/cranial nerve III (#4)

BENEDIKT SYNDROME

5

1 = Crus cerebri - corticospinal fibers and corticopontine fibers 2 = Spinothalamic tract 3 = Red nucleus 4 = Oculomotor nucleus with nerve (white arrow) 5 = Superior colliculus

CONTRALATERAL involuntary movements (including chorea and tremor) Damage to red nucleus IPSILATERAL oculomotor paresis Damage to oculomotor nucleus/cranial nerve III (#4)

Figure 2-46. Midbrain anatomy and main midbrain stroke syndromes.

Case Vignette A 60-year-old man with history of hypertension and heavy smoking was acutely evaluated in the emergency department for sudden onset of diplopia and right hemiparesis. On examination, he was hypertensive and had a left oculomotor nerve palsy and right hemiparesis with upper motor neuron pattern. CT scan was suspicious for an area of hypoattenuation in the middle aspect of the

midbrain, and MRI scan confirmed the diagnosis of acute mesencephalic infarction (Figure 2-47). No significant intracranial stenosis was noted on MRA. The patient was kept on antiplatelet therapy, and measures to control his vascular risk factors. The deficits remained stable and moderately disabling at 4 months. He has continued to smoke.

Clinical-Anatomical Syndromes of Ischemic Infarction

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Figure 2-47. Computed tomography scan (left) and T2-weighted sequence of the magnetic resonance imaging (right) showing a right paramedian midbrain infarction (arrows).

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Pure midbrain infarctions present most commonly with gait and limb ataxia (limb ataxia may be bilateral), dysarthria, oculomotor palsy, and, less commonly, internuclear ophtalmoplegia.67 Sensory symptoms are relatively common. Hemiparesis is often an indicator of larger infarction; the combination of hemiparesis with oculomotor palsy or ataxia is typically related to large artery disease.67

References 1. Kim EY, Lee SK, Kim DJ, Suh SH, Kim J, Heo JH, et al. Detection of thrombus in acute ischemic stroke: value of thin-section noncontrast-computed tomography. Stroke 2005; 36:2745–2747. 2. Assouline E, Benziane K, Reizine D, Guichard JP, Pico F, Merland JJ, et al. Intra-arterial thrombus visualized on T2* gradient echo imaging in acute ischemic stroke. Cerebrovasc Dis 2005; 20:6–11. 3. Sugg RM, Malkoff MD, Noser EA, Shaltoni HM, Weir R, Cacayorin ED, et al. Endovascular recanalization of internal carotid artery occlusion in acute ischemic stroke. AJNR Am J Neuroradiol 2005; 26:2591–2594. 4. Rabinstein AA, Wijdicks EF, Nichols DA. Complete recovery after early intraarterial recombinant tissue plasminogen activator thrombolysis of carotid T occlusion. AJNR Am J Neuroradiol 2002; 23:1596–1599. 5. Tomsick T, Brott T, Barsan W, Broderick J, Haley EC, Spilker J, et al. Prognostic value of the hyperdense middle cerebral artery sign and stroke scale score before ultraearly thrombolytic therapy. AJNR Am J Neuroradiol 1996; 17:79–85. 6. Qureshi AI, Ezzeddine MA, Nasar A, Suri MF, Kirmani JF, Janjua N, et al. Is IV tissue plasminogen activator beneficial in patients with hyperdense artery sign? Neurology 2006; 66:1171–1174.

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Pure midbrain infarctions have a relatively good prognosis. However, bilateral midbrain infarctions, most often encountered in association with more extensive infarctions of the posterior circulation (such as in the rostral basilar artery syndrome or after treatment of basilar artery aneurysms), produce substantial permanent disability.67,68 Therefore precise delineation of the ischemic lesion(s) using MRI has considerable prognostic value.

7. Manno EM, Nichols DA, Fulgham JR, Wijdicks EF. Computed tomographic determinants of neurologic deterioration in patients with large middle cerebral artery infarctions. Mayo Clin Proc 2003; 78:156–160. 8. Agarwal P, Kumar S, Hariharan S, Eshkar N, Verro P, Cohen B, et al. Hyperdense middle cerebral artery sign: can it be used to select intra-arterial versus intravenous thrombolysis in acute ischemic stroke? Cerebrovasc Dis 2004; 17:182–190. 9. Marinkovic SV, Kovacevic MS, Marinkovic JM. Perforating branches of the middle cerebral artery. Microsurgical anatomy of their extracerebral segments. J Neurosurg 1985; 63:266–271. 10. Fisher CM. Capsular infarcts: the underlying vascular lesions. Arch Neurol 1979; 36:65–73. 11. Nicolai A, Lazzarino LG, Biasutti E. Large striatocapsular infarcts: clinical features and risk factors. J Neurol 1996; 243:44–50. 12. Marinkovic SV, Milisavljevic MM, Kovacevic MS, Stevic ZD. Perforating branches of the middle cerebral artery. Microanatomy and clinical significance of their intracerebral segments. Stroke 1985; 16:1022–1029. 13. Fenelon G, Houeto JL. Unilateral parkinsonism following a large infarct in the territory of the lenticulostriate arteries. Mov Disord 1997; 12:1086–1090. 14. Caplan LR, Schmahmann JD, Kase CS, Feldmann E, Baquis G, Greenberg JP, et al. Caudate infarcts. Arch Neurol 1990; 47:133–143.

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15. Bogousslavsky J, Van Melle G, Regli F. Middle cerebral artery pial territory infarcts: a study of the Lausanne Stroke Registry. Ann Neurol 1989; 25:555–560. 16. Caplan LR, Kelly M, Kase CS, Hier DB, White JL, Tatemichi T, et al. Infarcts of the inferior division of the right middle cerebral artery: mirror image of Wernicke’s aphasia. Neurology 1986; 36:1015–1020. 17. Fink JN, Selim MH, Kumar S, Voetsch B, Fong WC, Caplan LR. Insular cortex infarction in acute middle cerebral artery territory stroke: predictor of stroke severity and vascular lesion. Arch Neurol 2005; 62:1081–1085. 18. Abboud H, Berroir S, Labreuche J, Orjuela K, Amarenco P. Insular involvement in brain infarction increases risk for cardiac arrhythmia and death. Ann Neurol 2006; 59:691–699. 19. Ay H, Koroshetz WJ, Benner T, Vangel MG, Melinosky C, Arsava EM, et al. Neuroanatomic correlates of strokerelated myocardial injury. Neurology 2006; 66:1325– 1329. 20. Laowattana S, Zeger SL, Lima JA, Goodman SN, Wittstein IS, Oppenheimer SM. Left insular stroke is associated with adverse cardiac outcome. Neurology 2006; 66:477–483. 21. Ay H, Arsava EM, Koroshetz WJ, Sorensen AG. Middle cerebral artery infarcts encompassing the insula are more prone to growth. Stroke 2008; 39:373–378. 22. Minematsu K, Yamaguchi T, Omae T. “Spectacular shrinking deficit”: rapid recovery from a major hemispheric syndrome by migration of an embolus. Neurology 1992; 42:157–162. 23. Baird AE, Donnan GA, Austin MC, McKay WJ. Early reperfusion in the “spectacular shrinking deficit” demonstrated by single-photon emission computed tomography. Neurology 1995; 45:1335–1339. 24. Sage JI, Van Uitert RL. Man-in-the-barrel syndrome. Neurology 1986; 36:1102–1103. 25. Hurley JP, Wood AE. Isolated man-in-the-barrel syndrome following cardiac surgery. Thorac Cardiovasc Surg 1993; 41:252–254. 26. Riggs HE, Rupp C. Variation in form of circle of Willis. The relation of the variations to collateral circulation: anatomic analysis. Arch Neurol 1963; 8:8–14. 27. Marinkovic S, Kovacevic M, Milisavljevic M. Hypoplasia of the proximal segment of the anterior cerebral artery. Anat Anz 1989; 168:145–154. 28. Dunker RO, Harris AB. Surgical anatomy of the proximal anterior cerebral artery. J Neurosurg 1976; 44:359–367. 29. Ogawa A, Suzuki M, Sakurai Y, Yoshimoto T. Vascular anomalies associated with aneurysms of the anterior communicating artery: microsurgical observations. J Neurosurg 1990; 72:706–709. 30. Caplan LR, Schmahmann JD, Kase CS, Feldmann E, Baquis G, Greenberg JP, et al. Caudate infarcts. Arch Neurol 1990; 47:133–143. 31. Nagaratnam N, Nagaratnam K, Ng K, Diu P. Akinetic mutism following stroke. J Clin Neurosci 2004; 11:25–30. 32. Gelmers HJ. Non-paralytic motor disturbances and speech disorders: the role of the supplementary motor area. J Neurol Neurosurg Psychiatry 1983; 46:1052–1054. 33. Hupperts RM, Lodder J, Heuts-van Raak EP, Kessels F. Infarcts in the anterior choroidal artery territory. Anatomical

distribution, clinical syndromes, presumed pathogenesis and early outcome. Brain 1994; 117(Pt 4):825–834. 34. Takahashi S, Ishii K, Matsumoto K, Higano S, Ishibashi T, Suzuki M, et al. The anterior choroidal artery syndrome. II. CT and/or MR in angiographically verified cases. Neuroradiology 1994; 36:340–345. 35. Levy R, Duyckaerts C, Hauw JJ. Massive infarcts involving the territory of the anterior choroidal artery and cardioembolism. Stroke 1995; 26:609–613. 36. Friedman JA, Pichelmann MA, Piepgras DG, Atkinson JL, Maher CO, Meyer FB, et al. Ischemic complications of surgery for anterior choroidal artery aneurysms. J Neurosurg 2001; 94:565–572. 37. Bisaria KK. Anomalies of the posterior communicating artery and their potential clinical significance. J Neurosurg 1984; 60:572–576. 38. Pedroza A, Dujovny M, Artero JC, Umansky F, Berman SK, Diaz FG, et al. Microanatomy of the posterior communicating artery. Neurosurgery 1987; 20:228–235. 39. Waterston JA, Stark RJ, Gilligan BS. Paramedian thalamic and midbrain infarction: the “mesencephalothalamic syndrome.” Clin Exp Neurol 1987; 24:45–53. 40. Auchus AP, Chen CP, Sodagar SN, Thong M, Sng EC. Single stroke dementia: insights from 12 cases in Singapore. J Neurol Sci 2002; 203–204:85–89. 41. Tay KY, King-Im JM, Trivedi RA, Higgins NJ, Cross JJ, Davies JR, et al. Imaging the vertebral artery. Eur Radiol 2005; 15:1329–1343. 42. Caplan LR, Wityk RJ, Glass TA, Tapia J, Pazdera L, Chang HM, et al. New England Medical Center Posterior Circulation registry. Ann Neurol 2004; 56:389–398. 43. Koch S, Amir M, Rabinstein AA, Reyes-Iglesias Y, Romano JG, Forteza A. Diffusion-weighted magnetic resonance imaging in symptomatic vertebrobasilar atherosclerosis and dissection. Arch Neurol 2005; 62:1228–1231. 44. Caplan LR. “Top of the basilar” syndrome. Neurology 1980; 30:72–79. 45. Kumral E, Kisabay A, Atac C. Lesion patterns and etiology of ischemia in the anterior inferior cerebellar artery territory involvement: a clinical–diffusion weighted–MRI study. Eur J Neurol 2006; 13:395–401. 46. Kumral E, Kisabay A, Atac C. Lesion patterns and etiology of ischemia in superior cerebellar artery territory infarcts. Cerebrovasc Dis 2005; 19:283–290. 47. Barth A, Bogousslavsky J, Regli F. The clinical and topographic spectrum of cerebellar infarcts: a clinical-magnetic resonance imaging correlation study. Ann Neurol 1993; 33:451–456. 48. Canaple S, Bogousslavsky J. Multiple large and small cerebellar infarcts. J Neurol Neurosurg Psychiatry 1999; 66:739–745. 49. Min WK, Kim YS, Kim JY, Park SP, Suh CK. Atherothrombotic cerebellar infarction: vascular lesion-MRI correlation of 31 cases. Stroke 1999; 30:2376–2381. 50. Koh MG, Phan TG, Atkinson JL, Wijdicks EF. Neuroimaging in deteriorating patients with cerebellar infarcts and mass effect. Stroke 2000; 31:2062–2067. 51. Jauss M, Muffelmann B, Krieger D, Zeumer H, Busse O. A computed tomography score for assessment of mass effect in space-occupying cerebellar infarction. J Neuroimaging 2001; 11:268–271.

Clinical-Anatomical Syndromes of Ischemic Infarction 52. Jauss M, Krieger D, Hornig C, Schramm J, Busse O. Surgical and medical management of patients with massive cerebellar infarctions: results of the German-Austrian Cerebellar Infarction Study. J Neurol 1999; 246:257–264. 53 Chaves CJ, Caplan LR, Chung CS, Tapia J, Amarenco P, Teal P, et al. Cerebellar infarcts in the New England Medical Center Posterior Circulation Stroke Registry. Neurology 1994; 44:1385–1390. 54. Amarenco P, Hauw JJ. Cerebellar infarction in the territory of the anterior and inferior cerebellar artery. A clinicopathological study of 20 cases. Brain 1990; 113:139–155. 55. Sohn SI, Lee H, Lee SR, Baloh RW. Cerebellar infarction in the territory of the medial branch of the superior cerebellar artery. Neurology 2006; 66:115–117. 56. Amarenco P, Hauw JJ. Cerebellar infarction in the territory of the superior cerebellar artery: a clinicopathologic study of 33 cases. Neurology 1990; 40:1383–1390. 57. Kim HA, Lee H, Sohn SI, Yi HA, Cho YW, Lee SR, et al. Bilateral infarcts in the territory of the superior cerebellar artery: clinical presentation, presumed cause, and outcome. J Neurol Sci 2006; 246:103–109. 58. Amarenco P, Kase CS, Rosengart A, Pessin MS, Bousser MG, Caplan LR. Very small (border zone) cerebellar infarcts. Distribution, causes, mechanisms and clinical features. Brain 1993; 116:161–186. 59. Sacco RL, Freddo L, Bello JA, Odel JG, Onesti ST, Mohr JP. Wallenberg’s lateral medullary syndrome. Clinical-magnetic resonance imaging correlations. Arch Neurol 1993; 50:609–614.

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60. Sacco RL, Freddo L, Bello JA, Odel JG, Onesti ST, Mohr JP. Wallenberg’s lateral medullary syndrome. Clinical-magnetic resonance imaging correlations. Arch Neurol 1993; 50:609–614. 61. Milandre L, Lucchini P, Khalil R. [Lateral bulbar infarctions. Distribution, etiology and prognosis in 40 cases diagnosed by MRI]. Rev Neurol (Paris) 1995; 151:714– 721. 62. Frumkin LR, Baloh RW. Wallenberg’s syndrome following neck manipulation. Neurology 1990; 40:611–615. 63. Kitis O, Calli C, Yunten N, Kocaman A, Sirin H. Wallenberg’s lateral medullary syndrome: diffusion-weighted imaging findings. Acta Radiol 2004; 45:78–84. 64. Ross MA, Biller J, Adams HP Jr, Dunn V. Magnetic resonance imaging in Wallenberg’s lateral medullary syndrome. Stroke 1986; 17:542–545. 65. Erro ME, Gallego J, Herrera M, Bermejo B. Isolated pontine infarcts: etiopathogenic mechanisms. Eur J Neurol 2005; 12:984–988. 66. Klein IF, Lavallee PC, Schouman-Claeys E, Amarenco P. High-resolution MRI identifies basilar artery plaques in paramedian pontine infarct. Neurology 2005; 64:551– 552. 67. Kim JS, Kim J. Pure midbrain infarction: clinical, radiologic, and pathophysiologic findings. Neurology 2005; 64:1227–1232. 68. Kumral E, Bayulkem G, Akyol A, Yunten N, Sirin H, Sagduyu A. Mesencephalic and associated posterior circulation infarcts. Stroke 2002; 33:2224–2231.

Chapter

3

Acute Stroke Imaging Alejandro A. Rabinstein and Steven J. Resnick

T

here was a time, not too long ago, when acute brain imaging in patients with suspected stroke was thought to be useful only to exclude hemorrhage or obvious stroke mimickers, such as tumors. The introduction of effective acute stroke therapies changed this conception completely, however. Today emergency brain imaging is essential for the management of acute stroke patients. We have learned that computed tomography (CT) scans can offer valuable information even when obtained within the first few hours of the ischemic event (dispelling the notion that CT scans are not useful for ischemic strokes until 1 or 2 days after onset). New CT-based protocols, including CT perfusion (CTP) scans and CT angiograms, are rapidly gaining ground in clinical practice. Diffusion-weighted and perfusionweighted (DWI and PWI) magnetic resonance imaging (MRI) provide the ability to depict the penumbra and promise expansion of the therapeutic window for vessel

opening on individual cases based on the subsistence of salvageable tissue. Conventional angiography has been transformed from a purely diagnostic test into a means for therapeutic intervention. Even transcranial Doppler may have an important role in the emergent evaluation and management of acute ischemic stroke, providing proof of large intracranial vessel occlusion and possibly improving the chances of recanalization with thrombolysis when continuous insonation is employed. The uses of various neuroimaging techniques in acute stroke are multiple and continue to expand. The most common current indications and purposes of acute neuroimaging in stroke patients are listed in Table 3-1. This chapter illustrates and summarizes the multiple values of brain imaging in the acute phase of ischemic stroke and concludes with a succinct discussion on the radiological features of subacute and chronic infarctions that allow timing of ischemic strokes.

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TABLE 3-1. Indications and purposes of emergency neuroimaging in patients with suspected acute ischemic stroke Indication/purpose

Imaging modality

Confirmation of diagnosis (TIA vs. stroke vs. stroke mimics)

CT/MRI

Differentiation of ischemia vs. hemorrhage

CT/MRI

Visualization of established infarction (as contraindication for thrombolysis)

CT

Localization of ischemia/stroke pattern (which may guide evaluation of stroke mechanism)

CT/MRI

Evaluation of penumbra (which may extend therapeutic window for acute revascularization)

DWI-PWI/CTP

Identification of early prognostic markers (e.g., HDMCA sign, extensive high ASPECTS score, large volume of DWI restriction)

CT/MRI

Visualization of arterial site of occlusion

MRA/CTA/catheter angiography

Documentation of recanalization

MRA/CTA/catheter angiography/TCD

US-assisted intravenous thrombolysis

TCD

Access and information to make endovascular treatment possible

Catheter angiography

ASPECTS, Alberta Stroke Program Early CT Score; CT, computed tomography; CTA, CT angiography; CTP, CT perfusion; DWI, diffusion-weighted imaging; HDMCA, hyperdense middle cerebral artery; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; PWI, perfusion-weighted imaging; TCD, transcranial Doppler; TIA, transient ischemic attack; US, ultrasound.

COMPUTED TOMOGRAPHY CT Signs of Acute Ischemia Case Vignette A 50-year-old man with a history of hypertension and rapid palpitations presented to the emergency department with acute left hemiparesis. Neurological examination showed right gaze preference, left homonymous hemianopia, left hemiparesis, and left hemineglect. Initial CT scan obtained 5 hours and 20 minutes after symptom onset revealed early signs of edema and infarction throughout the territory of the right middle cerebral artery (Figure 3-1, upper row).

Because of the presence of these radiological findings, endovascular revascularization treatments were not attempted. On Day 3, he was more somnolent, and a repeat CT scan showed spontaneous hemorrhage in the area of infarction (Figure 3-1, lower row). The patient was diagnosed with atrial fibrillation, and anticoagulation was subsequently started for secondary stroke prevention. He survived his stroke but remained moderately disabled.

Acute Stroke Imaging

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B

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D

Figure 3-1. Top row: Nonenhanced computed tomography (CT) scan of the brain showing early signs of edema (sulcal effacement, loss of differentiation of gray and white matter) and infarction (hypoattenuation) in the territory of the right middle cerebral artery (arrows). Bottom row: Repeat CT scan showing evolution of the extensive ischemic stroke with evidence of hemorrhage within the infarction.

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Far from being uninformative, the CT scan of the brain performed in the emergency department can provide valuable diagnostic and prognostic information and may be crucial in the selection of early management options. CT scan is available in most emergency departments and can be rapidly obtained. It must be performed in all patients suspected of having an acute stroke, and it is the only radiological study needed before deciding the administration of intravenous thrombolysis.1 Noncontrast CT can readily and reliably exclude hemorrhage, demonstrate the fresh intraluminal thrombus, and display early signs of brain ischemia (Table 3-2 and Figure 3-2).

TABLE 3-2. Early signs of ischemic stroke on brain CT scan. Sign

Significance

Hyperdense vessel sign

Intraluminal thrombus

Loss of insular ribbon

Focal tissue edema

Obscuration of the lenticular nucleus

Focal tissue edema

Loss of gray–white matter distinction

Focal tissue edema

Sulcal effacement

Focal tissue edema

Areas of hypoattenuation

Tissue infarction

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B

Figure 3-2. Nonenhanced computed tomography scan of the brain revealing a hyperdense vessel sign in the Sylvian fissure (arrowhead) and early hypoattenuation involving the right lenticular nucleus and insular region (open arrows). Notice loss of differentiation of the insular ribbon and margins of the lenticular nucleus, as well as partial effacement of the Sylvian fissure (solid arrow).

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When carefully reviewed, noncontrast CT scan of the brain can reveal these signs of ischemia in up to 75% of patients with territorial MCA stroke.2 It is important to discriminate signs of brain edema, such as loss of insular ribbon (Figure 3-3), obscura-

tion of lenticular nucleus (Figure 3-4), loss of gray–white matter differentiation, and sulcal effacement (Figure 3-5) from areas of hypoattenuation, because only the latter represents irreversible damage (established infarction).3,4

Acute Stroke Imaging EARLY SIGNS OF ISCHEMIA ON CT SCAN Admission

24 hours

48 hours

Insular ribbon sign

Figure 3-3. Example of early brain ischemia in the anterior division of the right middle cerebral artery causing loss of visualization of the insular cortex (insular ribbon sign).

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Figure 3-4. Example of early ischemia in the territory of the right middle cerebral artery causing loss of differentiation of the boundaries of the lenticular nucleus (arrows). Notice gaze deviation to the right, a clinical sign pointing to the side of the stroke (arrowheads).

Figure 3-5. Prominent sulcal ef-

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B

facement and loss of gray–white matter differentiation (arrows) in a patient with early right middle cerebral artery ischemia.

Acute Stroke Imaging ❖

provided by the history and physical examination and to follow a methodical approach to maximize the yield of CT scan interpretation. Modifications of window settings may also increase the sensitivity of CT scanning to detect early ischemic changes (Figure 3-6).7

Interobserver agreement for the recognition of early ischemic changes is only fair when performed without following a formal method and without considering the clinical information.5,6 Thus it is crucial to know the expected location of the ischemic insult on the basis of the information

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B

Figure 3-6. Computed tomography scan of the brain of a patient who presented with symptoms suspicious for right middle cerebral artery stroke. (A) Brain window barely reveals subtle loss of differentiation of gray and white matter in a portion of the posterior right frontal cortex (arrows). (B) The early changes become much more noticeable (arrows) after modifying the window settings to increase the contrast.

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Visual identification of early signs of ischemia (particularly hypoattenuation) involving more than one third of the estimated middle cerebral artery (MCA) territory was considered an exclusion criterion for enrollment in several thrombolysis trials, most notably those conducted by the European Acute Stroke Study (ECASS) investigators,8,9 on the basis of a reasonable but unproved assumption that patients with early signs of extensive ischemia would have higher risk of bleeding after thrombolysis. However, this preconception was not validated by the analysis of the radiological data from the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA study, which did not include this radiological exclusion criterion.10 In this trial, ischemic changes on baseline CT scan were observed in 31% of patients. They correlated with greater severity of initial clinical deficits and with longer time from symptom onset but were not independently associated with functional outcome after controlling for other baseline variables. Early ischemic changes were not associated with clinical deterioration within the first 24 hours or symptomatic intracranial hemorrhage within the first 36 hours in the adjusted analysis.11

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Moreover, although there is some evidence that extensive early ischemic changes may portend higher risk of intracerebral hemorrhage,12 there is no proof that the extension of early ischemic changes significantly affects the chances of functional recovery after thrombolysis.12,13 Nonetheless, most current acute stroke management guidelines include extensive early signs of ischemia as a contraindication for thrombolysis. The guidelines sponsored by the American Heart Association indicate that thrombolysis should not be used if the baseline CT scan shows multilobar hypodensity involving more than one third of the cerebral hemisphere.1 This carefully crafted recommendation appears prudent. It is important to notice that it intentionally indicates hypodensity (as opposed to other early signs that may represent only tissue swelling and are more difficult to identify) and eliminates the need to estimate the MCA territory as a parameter to define the extension of the changes. On the basis of current evidence, withholding thrombolysis in patients with early signs of tissue edema but no large hypodensities is not justified. The extension of ischemic changes in the territory of the middle cerebral artery can be quantified

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using the Alberta Stroke Program Early CT Score (ASPECTS) (Figures 3-7 and 3-8), a 10-point topographic scoring system that has been shown to be easy to use in real time with moderately good interrater reliability.2,14,15 A cutoff score of less than 7 points is most useful to determine ischemia involving more than one third of the MCA terri-

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tory.15 Notice that this score can only be used in cases of middle cerebral artery ischemia. CT scan may allow visualization of intraluminal thrombi in the terminal carotid, middle cerebral trunk, middle cerebral branches, and basilar arteries (Figure 3-9).

B

Figure 3-7. Illustration of the Alberta Stroke Program Early CT Score (ASPECTS) scoring system to classify the extension of early ischemic changes in the middle cerebral artery territory on computed tomography scan. The entire middle cerebral artery territory is allotted 10 points; 1 point is subtracted for each of the defined regions affected with early ischemic changes. Thus lower scores indicate larger areas of ischemia.

M1

M4

I

M5

M6

A

B

Figure 3-8. Extensive right middle cerebral artery territory stroke on early computed tomography scan shown to exemplify the use of the Alberta Stroke Program Early CT Score (ASPECTS) score. The ASPECTS score in this case is 5 because of changes in the regions M1, I, M4, M5, and M6.

Acute Stroke Imaging INTRA-ARTERIAL THROMBUS ON CT SCAN CT scan

MRI-DWI

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B

C

D Figure 3-9. Examples of hyperdense vessel sign on the middle cerebral artery (A), Sylvian branch of the middle cerebral artery (linear hyperdensity shown in B and dot sign shown in C), and basilar artery (D).

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Acute Stroke Imaging

The hyperdense MCA sign has good specificity for thrombotic MCA occlusion (it can be mimicked by a calcified plaque or high hematocrit, but in these cases the hyperdensity is typically bilateral), but its sensitivity is poor (approximately 30%).16 The hyperdense MCA sign on baseline CT scan has been found to be associated with poor prognosis17,18 and a higher risk of hemorrhage after thrombolysis.19 The combination of hyperdense MCA sign and extensive sulcal effacement predicts massive swelling and brain herniation.20 Conversely, early resolution of the hyperdensity in the MCA indicates successful reperfusion and is associated with favorable outcome after thrombolysis. Intravenous thrombolysis can be beneficial in patients presenting with the hyperdense MCA sign.18 However, when the hyperdense signal appears to involve the carotid terminus in a patient with signs suspicious for carotid bifurcation occlusion (depressed arousal, severe leg weakness), it may be more effective to pursue intra-arterial therapy directly if this is a pragmatically feasible option.21 Distal thrombi can sometimes be visualized generating the Sylvian fissure “dot” sign (Figure 3-9, C).22 Its sensitivity is modest (close to 40%), but when identified, it is very specific in predicting M2 or M3 branch occlusion.23 The dot sign is associated with better outcome than more proximal hyperdense vessel signals.22

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Rarely, air or fat emboli can produce hypodense vessel signs.24

CT Perfusion ❖

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There is growing interest in the application of CT protocols using multimodal CT scanning (CT scan, CT perfusion, and CT angiogram) for the emergency diagnosis and management of ischemic stroke.3,25 The most attractive features of CT perfusion imaging are its potential for widespread availability (it can be performed on any standard helical CT scanner) and the short time required for the acquisition of data (with adequate training, CT perfusion and CT angiogram can be acquired in 15–20 minutes, and images can be processed and interpreted in 10 minutes or less).26,27 Dynamic contrast-enhanced CT perfusion imaging (bolus tracking CT perfusion) generates maps of mean transit time (MTT; reflecting the time difference between arterial inflow and venous outflow), time to peak (TTP; representing the time to maximal concentration of contrast enhancement in a region of interest), cerebral blood flow (CBF), and cerebral blood volume (CBV) (Figure 3-10). These physiological measures can be precisely quantified, which represents an advantage over PWI MRI (Table 3-3).

Acute Stroke Imaging

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D

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Figure 3-10. A 58-year-old patient with history of hypertension and hypercholesterolemia who presented to the emergency department with aphasia, right superior quadrantanopsia, mild right hemiparesis, and right hemisensory loss. Computed tomography (CT) scan (shown with contrast) 4.5 hours after symptom onset did not depict the infarction (A) but CT perfusion clearly delineated the area of ischemia. Mean transit time map (B) showed delayed perfusion in the territory of the posterior division of the left middle cerebral artery (arrows). Cerebral blood flow map (C) confirmed hypoperfusion in that brain region (arrows). However, cerebral blood volume was relatively preserved (D). CT angiogram (E) (three-dimensional reconstruction shown) revealed lack of filling of the branches of the posterior division of the left middle cerebral artery (arrow). One day later, diffusion-weighted magnetic resonance imaging (F) disclosed an acute infarction in the area previously characterized as penumbra by the CT perfusion scan.

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TABLE 3-3. Relative advantages of CT perfusion and DWI-PWI MRI for the assessment of ischemic penumbra. CT perfusion Easier access Rapid acquisition of images Robust quantitative physiological measurements

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Feasible in patients with contraindication for MRI DWI-PWI MRI May be easier to visualize the penumbra Depiction of cellular edema Greater spatial resolution (whole brain imaging) Does not require iodine contrast CT, computed tomography; DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging; PWI, perfusion-weighted imaging.

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However, CT perfusion has limited spatial resolution, because most multidetector scanners at present only allow coverage of four brain slices (20 mm) and do not directly depict acute cellular damage. CT perfusion imaging requires exposure to iodine contrast (50–80 ml of contrast medium containing 300 mg of iodine/ml infused over approximately 10 sec), but complications related to contrast exposure are extremely infrequent. Prolonged relative MTT and delayed relative TTP are the most sensitive physiological parameters to detect hypoperfusion.28 These measures correlate well with MRI abnormalities on PWI and accurately predict final infarct volume in patients who have persistent arterial occlusions (Figure 3-10).29,30 Meanwhile, reduced absolute CBV (or reduced

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relative CBV by visual inspection) is the best indicator of established infarction; it correlates well with DWI lesions on MRI and with final infarct size in patients who recanalize.28–30 The product CBF ⫻ CBV may have greater diagnostic accuracy than CBV alone, but this requires the use of quantitative measures.31 As with PWI, the main value of the CBF map on CT perfusion is the distinction between areas of hypoperfusion that may survive despite persistent vascular occlusion thanks to collateral circulation (although commonly included within the radiologically defined penumbra, these areas of oligemia are not at high risk of infarction unless there is a drop in cerebral perfusion pressure) from those destined to evolve to infarction unless prompt recanalization occurs. Although no definitive CBF thresholds have been defined for this distinction, the lower the CBF within an area of prolonged MTT, the higher the likelihood that the tissue will become infarcted unless rapidly reperfused.31 When quantitative measures are used, the optimal threshold to detect tissue at risk for infarction is a relative MTT of 145% (i.e., 45% longer than in the contralateral side) and the optimal threshold to define the infarction core is an absolute CBV of 2.0 ml ⫻ 100 g⫺1.32 The postprocessing technique that affords these quantitative measurements has been shown to be solidly reproducible.33 Nonetheless, qualitative visual interpretation of the MTT and CBV maps yield fast and reliable information to estimate the penumbra.28 Hence, the mismatch between the areas of prolonged MTT (hypoperfusion) and reduced CBV (ischemic core) constitutes the best indicator of the penumbra on CT perfusion imaging (Figure 3-11).28,31,32

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THE DEFINITIONS OF ISCHEMIA PENUMBRA Core Critical hypoperfusion without cellular death

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Figure 3-11. Definitions of ischemic penumbra by magnetic resonance imaging and computed tomography perfusion criteria.

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CT angiography is also widely available, because it can also be performed with any helical scanner, and should be part of a comprehensive, multimodal CT protocol for evaluation of acute brain ischemia. After a bolus of iodine contrast is injected to enhance the vessels (100–120 ml of contrast), high-speed, timed scanning is performed typically covering from the aortic arch to the circle of Willis. After acquisition, the data are digitally reformatted

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to generate multiplanar, three-dimensional, and maximum intensity projection images. Although CT angiography has not been formally tested against catheter angiography to determine its precise positive and negative predictive values, in practice it allows rapid and reliable demonstration of intracranial or extracranial vessel occlusion.34 Thus this technique may be valuable to guide timely therapeutic decisions, as illustrated by the case in Figure 3-12.

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Figure 3-12. A 58-year-old woman who presented with acute aphasia and right hemiparesis after a witnessed first generalized seizure. Computed tomography (CT) scan was negative. CT angiogram showed occlusion of the left M1 segment (arrow). The vascular occlusion recanalized with mechanical embolectomy and the patient recovered well.

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CT angiography has been shown to be safe.27 Renal complications related to contrast administration are exceptional and almost uniformly reversible. The source images of CT angiography have been used to estimate perfusion deficits (Figure 3-12 serves as example).35 The advantages of this method over dynamic CT perfusion imaging include visualization of the whole brain and use of a single bolus of contrast material.3 However, this application has not been validated, and its sensitivity is likely to be poorer than those of CT perfusion or DWI-PWI.

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for the diagnosis of acute hemorrhage.36 Thus solid arguments support the use of MRI as the primary imaging modality for the emergency evaluation of acute stroke patients if the study can be performed without delay.

Diffusion-Weighted and Perfusion-Weighted Imaging ❖

MAGNETIC RESONANCE IMAGING Although MRI scans provide better anatomical definition for the recognition of ischemic lesions than CT (particularly for small infarctions and strokes in the brainstem and posterior fossa), the added expense of MRI was deemed unjustified in the acute stroke setting until the introduction of physiological sequences: diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI). These new sequences are extremely valuable tools for the acute diagnosis of ischemic stroke and offer promise to expand the therapeutic window for recanalization. Equally important are the advances in our understanding of stroke pathophysiology facilitated by the information afforded by these imaging techniques. Furthermore, MRI (with DWI and susceptibility weighted sequence) has been proved superior to CT scanning for the detection of acute ischemia and chronic hemorrhage and at least comparable to CT

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DWI depicts the degree of diffusion of water molecules. Severe ischemia causes failure of ionic pumps at the cellular membrane and trapping of water molecules in the intracellular compartment (cellular edema) where water motion becomes limited (restricted diffusion). Evidence of restricted diffusion on DWI constitutes the most sensitive indicator of hyperacute and acute cerebral ischemia, greatly exceeding the sensitivity of CT scan37,38 and conventional MRI sequences.39 DWI is obtained within 2 minutes by applying ultrafast echo-planar MRI scanning. Hence, DWI is considerably less susceptible to motion artifacts than conventional MRI sequences. Areas with restricted diffusion due to cellular edema are hyperintense on the DWI sequence and hypointense on the apparent diffusion coefficient (ADC) map (Figure 3-13). The ADC value quantifies diffusion; the lower the value, the greater the restriction of motion of water molecules. Conversely, high ADC values are observed in areas of vasogenic edema and chronic infarction in which water molecules have freedom of motion.

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Figure 3-13. Example of acute right middle cerebral artery territory stroke on a magnetic resonance imaging scan performed 2 days after symptom onset. (A) Diffusion-weighted imaging (DWI) showing bright signal in the right insular cortex and anterior temporal lobe (arrows). (B) Corresponding low signal on apparent diffusion coefficient map (arrows) confirms that the area of hyperintense signal on DWI represented restricted diffusion, thus indicating cellular edema. (C) Magnetic resonance angiogram shows marked reduction of flow starting at the distal end of the horizontal segment of the right middle cerebral artery (arrow).

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When interpreting the MRI of a patient with acute stroke, it is essential to read the DWI images, ADC map, and T2-weighted sequence in combination. A bright signal on DWI matching with a dark signal on the ADC map will be indicative of restrictive diffusion (i.e., cellular edema consistent with acute

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ischemia). Bright signals appearing both on DWI and ADC map are caused by the “T2 shine through” phenomenon (Figure 3-14).40 Hence isolated review of the DWI sequence may be misleading and should always be avoided.

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Figure 3-14. Example of subacute right middle cerebral artery territory stroke on an magnetic resonance imaging scan performed 9 days after symptom onset. (A) Diffusion-weighted imaging showing heterogeneously bright signal in the right frontal lobe (arrows). (B) Apparent diffusion coefficient map shows a predominantly high signal in that region (i.e., diffusion is no longer restricted) from T2 shine through (arrows), thus indicating the subacute nature of the infarction. (C) Fluid-attenuated inversion recovery sequence already shows a well-delineated area of infarction.

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Decreased diffusion becomes apparent within 30 minutes of stroke onset and the reduction reaches its nadir 2 to 4 days later. ADC values then begin to increase until they return to baseline between 7 and 14 days later (pseudo-normalization) before increasing in the chronic phase.41,42 After pseudo-normalization of the ADC value, DWI may continue to show a mildly hyperintense signal generated by T2 shine through. DWI is extremely sensitive for the detection of acute ischemia. In fact, DWI lesions are often seen in patients with reversible neurological deficits classified clinically as transient ischemic

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attacks (Figure 3-15).43–46 The sensitivity of DWI only decreases slightly in cases of small medullary infarctions. Although highly indicative of acute ischemia in the right clinical setting, other mechanisms that produce intracellular edema may exhibit restricted diffusion on DWI. Examples include herpes encephalitis, Creutzfeldt-Jakob disease, diffuse axonal injury after brain trauma, and some acute demyelinating plaques among others.47 Table 3-4 lists the practical values of DWI in the evaluation of acute stroke patients.

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Figure 3-15. A 69-year-old man evaluated at an outside emergency department for acute right hemiparesis. Symptoms resolved in less than 2 hours, and the patient was discharged home on aspirin to be evaluated as an outpatient. He was seen in our clinic 4 days later. He had remained asymptomatic. Magnetic resonance imaging performed at that time showed two small foci of faint hypersensitivity on diffusion-weighted imaging (arrows) with matching low apparent diffusion coefficient (not shown) indicative of ischemic strokes. Prolonged Holter monitoring revealed paroxysmal atrial fibrillation, and transesophageal echocardiogram disclosed an enlarged left atrium with spontaneous echo contrast. He was anticoagulated with warfarin and has not had any stroke recurrence over the subsequent 2 years.

TABLE 3-4. Main practical uses of DWI in patients with acute stroke presentation. Hyperacute and acute diagnostic confirmation of ischemic stroke Differentiation of acute vs. subacute vs. chronic ischemic lesions Assessment of ischemic penumbra (in combination with PWI) Acute differential diagnosis between TIA and minor stroke with reversible neurological deficits Distinction of cytotoxic and vasogenic edema (in conditions such as eclampsia or hyperperfusion syndrome) Identification of patients at risk of severe reperfusion hemorrhage DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging; PWI, perfusion-weighted imaging; TIA, transient ischemic attack.

Acute Stroke Imaging

PWI-DWI Mismatch ❖

PWI techniques rely on measuring the concentration of contrast (typically gadolinium) as it passes through the cerebral microcirculation. Dynamic susceptibility-weighted (T2*-weighted) imaging is most commonly used to track the bolus of gadolinium, which produces a transient loss of T2* signal and allows the creation of a hemodynamic curve of signal intensity over time. Noninvasive techniques of PWI using endogenous contrast agents (deoxyhemoglobin in blood oxygen level dependent [BOLD] or hydrogen proton in arterial spin labeling [ASL]) are much less commonly employed in acute stroke protocols.

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PWI produces maps of MTT, TTP, CBF, and CBV. However, measurements are relative to the contralateral side as opposed to the absolute hemodynamic values provided by CTP. A TTP delay greater than 4 seconds relative to the contralateral hemisphere appears to be the best marker of the penumbra.48 Nonetheless, this measure may overestimate the size of penumbra in some cases.48 CBF maps most closely identify the final infarct volume.49,50 The ischemic penumbra is represented on MRI by the perfusion-diffusion (PWI-DWI) mismatch (Figures 3-11, 3-16, and 3-17). The PWI lesion corresponds to the area of hypoperfusion and the DWI lesion to the ischemic core.

Figure 3-16. A 64-year-old man presenting with fluent aphasia. Diffusion-weighted imaging (A) and apparent diffusion coefficient (B) showed a small area of restricted diffusion, indicating cellular edema from infarction (open arrows). This infarct core was surrounded by a larger region of hypoperfusion well delineated by the perfusion-weighted imaging scan (C, solid arrow). Notice the curves of signal intensity over time (D), showing the delayed perfusion peak in the affected region compared with the contralateral side.

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E Figure 3-17. A 79-year-old woman with left internal carotid occlusion near its origin who presented with severe symptoms of anterior circulation stroke. However, symptoms reversed almost completely with hemodynamic augmentation (crystalloids, colloids, and vasopressors to increase perfusion pressure). On the first day, diffusion-weighted imaging (DWI) (A) barely revealed a few punctuate areas of restricted diffusion (matching apparent diffusion coefficient map not shown) despite a very large region of compromised perfusion on perfusion-weighted imaging in the territory of the left middle cerebral artery (B). The patient remained stable over the subsequent 36 hours, and a repeat magnetic resonance imaging at that point showed some additional areas of restricted diffusion on DWI following the internal watershed distribution (C) and persistent hypoperfusion in the entire left middle cerebral artery territory (D); this large mismatch indicated the persistence of an extensive area of ischemic penumbra. Unfortunately, the patient developed pulmonary edema and myocardial ischemia on the fourth hospital day, requiring diuretic therapy and discontinuation of the vasopressors. Shortly after these therapeutic decisions were forced by the cardiopulmonary complications, the patient’s neurological status worsened considerably, and a repeat computed tomography scan then showed the expected large middle cerebral artery infarction (E).

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PWI-DWI mismatch is seen in approximately 70% of patients with proximal occlusion of the middle cerebral artery (MCA).51 Unfortunately, there is no validated definition of PWI-DWI mismatch.52 Different definitions have been used in published studies, and visual estimates are most commonly used in practice for acute decision making. In theory, the DWI lesion can expand to reach the size of the initial PWI deficit unless reperfusion occurs. However, confirmation of this hypothesis has proved elusive at times. In fact, some studies have shown that mismatch volume may fail to correlate with DWI lesion expansion.50,53 Possible explanations for this lack of correlation are that areas of ischemia are highly heterogeneous,54 DWI lesions may be reversible (normalization of ADC values has been noted in some patients after thrombolysis),55 and PWI lesions actually incorporate regions of true penumbra and regions of reversible oligemia.56 Determining whether PWI-DWI mismatch can be reliably used to identify salvageable tissue is of major practical importance. Because DWI expansion can be prevented by early reperfusion regardless of the presence of PWI-DWI mismatch,53 there is no indication for MRI before administering intravenous thrombolysis within 3 hours of symptom onset (there are some data suggesting greater safety for thrombolysis within 3 hours in patients selected with MRI vs. those only evaluated with CT scan,57 but not enough solid evidence to change current practice guidelines). However, all other acute revascularization treatments are not the standard of care, and there is considerable

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interest in developing imaging protocols to guide their application (penumbra-based protocols). MRI protocols have been used in research trials to select candidates for intravenous thrombolysis beyond the currently accepted therapeutic window.58,59 In a recent prospective, multicenter study of ischemic stroke patients treated with intravenous thrombolysis between 3 and 6 hours after symptom onset, those patients with larger PWI-DWI mismatch had greater likelihood of favorable clinical outcome after reperfusion.60 In this same study, patients with very large DWI or PWI lesion volumes had very high risk of fatal hemorrhagic conversion after reperfusion.60 Thus MRI profiles may help identify the best and worst candidates for revascularization therapy beyond 3 hours.52 In fact, the EPITHET trial has shown that penumbra defined by DWI-PWI mismatch is common (86% in this study) in patients evaluated between 3 and 6 hours after symptom onset. Treating these patients with intravenous thrombolysis was found to increase the chances of reperfusion, which in turn improves clinical outcomes.61 In centers in which PWI has not been standardized, clinicians may rely on the clinical-radiological mismatch, understood as the discrepancy between relatively small DWI lesions and severe clinical deficits (Figure 3-18).62 These patients are likely to have large areas of penumbra in which brain tissue is dysfunctional (hence the severe clinical deficits) but salvageable (hence the relatively small DWI lesion). This clinical-radiological mismatch has been found to predict the presence of PWI-DWI mismatch with high specificity, although low sensitivity.63

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Direct Thrombus Visualization ❖

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The intravascular occluding thrombus can be seen on T1-weighted sequence, and especially on fluidattenuated inversion recovery (FLAIR)64 and T2* sequences (Figure 3-19). The susceptibility vessel sign on T2* sequence may actually identify fibrin-rich emboli (more

Figure 3-18. A 54-year-old woman presented to the emergency department with global aphasia, right visual field impairment, and dense right facial and brachial paresis with associated sensory loss. National Institutes of Health Stroke Scale score (NIHSS) was 12. Computed tomography scan obtained nearly 4 hours after symptom onset was negative for signs of acute ischemia. Diffusion-weighted imaging only displayed scattered small areas of restricted diffusion in the left middle cerebral artery and internal watershed distribution (arrowheads), indicating a large clinical-diffusion mismatch. Perfusion-weighted imaging was not performed, but magnetic resonance angiography revealed distal occlusion of the M1 segment of the left middle cerebral artery (arrow). Successful recanalization was achieved with a combination of mechanical embolectomy and adjuvant intra-arterial thrombolysis. The patient improved substantially, and the following morning, her NIHSS had diminished to 4. She was discharged to rehabilitation in good functional status and recovered well with therapy.

likely to be originated by a cardiac source).65 It is unclear whether this sign may predict greater likelihood of recanalization, a notion supported by some studies65 but not by others.66 Disappearance of the sign on follow-up MRI after thrombolysis correlates with recanalization but does not necessarily portend favorable clinical outcome.67

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INTRA-ARTERIAL THROMBUS ON MRI T1-weighted

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Figure 3-19. Images illustrating visualization of acute intravascular thrombus on various magnetic resonance imaging/angiography sequences.

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MAGNETIC RESONANCE ANGIOGRAPHY ❖

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Magnetic resonance angiography (MRA) can be valuable in the acute setting to determine the actual site of the vascular occlusion (see Figure 3-18) and to assess whether the vessel was successfully opened after noninvasive revascularization treatments (Figure 3-20). Stroke protocols typically include two-dimensional and three-dimensional time-of-flight (2D and 3D TOF) and contrast-enhanced MRA images of the neck and 3D TOF MRA images of the intracranial circulation. For acute evaluations, often only intracranial MRA is obtained. It is important to be aware that saturation artifact may produce loss of signal, which may be misinterpreted as occlusion. This type of artifact occurs because whereas blood flow perpendicular to the plane of application of radiofrequency pulses is exposed briefly to these pulses and can be well imaged, blood flowing in the same plane as the angle of imaging is exposed to an excessive amount of radiofrequency pulses, leading to saturation and signal loss.68 Saturation artifact is commonly

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encountered at the levels of the horizontal turns of the vertebral arteries and in the knees of the petrous carotid arteries, but it can also be found in distal branches of the circle of Willis, where it can be more deceiving. Contrast-enhanced images may improve accuracy in the assessment of patency of distal arterial branches.69 In addition, slow or turbulent flow may also generate loss of signal, a phenomenon known as flowrelated artifact.68 Despite these pitfalls, MRA remains an accurate noninvasive technique to assess vessel pathology in acute ischemic stroke. Nonetheless, CT angiography has the advantage of providing confirmation of large vessel occlusion faster than MRA and may therefore be preferable for the emergency evaluation. Transcranial Doppler (TCD) can be performed in the emergency department and may also be used for this purpose, although its value is limited to proximal M1 occlusions.64 When administration of gadolinium is considered, the small risk of inducing nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) in patients with renal failure should be kept in mind.70–72

IMAGING IN STROKE EMERGENCIES Intravenous Thrombolysis Case Vignette A 72-year-old man presented to the emergency department with sudden onset of visual disturbance and behavioral changes. On neurological examination, he was mildly confused and had a dense left homonymous hemianopia. He also had slight weakness in the left upper extremity and possible mild hypoesthesia on the left hemibody. CT scan obtained 90 minutes after symptom onset demonstrated no acute changes. He underwent intravenous thrombolysis starting 115 minutes after symptom onset. Over the following 12 hours, his symptoms gradually improved and 24 hours later, he had no residual deficits. Brain MRI at that point

revealed an acute infarction involving the posterior aspect of the right medial temporal lobe and a small area of the posterior limb of the right internal capsule (see Figure 3-20). MRA of intracranial circulation demonstrated distal occlusion of the terminal segment of the posterior cerebral artery (see Figure 3-20). Because the patient’s clinical syndrome at presentation had been consistent with a proximal occlusion of the posterior cerebral artery, these radiological findings were most likely caused by fragmentation of the initially larger clot due to successful thrombolysis that subsequently led to a more distal (and asymptomatic) vessel occlusion.

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C Figure 3-20. Magnetic resonance imaging of the brain showing small areas of acute infarction (arrows) on diffusion-weighted imaging involving the right lateral thalamus/dorsal end of the posterior limb of the internal capsule (A) and the posterior aspect of the right medial temporal lobe (B), corresponding to the distribution of the right posterior cerebral artery. Magnetic resonance angiography of the intracranial circulation disclosed a distal occlusion of this vessel (arrowhead).

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As noted in our previous discussion, CT scan is indicated before infusing intravenous thrombolytic agents. The main goals of CT scanning are excluding hemorrhage or a large hypodensity. These are the only radiological contraindications for the use of intravenous thrombolysis within 3 hours of symptom onset. A repeat CT scan must be obtained 24 hours after thrombolysis to exclude hemorrhagic conversion before starting any antithrombotic therapy for secondary stroke prevention. The risk of symptomatic intracranial hemorrhage after intravenous thrombolysis was 6.4% in the landmark NINDS trial,10 and similar or even lower rates have been reported in subsequent studies and from community registries.73 MRI protocols are being evaluated to expand the therapeutic window of intravenous thrombolysis. Initial results indicate that patients with persistent

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penumbra defined by PWI-DWI mismatch beyond 3 hours from symptom onset may significantly benefit from recanalization.60 CT protocols may offer similar information on the penumbra and should be evaluated as alternatives to identify candidates for delayed revascularization because CT imaging is more widely accessible and information can be quickly acquired. The likelihood of recanalization with intravenous thrombolysis may be increased by combining it with continuous insonation of the site of the occlusion using TCD.74 A Phase II trial evaluating this approach showed promising results. However, correct application of this combined therapeutic modality is labor intensive and requires TCD expertise. TCD may also be used to diagnose early reocclusion after initially successful recanalization; this finding is strongly predictive of clinical decline and poor functional outcome.75

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Intra-Arterial Revascularization Therapies Case Vignette A 52-year-old woman presented to a local hospital with acute aphasia and right hemiplegia. CT scan was negative for hemorrhage, and she was referred to our academic hospital for acute management. Upon arrival to our emergency department 3 hours and 30 minutes after symptom onset, her examination revealed global aphasia, left gaze preference, right homonymous hemianopia, paralysis of the lower right face and the right arm, comparatively milder weakness of the right leg, and right hemihypoesthesia. Her initial National Institutes of Health Stroke Scale score (NIHSS) was 20. Because she was outside of the accepted therapeutic window for intravenous thrombolysis, she was immediately

taken to the angiographic suite. Digital subtraction angiography demonstrated a proximal occlusion of the M1 segment of the left middle cerebral artery. Intra-arterial infusion of the rt-PA (22 mg) combined with mechanical disruption of the clot and subsequent angioplasty of the previously occluded segment resulted in successful vessel recanalization (Figure 3-21). Over the following 24 hours, the patient recovered substantially from her initially severe deficits. Repeat brain imaging only showed a small left periopercular infarction. Her NIHSS at discharge was 4, and after a few weeks of outpatient rehabilitation, she was able to return to work with no functional restrictions.

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Figure 3-21. DSA after left carotid injection showing proximal occlusion of the M1 segment of the middle cerebral artery on anteroposterior (A) and lateral (B) views (arrows). Initial infusion of intra-arterial rt-PA only achieved minimal opening of the vessel (C). Therefore, additional administration of the thrombolytic agent was combined with gentle acute angioplasty (arrows) (D, E). Postintervention DSA shows successful recanalization of the M1 segment and distal branches of the middle cerebral artery (F, anteroposterior view; G, lateral view). Notice residual irregularity of the previously occluded segment indicated by the arrowhead. (Images courtesy of Dr. Ajay Wakhloo.)

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Intra-arterial revascularization can be achieved using intra-arterial infusion of thrombolytic agents, mechanical disruption of the clot, mechanical embolectomy, or, less commonly, angioplasty. These interventions are often combined or used sequentially after one of them fails. Intra-arterial thrombolysis (without mechanical disruption of the clot) may achieve recanalization in two thirds of patients with proximal MCA occlusions when infusion of the drug is started within 6 hours of symptom onset.76 The rate of

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symptomatic intracranial hemorrhage in these cases is approximately 10%.76 Mechanical embolectomy using an embolus retrieving device (MERCI Retriever Concentric Medical, Mountain View, CA) has been reported to achieve recanalization in more than half of patients with large intracranial artery occlusions treated between 3 and 8 hours from stroke onset (Figure 3-22).77–79 Use of adjuvant intra-arterial rt-PA can increase the rate of recanalization up to 57%.79

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Figure 3-22. A 56-year-old woman with history of hypertension, atrial fibrillation on chronic anticoagulation, and hysterectomy 5 days before was found by her sister confused and dragging her left leg. She deteriorated en route to the hospital. On evaluation in the emergency department, she had right gaze deviation, left homonymous hemianopia, left hemiplegia, and left-sided neglect. National Institutes of Health Stroke Scale score (NIHSS) was 16. INR was 2.3 but had been 1.6 the previous day. Computed tomography scan of the brain was unremarkable (not shown), but Digital substraction angiography (DSA) showed a carotid T occlusion (A). She was treated with mechanical embolectomy using the Merci Retriever, with the procedure starting 3.5 hours after symptom onset. The intervention was successful, and she achieved excellent recanalization (B). Her deficits improved substantially over the following 24 hours (NIHSS decreased to 4), and repeat brain imaging showed only a relatively small insular infarction. Six weeks later, she had returned to work with minimal residual symptoms.

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This recanalization rate is obviously far greater than the rate of spontaneous recanalization in the placebo arm of the largest intra-arterial thrombolysis trial (PROACT II) but does not compare favorably against the rate of recanalization of MCA occlusions in the treatment arm (i.e., patients who were actually treated with intra-arterial thrombolysis) of the same trial (57% with embolectomy vs 66% with intra-arterial thrombolysis). The functional outcomes of patients treated with mechanical embolectomy are similar to those observed in the PROACT II trial (36% with embolectomy regained functional independence vs 40% with intraarterial thrombolysis), and mortality rate was slightly higher in the studies evaluating the MERCI device (34% vs. 25% in the treatment arm of PROACT II).76,79 However, because failure of the Merci Retriever can be followed by intra-arterial thrombolysis, it has become a common practice in many centers to attempt embolectomy first. Mechanical embolectomy, with or without intraarterial thrombolysis, can be safely attempted and may achieve recanalization in patients initially treated unsuccessfully with intravenous thrombolysis.78,79 The rate of symptomatic complications in the MERCI trial has been acceptable (7.8%–9.8% rate of symptomatic ICH).77–79 The possibility of vessel wall perforation was a major concern with the first generation of the device,77 but the newer generation (L5 Retriever) has proved substantially safer.78,79 Nonetheless, procedural complications still occur in more than 5% of cases.79 The Merci Retriever should be used in patients with large intracranial vessel occlusions, such as M1 segment of the middle cerebral artery, and particularly the terminal carotid, vertebral, and basilar arteries. Occlusive thrombi in more distal or smaller branches should not be treated with mechanical embolectomy, but intra-arterial thrombolysis may be useful in selected cases. Advances in technology are constantly improving these new intravascular devices. The latest generation of the Merci device includes the possibility of using the EKOS (EKOS Corporation, Bothell, WA)

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microcatheter, which allows insonation of the clot with ultrasound delivered intravascularly at the site of occlusion.78 Multiple new devices are being tested. A promising example is the Penumbra (Penumbra, Inc., Alameda, CA) aspiration catheter, which enables the operator to combine aspiration and grasping to remove the occlusive thrombus. Initial reports of the experience with this device claim partial or complete recanalization rates exceeding 80% with acceptable rates of hemorrhage and procedural complications. Interventionalists employing new recanalization devices should report their results in the literature to better define the true efficacy and safety of this treatment modality. There is considerable interest in exploring the therapeutic option of pursuing intra-arterial thrombolysis in patients who fail to recanalize after receiving a bridging dose (0.6 mg/kg as opposed to the full dose of 0.9 mg/kg) of intravenous rt-PA within the first 3 hours of deficits.80 This approach has been proven feasible and relatively safe in a Phase II trial that showed promising clinical results in patients with severe strokes at presentation;81 a Phase III trial is underway. Aggressive mechanical clot disruption, often attempted in practice along with intra-arterial thrombolysis, may increase the rate of recanalization in patients with large intracranial vessel occlusion.82 The most commonly used technique consists of trying to macerate the clot by repeat passes of the microwire or microcatheter. Acute angioplasty (with or without stenting) of the vessel may be successful in selected patients with resistant occlusions,83 as illustrated by our case (Figure 3-21). Intra-arterial (or intravenous) IIb–IIIa antagonists may be used as part of a multimodality approach.84 Perhaps the most valuable role of these agents is preventing reocclusion of a partially recanalized vessel. Excellent results with the use of these agents for the treatment of acute thromboembolic complications during neuroendovascular procedures have been reported.85

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Massive Hemispheric Infarction Case Vignette A 44-year-old woman was found collapsed in her apartment by her neighbor and brought emergently to the hospital. On examination, she was awake but incoherent. She had left hemianopia, hemiplegia, hyperreflexia, Babinski sign, and hemineglect. CT scan of the brain confirmed the presence of extensive infarction in the right middle cerebral artery territory (Figure 3-23, A). The patient was carefully monitored in the stroke unit, and 36 hours later, she was noticed to have difficulty opening her eyes despite being awake and able to follow other commands (cerebral ptosis). She had also developed Babinski sign on the right side (i.e., ipsilateral to the infarcted hemisphere). Repeat CT scan showed progression of mass effect and midline shift (Figure 3-23, B). Forty-two hours after admission, she became less arousable,

and a new CT scan disclosed a 15-mm displacement of the septum pellucidum (Figure 3-23, C). Her pupils remained isocoric and reactive to light. She was intubated, hyperventilated, treated with 1 g/kg of 20% mannitol, and taken to the operating room. Decompressive hemicraniectomy and duroplasty were performed without complications. Repeat CT scan 18 hours after surgery demonstrated outward brain herniation through the site of craniectomy with partial improvement in the midline shift (Figure 3-23, D). The patient’s level of consciousness improved after surgery and did not decline again. Six months after the stroke, she had achieved meaningful functional recovery, with moderate residual disability. She underwent replacement of the bone flap with no complications.

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Figure 3-23. Serial computed tomography (CT) scans of the brain in a patient with massive right middle cerebral artery stroke requiring decompressive hemicraniectomy. (A) Initial CT scan with early ischemic changes throughout the right middle cerebral artery territory. (B) Evolution of low attenuation changes in the large area of infarction with incipient mass effect and mild midline shift. (C) Marked increased in mass effect causing a 10-mm shift of the septum pellucidum. (D) Improvement in hemispheric mass effect and midline shift after decompressive hemicraniectomy. Notice outward herniation of the brain tissue through the bone defect.

Acute Stroke Imaging ❖

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Baseline and serial CT scans are useful prognosticators for the development of massive brain swelling and herniation after a large hemispheric stroke (terminal carotid artery or proximal MCA occlusion).86 Radiological markers of poor outcome on CT scan include: ❖ Involvement of more than one vascular territory87,88 ❖ Shift of the septum pellucidum 9 mm or more or the pineal gland 4 mm or more at 48 hours89 ❖ Hypodensity exceeding 50% of the MCA territory (with associated occlusion of the MCA on CTA)90 ❖ Hyperdense MCA sign (especially when combined with extensive sulcal effacement on baseline CT scan)91,92 Still, radiological findings should never be interpreted in isolation. Stroke severity (measured by the NIHSS)93 and level of responsiveness89 remain the strongest predictors of outcome. For instance, although the presence of extensive areas of restricted diffusion on baseline DWI usually portend poor outcome, it has been shown that DWI should not replace clinical evaluation of stroke severity in the prognostication of acute ischemic stroke.93,94 Vascular studies indicating persisting large vessel occlusion or poor collateral flow also predict poor outcome.95 Ischemic edema most often peaks around Day 3 after the stroke; however, large infarctions may swell as early as during the first 24 hours (malignant edema), whereas in other cases, the edema may be maximal 5 or more days after the stroke. Also, hemorrhagic conversion may rapidly accelerate the progression of mass effect. Thus temporal evolution of ischemic brain edema is not truly predictable, and close clinical and radiological monitoring is indispensable. Recognizing the clinical and radiological signs that predict high risk of malignant brain edema and monitoring for imminent signs of brain herniation and progression of mass effect on brain imaging are crucial in young patients with large MCA strokes because timely decompressive hemicraniectomy (with duroplasty) is effective in improving not only survival but also functional outcome in these patients.96

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Some clinical signs, such as the development of cerebral ptosis 97or ipsilateral Babinski sign, and serial CT scans to monitor the progression of midline shift may be helpful to guide the timing of hemicraniectomy. However, other neuroimaging techniques may allow earlier prediction of malignant edema formation. Deficit of ligand uptake throughout the whole MCA territory on 99m ethylcysteinate-single photon emission CT (SPECT) within 6 hours of stroke onset98 and 99m diethylenetriaminepentaacetic-SPECT imaging at 36 hours demonstrating extensive disruption of blood brain barrier permeability99 have been reported to predict malignant infarction with high reliability. Unfortunately, these techniques are not widely available at present. It is important to identify multiterritorial infarction (anterior cerebral artery [ACA]-MCA or MCA-posterior cerebral artery [PCA]) because their presence is almost invariably associated with poor prognosis even if hemicraniectomy is performed.100

Acute Internal Carotid Artery Occlusion

Case Vignette A 49-year-old woman with history of hypertension and hyperlipidemia presented to our emergency department with fluctuating depression in her level of consciousness; forced right gaze deviation; dense left hemianopia; left hemiplegia involving face, arm, and leg; and left hemineglect. At her worst, her NIHSS was 22. Initial CT scan of the brain was unremarkable except for possible slight effacement of the insular ribbon. CT angiogram revealed occlusion of the right cervical internal carotid artery near its origin (Figure 3-24, A). The patient was aggressively treated with intravenous fluids and phenylephrine to elevate her blood pressure and started to respond within minutes to this treatment. A few hours later, her examination had essentially normalized. Her mean arterial pressure was maintained above 120 mm Hg over the following 24 hours, and then fluids and vasopressor were gradually tapered. Her deficits did not recur, and she was discharged home 2 days later with normal neurological function and CT scan of the brain (Figure 3-24, B).

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Figure 3-24. (A) Computed tomography (CT) angiogram showing tapering and occlusion of the flow in the right internal carotid artery near its origin (arrow). (B) Normal CT scan of the brain upon hospital discharge despite severe neurological deficits on admission.

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The case illustrates a situation we have often encountered in practice. Prompt recognition of a discrepancy between the clinical deficits on examination and the baseline radiological findings may streamline the diagnostic evaluation and facilitate successful treatment. In patients with internal carotid artery occlusion, the penumbra is often extensive and manifests as a large clinical-radiological mismatch. Thus patients with symptoms and signs of ACA/MCA ischemia but a relatively normal brain parenchyma on CT scan and no evidence of a hyperdense vessel sign (which is often seen in cases of carotid terminus

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occlusion) should be emergently studied with noninvasive angiograms of the neck and brain and, if available, perfusion scans. When these tests are not available, carotid duplex may suffice to make the diagnosis and guide therapy. Occlusions of the cervical internal carotid artery are generally not amenable to revascularization procedures (the clot is too large to be dissolved with thrombolytic agents, and the risk of reperfusion injury is too high to consider endovascular interventions), but hemodynamic augmentation may effectively salvage the hypoperfused tissue when collateral pathways are anatomically favorable.

Basilar Artery Occlusion

Case Vignette A 52-year-old man with history of uncontrolled hypertension, diabetes, hyperlipidemia, and smoking was admitted with bilateral acute cerebellar infarctions. Brain MRI (Figure 3-25, A–D) confirmed the areas of cerebellar ischemia and also showed changes consistent with acute basilar trunk occlusion (hyperintense vessel signal on FLAIR and absent basilar flow on MRA, which allowed visualization of bilaterally patent posterior communicating arteries). During the first day, the patient remained stable on intravenous crystalloids, colloids, and heparin. The following morning, however, he became more difficult to arouse, and he developed diplopia with disconjugate gaze and worsening bilateral weakness. Dopamine infusion was

initiated to elevate his blood pressure resulting in partial improvement of his new deficits. He then underwent emergent catheter angiography, which demonstrated a proximal occlusion of the basilar artery (Figure 3-25, E). The patient was treated with mechanical clot disruption and angioplasty of the basilar artery with excellent radiographic results (Figure 3-25, F and G). After the procedure, his deficits improved, and he was discharged home 10 days later with residual ataxia. His residual deficits continued to improve steadily over the following year. Three years later, the patient remained free of recurrent ischemic neurological symptoms, and his basilar artery remained widely patent on follow-up noninvasive angiography.

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Figure 3-25. (A) Diffusion-weighted imaging show-

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ing bilateral cerebellar and left occipital acute infarction. (B) Magnetic resonance angiography reveals no flow in the basilar artery but allows visualization of both posterior communicating arteries (arrowheads). This noninvasive angiogram suggests that the right posterior cerebral artery could have fetal origin (i.e., filling exclusively from the anterior circulation due to a lack of P1 segment connecting the vessel with the basilar artery). (C) Fluid-attenuated inversion recovery displaying the early changes of infarction in the left posterior cerebral artery territory but also showing a hyperintense signal in the basilar artery, indicative of acute thrombosis. This finding is better seen on panel D (arrow). (E) DSA demonstrating occlusion of the basilar artery between its proximal and middle thirds (arrow). (F) Successful recanalization of the basilar artery; notice good filling of the superior cerebellar arteries and the left posterior cerebral artery. The right posterior cerebral artery had fetal origin. (G) Final DSA confirming excellent angiographic results.

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The clinical suspicion of basilar artery occlusion represents a neurological emergency that requires immediate angiographic evaluation. When a noninvasive angiogram (MRA or CTA) can be performed expeditiously, it may have a role in confirming the diagnosis. MRI has the advantage of disclosing the extent of ischemia on DWI, as seen in the case presented. If extensive brainstem infarction is seen on MRI, recanalization efforts will be futile (Figure 3-26). However, we often prefer to proceed directly with catheter angiography because this modality provides access for treatment and time is invaluable in these cases. In the absence of revascularization, 80% of patients with basilar artery occlusion have poor prognosis.101

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In patients with basilar thrombosis, revascularization may be compatible with favorable functional outcomes even if achieved after 12 hours or more from the onset of deficits.102 This is the case because midbasilar thrombotic occlusions often present with progressive symptoms (indicative of worsening compromise of perfusion) before irreversible ischemia ensues.103 Intra-arterial thrombolysis, mechanical embolectomy, and acute angioplasty and stenting are the best treatment options in these situations.83,102,104,105 However, intravenous thrombolysis can be successful in patients presenting within 3 hours of symptom onset106,107 and probably represents the treatment of choice in cases of top-of-the-basilar syndrome evaluated within this time window.

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Figure 3-26. A 64-year-old woman with history of hypertension and smoking presented with progressive loss of brainstem function over 72 hours. Over the 18 hours before transfer to our hospital, she had become locked in. Magnetic resonance imaging scan on arrival confirmed the clinical diagnosis of basilar artery thrombosis: diffusion-weighted imaging (A) and apparent diffusion coefficient (B) showed extensive acute infarction of the pons. The area of infarction was already visible on fluid-attenuated inversion recovery (C), indicating that the ischemia was no longer hyperacute. Magnetic resonance angiogram of the neck (D) and intracranial circulation (E) displayed the occlusion of the basilar artery beyond its proximal portion (arrows).

Massive Cerebellar Infarction Case Vignette A 42-year-old woman with history of hypertension and diabetes presented with sudden onset of acute ataxia. Brain imaging (CT scan and MRI) disclosed patchy cerebellar infarctions, mostly involving the right posterior inferior cerebellar artery territory (Figure 3-27, A and B). MRA of the intracranial circulation revealed occlusion of the right vertebral artery (Figure 3-27, C). The following day, the patient was clinically stable, but swelling of the infarction was already evident on repeat CT scan (Figure 3-27, D). Early on

the third hospital day, she became drowsy and developed new right facial and abducens palsies. A new CT scan revealed further progression of mass effect (Figure 3-27, E). She underwent emergency suboccipital craniectomy. After surgery, her level of consciousness improved, but her right esotropia persisted. Postsurgical imaging confirmed adequate decompression (Figure 3-27, F). Although no additional complications occurred during the rest of the hospitalization, her functional recovery was limited.

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Figure 3-27. Initial computed tomography (CT) scan (A) and diffusion-weighted magnetic resonance imaging (B) showing areas of bilateral cerebellar infarction, predominantly affecting the right posterior-cerebral artery territory (arrows). On magnetic resonance angiogram of the intracranial circulation (C), the right vertebral artery was not visualized. Repeat CT scans of the brain on the second (D) and third (E) hospital days revealed progressive worsening of cerebellar edema with regional mass effect, causing effacement of the peripontine cistern, deformity of the fourth ventricle, and compression of the pons (small arrows). Delayed CT scan after decompressive suboccipital craniectomy (F) shows resolution of the swelling and full reopening of the fourth ventricle without additional areas of ischemic damage.

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Cerebellar infarctions can be complicated with massive and potentially fatal swelling.108,109 The causes of deterioration from progression of mass effect in patients with cerebellar infarctions are similar to those observed in cases of cerebellar hematomas— namely, direct brainstem compression (Figure 3-27), obstructive hydrocephalus from compression of the fourth ventricle (Figure 3-28, A and B), and aqueduc-

tal occlusion from upward herniation of the vermis through the tentorial notch (Figure 3-28, C and D). Apart from edema, sudden increment in mass effect can be produced by hemorrhagic conversion of the ischemic infarction. All of these mechanisms may be reliably diagnosed and differentiated by brain imaging, allowing timely surgical intervention when necessary.109

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Figure 3-28. Possible causes of deterioration in patients with massive cerebellar infarction. Obstructive hydrocephalus (arrows) from compressive occlusion of the fourth ventricle (A and B) and upward herniation with compromise of the aqueduct (C and D, arrows).

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The risk of herniation is only significant after infarctions of the posterior-inferior cerebellar artery (PICA) territory. Although patients with strokes in the anterior-inferior or superior cerebellar artery distributions may develop clinical worsening during their acute phase, mass effect is typically not life-threatening in these cases. As illustrated by our case, the initial size of the infarction may be deceivingly reassuring. After PICA occlusion, cerebellar infarctions of relatively small initial size (especially when bilateral) may progress to produce massive edema in the posterior fossa. Thus serial neurological examinations and brain scans are indicated in all these cases (nonenhanced CT scans are sufficient for this purpose).

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Our case also illustrates that surgical management with suboccipital craniectomy may preserve life and function in deteriorating patients.108,110 External ventricular drainage should probably be avoided in patients with radiological signs of upward herniation because it may exacerbate the tissue displacement in these cases.

Subacute and Chronic Infarctions ❖

DWI (in conjunction with the ADC map) is unrivaled in its ability to diagnose acute ischemic lesions and distinguish them from late subacute or chronic infarctions (Figure 3-29).

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Figure 3-29. Illustration of the value of diffusion-weighted imaging (DWI)–apparent diffusion coefficient (ADC) for the distinction of acute versus chronic brain infarctions. (A and B) computed tomography scans showing extensive low attenuation changes in both cerebral hemispheres; timing of the lesions is not reliable with this imaging modality. (C) DWI and (D) ADC map demonstrate an area of restricted diffusion in the right corona radiata, indicating of acute infarction (open arrows); notice the low signal of DWI and the bright signal on ADC in other regions of chronic ischemia (solid arrows). (E and F) Fluid-attenuated inversion recovery sequence is less useful for the timing of ischemic lesions but displays characteristic findings in chronic infarctions: hypointense core (filled with fluid) and hyperintense borders (from gliosis) (open arrows).

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Subacute lesions are more hypodense on CT scan, hypointense on T1, hyperintense on T2 and FLAIR, less bright on DWI, and less dark on ADC (as diffusion increases in the infarcted tissue, the ADC map

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appears to normalize after 7–10 days, before the diffusion coefficient becomes elevated and the signal becomes bright) (Figure 3-30).

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Figure 3-30. Illustration of the imaging characteristics of a subacute ischemic infarction (arrows). (A) Computed tomography scan showing a fairly well-defined area of low attenuation in the right occipital lobe. (B) Diffusion-weighted imaging displaying faint brightness in the area of the infarction (apparent diffusion coefficient appeared normal in that region). (C) T1-weighted sequence disclosing low-intensity signal in the core of the stroke with high-intensity signal in the cortex. (D) T2-weighted sequence with increased signal intensity in the zone of the ischemic lesion.

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Some degree of hemorrhagic transformation is seen in nearly one third of MCA infarctions within the first 72 hours of evolution (and in up to three quarters of patients with fatal hemispheric infarctions).111 Gradient-recalled echo (T2*) is particularly sensitive for the detection of small hemorrhagic components within the infarction. On contrast scans, patchy or gyral enhancement begins to appear 2 to 3 days after the stroke (Figure 3-31), peaks after 2 to 3 weeks (Figure 3-32), and may persist for up to 10 weeks. Recognizing these areas of enhancement is important to avoid confusing a subacute ischemic lesion with tumors or

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cerebritis (the distribution of the ischemic infarction in a specific vascular distribution is pivotal in making this distinction). In the early subacute phase (2–7 days), edema may also be observed surrounding the infarction and grossly sharing the signal characteristics of the infarcted tissue. Hence, edema appears as hypodense signal on CT scan (although less dark and less well delineated than the area of infarction), hypointense signal on T1, and hyperintense signal on T2 and FLAIR. This edema is predominantly vasogenic, and therefore it appears bright on DWI and bright on the ADC map.

Figure 3-31. Acute infarction of the left middle cerebral artery territory, as documented by the restricted diffusion on diffusion-weighted imaging (A) and apparent diffusion coefficient map (B), showing early gyral and basal ganglia enhancement on the T1-weighted sequence with gadolinium (C and D, arrows).

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Figure 3-32. Subacute infarction in the right posterior cerebral artery distribution, as documented by the absence of bright signal on diffusion-weighted imagery (A) and the visualization of the lesion on fluid-attenuated inversion recovery (B, arrow), showing strong enhancement on the axial (C) and sagittal (D) views of the T1-weighted sequence after administration of gadolinium (arrows).

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During the late subacute phase, areas of infarction may appear deceivingly normal in noncontrast scans because of a phenomenon known as “fogging effect.” This phenomenon, ascribed to the development of new capillaries, influx of lipid-laden macrophages, and relative decrease of water content in the evolved infarction, has been reported 2 to 3 weeks after a stroke on CT scans112 and 10 to 14 days after on T2-weighted imaging113 (and to a lesser degree on FLAIR).114 The fogging effect is more likely to compromise diagnostic sensitivity in cases of small cortical infarctions and cerebellar infarctions. Strong enhancement after contrast administration reliably discloses the subacute infarction in these cases. Chronic infarctions are hypodense on CT scan, hypointense on T1, and hyperintense on T2. FLAIR is particularly useful to differentiate chronic from subacute lesions: in chronic infarctions, FLAIR demonstrates a hypointense cystic core (filled with

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fluid) with hyperintense borders (from gliosis) (Figure 3-29, E and F, arrows), whereas in subacute strokes, core and borders are hyperintense. DWI may be normal or show a bright signal related to the T2 shine-through phenomenon, but the signal is always bright on the ADC map (high diffusion coefficient because water molecules can move freely in the cystic old infarction). Infarct borders are much better delineated in chronic ischemic infarctions because they have become gliotic. Edema, hemorrhage, and contrast enhancement are no longer present. Because of tissue loss, adjacent sulci become more prominent, and the ipsilateral ventricle enlarges losing its natural shape. Dystrophic calcifications occasionally occur and are best recognized by CT scan. Previous hemorrhage within the infarction can be inferred by the presence of hemosiderin recognized on gradient-recalled echo (or T2*).

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57. Kohrmann M, Juttler E, Fiebach JB, Huttner HB, Siebert S, Schwark C, et al. MRI versus CT-based thrombolysis treatment within and beyond the 3 h time window after stroke onset: a cohort study. Lancet Neurol 2006; 5:661–667. 58. Furlan AJ, Eyding D, Albers GW, Al Rawi Y, Lees KR, Rowley HA, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 2006; 37:1227–1231. 59. Hacke W, Albers G, Al Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a Phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 2005; 36:66–73. 60. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006; 60:508–517. 61. Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008; 7:299–309. 62. Davalos A, Blanco M, Pedraza S, Leira R, Castellanos M, Pumar JM, et al. The clinical-DWI mismatch: a new diagnostic approach to the brain tissue at risk of infarction. Neurology 2004; 62:2187–2192. 63. Prosser J, Butcher K, Allport L, Parsons M, MacGregor L, Desmond P, et al. Clinical-diffusion mismatch predicts the putative penumbra with high specificity. Stroke 2005; 36:1700–1704. 64. Saqqur M, Hill MD, Alexandrov AV, Roy J, Schebel M, Krol A, et al. Derivation of power M-mode transcranial Doppler criteria for angiographic proven MCA occlusion. J Neuroimaging 2006; 16:323–328. 65. Cho KH, Kim JS, Kwon SU, Cho AH, Kang DW. Significance of susceptibility vessel sign on T2*-weighted gradient echo imaging for identification of stroke subtypes. Stroke 2005; 36:2379–2383. 66. Schellinger PD, Chalela JA, Kang DW, Latour LL, Warach S. Diagnostic and prognostic value of early MR Imaging vessel signs in hyperacute stroke patients imaged ⬍3 hours and treated with recombinant tissue plasminogen activator. AJNR Am J Neuroradiol 2005; 26:618–624. 67. Kim HS, Lee DH, Choi CG, Kim SJ, Suh DC. Progression of middle cerebral artery susceptibility sign on T2*weighted images: its effect on recanalization and clinical outcome after thrombolysis. AJR Am J Roentgenol 2006; 187:W650–W657. 68. Wilcock DJ, Jaspan T, Worthington BS. Problems and pitfalls of 3-D TOF magnetic resonance angiography of the intracranial circulation. Clin Radiol 1995; 50:526–532. 69. Yang JJ, Hill MD, Morrish WF, Hudon ME, Barber PA, Demchuk AM, et al. Comparison of pre- and postcontrast 3D time-of-flight MR angiography for the evaluation of distal intracranial branch occlusions in acute ischemic stroke. AJNR Am J Neuroradiol 2002; 23:557–567. 70. Wiginton CD, Kelly B, Oto A, Jesse M, Aristimuno P, Ernst R, et al. Gadolinium-based contrast exposure, nephrogenic systemic fibrosis, and gadolinium detection in tissue. AJR Am J Roentgenol 2008; 190:1060–1068.

71. Moreno-Romero JA, Segura S, Mascaro JM Jr, Cowper SE, Julia M, Poch E, et al. Nephrogenic systemic fibrosis: a case series suggesting gadolinium as a possible aetiological factor. Br J Dermatol 2007; 157:783–787. 72. Shabana WM, Cohan RH, Ellis JH, Hussain HK, Francis IR, Su LD, et al. Nephrogenic systemic fibrosis: a report of 29 cases. AJR Am J Roentgenol 2008; 190:736–741. 73. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, et al. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 2007; 369:275–282. 74. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med 2004; 351:2170–2178. 75. Saqqur M, Molina CA, Salam A, Siddiqui M, Ribo M, Uchino K, et al. Clinical deterioration after intravenous recombinant tissue plasminogen activator treatment: a multicenter transcranial Doppler study. Stroke 2007; 38:69–74. 76. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 1999; 282:2003–2011. 77. Smith WS, Sung G, Starkman S, Saver JL, Kidwell CS, Gobin YP, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2005; 36:1432–1438. 78. Smith WS. Safety of mechanical thrombectomy and intravenous tissue plasminogen activator in acute ischemic stroke. Results of the multi Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial, part I. AJNR Am J Neuroradiol 2006; 27:1177–1182. 79. Smith WS, Sung G, Saver J, Budzik R, Duckwiler G, Liebeskind DS, et al. Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke 2008; 39:1205–1212. 80. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke 2004; 35:904–911. 81. The Interventional Management of Stroke (IMS) II Study. Stroke 2007; 38:2127-2135. 82. Noser EA, Shaltoni HM, Hall CE, Alexandrov AV, Garami Z, Cacayorin ED, et al. Aggressive mechanical clot disruption: a safe adjunct to thrombolytic therapy in acute stroke? Stroke 2005; 36:292–296. 83. Levy EI, Ecker RD, Horowitz MB, Gupta R, Hanel RA, Sauvageau E, et al. Stent-assisted intracranial recanalization for acute stroke: early results. Neurosurgery 2006; 58:458–463. 84. Abou-Chebl A, Bajzer CT, Krieger DW, Furlan AJ, Yadav JS. Multimodal therapy for the treatment of severe ischemic stroke combining GPIIb/IIIa antagonists and angioplasty after failure of thrombolysis. Stroke 2005; 36:2286–2288. 85. Velat GJ, Burry MV, Eskioglu E, Dettorre RR, Firment CS, Mericle RA. The use of abciximab in the treatment of acute cerebral thromboembolic events during neuroendovascular procedures. Surg Neurol 2006; 65:352–358, discussion.

Acute Stroke Imaging 86. Wijdicks EF, Rabinstein AA. Absolutely no hope? Some ambiguity of futility of care in devastating acute stroke. Crit Care Med 2004; 32:2332–2342. 87. Barber PA, Demchuk AM, Zhang J, Kasner SE, Hill MD, Berrouschot J, et al. Computed tomographic parameters predicting fatal outcome in large middle cerebral artery infarction. Cerebrovasc Dis 2003; 16:230–235. 88. Kasner SE, Demchuk AM, Berrouschot J, Schmutzhard E, Harms L, Verro P, et al. Predictors of fatal brain edema in massive hemispheric ischemic stroke. Stroke 2001; 32:2117–2123. 89. Pullicino PM, Alexandrov AV, Shelton JA, Alexandrova NA, Smurawska LT, Norris JW. Mass effect and death from severe acute stroke. Neurology 1997; 49:1090–1095. 90. Krieger DW, Demchuk AM, Kasner SE, Jauss M, Hantson L. Early clinical and radiological predictors of fatal brain swelling in ischemic stroke. Stroke 1999; 30:287–292. 91. Manno EM, Nichols DA, Fulgham JR, Wijdicks EF. Computed tomographic determinants of neurologic deterioration in patients with large middle cerebral artery infarctions. Mayo Clin Proc 2003; 78:156–160. 92. Wijdicks EF, Diringer MN. Middle cerebral artery territory infarction and early brain swelling: progression and effect of age on outcome. Mayo Clin Proc 1998; 73:829–836. 93. Barber PA, Powers W. MR DWI does not substitute for stroke severity scores in predicting stroke outcome. Neurology 2006; 66:1138–1139. 94. Hand PJ, Wardlaw JM, Rivers CS, Armitage PA, Bastin ME, Lindley RI, et al. MR diffusion-weighted imaging and outcome prediction after ischemic stroke. Neurology 2006; 66:1159–1163. 95. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R. “Malignant” middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol 1996; 53:309–315. 96. Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol 2007; 6:215–222. 97. Averbuch-Heller L, Leigh RJ, Mermelstein V, Zagalsky L, Streifler JY. Ptosis in patients with hemispheric strokes. Neurology 2002; 58:620–624. 98. Berrouschot J, Barthel H, von Kummer R, Knapp WH, Hesse S, Schneider D. 99m technetium-ethyl-cysteinatedimer single-photon emission CT can predict fatal ischemic brain edema. Stroke 1998; 29:2556–2562. 99. Lampl Y, Sadeh M, Lorberboym M. Prospective evaluation of malignant middle cerebral artery infarction with blood-brain barrier imaging using Tc-99m DTPA SPECT. Brain Res 2006; 1113:194–199.

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100. Maramattom BV, Bahn MM, Wijdicks EF. Which patient fares worse after early deterioration due to swelling from hemispheric stroke? Neurology 2004; 63:2142–2145. 101. Schonewille WJ, Algra A, Serena J, Molina CA, Kappelle LJ. Outcome in patients with basilar artery occlusion treated conventionally. J Neurol Neurosurg Psychiatry 2005; 76:1238–1241. 102. Wijdicks EF, Nichols DA, Thielen KR, Fulgham JR, Brown RD Jr. Meissner I, et al. Intra-arterial thrombolysis in acute basilar artery thromboembolism: the initial Mayo Clinic experience. Mayo Clin Proc 1997; 72: 1005–1013. 103. von Campe G, Regli F, Bogousslavsky J. Heralding manifestations of basilar artery occlusion with lethal or severe stroke. J Neurol Neurosurg Psychiatry 2003; 74:1621– 1626. 104. Baird TA, Muir KW, Bone I. Basilar artery occlusion. Neurocrit Care 2004; 1:319–329. 105. Bergui M, Stura G, Daniele D, Cerrato P, Berardino M, Bradac GB. Mechanical thrombolysis in ischemic stroke attributable to basilar artery occlusion as first-line treatment. Stroke 2006; 37:145–150. 106. Lee KY, Han SW, Kim SH, Nam HS, Ahn SW, Kim DJ, et al. Early recanalization after intravenous administration of recombinant tissue plasminogen activator as assessed by pre- and post-thrombolytic angiography in acute ischemic stroke patients. Stroke 2007; 38:192–193. 107. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke 2006; 37:922–928. 108. Macdonell RA, Kalnins RM, Donnan GA. Cerebellar infarction: natural history, prognosis, and pathology. Stroke 1987; 18:849–855. 109. Jensen MB, St Louis EK. Management of acute cerebellar stroke. Arch Neurol 2005; 62:537–544. 110. Mathew P, Teasdale G, Bannan A, Oluoch-Olunya D. Neurosurgical management of cerebellar haematoma and infarct. J Neurol Neurosurg Psychiatry 1995; 59:287–292. 111. Lodder J, Krijne-Kubat B, van der Lugt PJ. Timing of autopsy-confirmed hemorrhagic infarction with reference to cardioembolic stroke. Stroke 1988; 19:1482–1484. 112. Chalela JA, Kasner SE. The fogging effect. Neurology 2000; 55:315. 113. Scuotto A, Cappabianca S, Melone MB, Puoti G. MRI “fogging” in cerebellar ischaemia: case report. Neuroradiology 1997; 39:785–787. 114. Uchino A, Sawada YA, Imaizumi T, Mineta T, Kudo S. Report of fogging effect on fast FLAIR magnetic resonance images of cerebral infarctions. Neuroradiology 2004; 46:40–43.

Chapter

4

Cardiac Embolism Alejandro A. Rabinstein and Steven J. Resnick

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ardiac embolism represents one of the most common mechanisms of ischemic stroke. It is most common in the elderly as a consequence of the high incidence of atrial fibrillation, but it is also one of the most frequent causes of stroke in the young. Yet several factors often make the diagnosis of cardiac embolism complicated: (1) cardiac embolism can produce infarctions in any vascular distribution; (2) some of the potential sources of cardiac embolism are prevalent in the general population; (3) cardioembolic sources often coexist with atherosclerotic vascular lesions in the cerebral vasculature. Furthermore, even when the diagnosis of a cardioembolic stroke is typically followed by the initiation of anticoagulation for secondary prevention, this intervention has only been scientifically validated for atrial fibrillation and mechanical valve prosthesis. With these caveats in mind, Table 4-1 lists the potential causes of cardiac embolism divided according to the strength of the evidence supporting the pathophysiological association. Brain infarctions caused by cardiac embolism tend to share similar radiological characteristics regardless of the type of cardiac disease responsible for the embolism. These general characteristics are listed in Table 4-2 and illustrated in Figure 4-1. The pattern of acute multiple bilateral infarctions on diffusion-weighted imaging (DWI), especially when involving the anterior and posterior circulation territories, is strongly associated with cardiac embolism.1,2 Infarctions with embolic appearance

and acute multiple brain infarctions on DWI2–4 should raise suspicion of a cardiac source but may also be produced by artery-to-artery embolism. In fact, it is essentially impossible solely on the basis of brain imaging to distinguish cardioembolic infarctions from infarctions due to aortic embolism. It is important to keep in mind that cardioembolic strokes can have atypical presentations, such as relatively small subcortical infarctions.5 Thus the presence of radiological features highly suggestive of cardiac embolism should prompt comprehensive cardiac assessment, but their absence does not exclude the possibility of a cardioembolic mechanism. The advent of echocardiography, particularly transesophageal echocardiography (TEE), has provided a wealth of information on various cardiac abnormalities that may increase the risk of ischemic stroke. Transthoracic echocardiography (TTE) provides better visualization of the left ventricle and mitral valve, but it typically adds little to TEE in the evaluation of stroke patients. TEE offers better visualization of the left atrium, left atrial appendage, interatrial septum, aortic valve, and aortic arch. The superiority of TEE for the study of the cardiac structures more commonly associated with embolism makes it the preferred choice for the evaluation of cardiac embolism in combination with electrocardiography (to detect myocardial ischemia and arrhythmias) and Holter monitoring (to recognized paroxysmal arrhythmias not apparent on the electrocardiogram [ECG]).6 115

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TABLE 4-1. Cardiac sources of embolism. Definite

TABLE 4-2. Radiological characteristics of cardioembolic strokes. Wedge-shaped infarctions based in the cortex

Atrial fibrillation (chronic and paroxysmal)* Mechanical valve prosthesis Rheumatic valve disease Infective endocarditis Nonbacterial thrombotic endocarditis Dilated cardiomyopathy with severely reduced left ventricular ejection fraction

Concurrent acute bilateral infarctions Concurrent acute infarctions in the anterior and posterior circulations Multiple cortical infarctions in various vascular distributions (even if infarctions are of different ages) Greater tendency to hemorrhagic transformation

Acute transmural myocardial infarction (especially of the anterior wall) Mural thrombi Apical aneurysm Left atrial thrombus Atrial myxoma *Includes atrial flutter.

Probable Patent foramen ovale with atrial septal aneurysm Biological prosthetic valves (early after surgery)

Possible Patent foramen ovale Spontaneous echo contrast Left atrial enlargement Degenerative mitral or aortic valve disease Valve strands Mitral annular calcification Valvular fibroelastoma Nondilatated cardiomyopathies Sick sinus syndrome

TTE is justified when myocardial ischemia, areas of ventricular hypokinesis/akinesis, or dilatated cardiomyopathy are suspected by the history or the initial ECG. Although we strongly advocate the use of TEE for the study of cardiac sources of embolism after a transient ischemic attack (TIA) or stroke, in this chapter we present several examples of diagnostic TTE, because it was the institutional practice at Jackson Memorial Hospital—University of Miami to perform a transthoracic study first. This chapter summarizes information on the most commonly encountered sources of cardiac embolism. It presents various illustrations of the radiological pattern of the brain infarctions and echocardiographic appearance of the cardiac disorders. It concludes with a reference to aortic, embolism, which that is included here because its diagnosis hinges on the use of TEE and the neuroimaging features of strokes caused by aortic embolism are essentially indistinguishable from those due to cardiac embolism.

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CARDIOEMBOLIC STROKE PATTERNS

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Figure 4-1. Patterns of ischemic infarction from cardiac embolism. (A) Computed tomography (CT) scan shows infarctions in two vascular territories (bilateral middle cerebral artery strokes). (B) CT scan reveals anterior and posterior circulation strokes. (C) CT scan displays a typical wedgeshaped infarction based on the cortex. (D) CT scan shows a wedge-shaped cortical infarction associated with a hyperdense vessel sign in an M2 branch of the right middle cerebral artery (arrow). (E) Axial diffusion-weighted imaging magnetic resonance imaging (DWI MRI) revealing scattered areas of restricted diffusion indicative of acute ischemia within the left middle cerebral artery territory. (F) DWI MRI showing multiple small ischemic infarction in a pattern consistent with “embolic shower.”

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ATRIAL FIBRILLATION

Case Vignette A 72-year-old man with history of hypertension, dyslipidemia, and coronary artery disease presented with sudden left-sided weakness. Examination revealed an irregularly irregular pulse, left visual field deficit, left hemiparesis, and left hemihypoesthesia with neglect. ECG confirmed the suspicion of atrial fibrillation, and brain imaging showed a right middle cerebral artery infarction (Figure 4-2). TEE was remarkable for left atrial enlargement but did not

show any atrial thrombus or dense spontaneous echo contrast. The patient was initially treated with aspirin because of concerns about possible hemorrhagic transformation of the cerebral infarction. Beta-blockers were successful in maintaining the ventricular rate controlled. Warfarin was started 3 days after the stroke without complications. The patient evolved favorably and remained free of stroke recurrence 3 years later.

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Figure 4-2. (A) Twelve-lead electrocardiogram showing irregular rhythm and absence of p waves, which characterize atrial fibrillation. Atrial activity is represented by fibrillatory or f waves, seen between QRS complexes. (B) Computed tomography scan of the brain shows two areas of infarction in the right hemisphere, an acute lesion in the right middle cerebral artery territory and a more chronic stroke in the border zone between the middle and posterior cerebral arteries. (C) Diffusion-weighted sequence of the brain magnetic resonance imaging confirms the area of acute ischemia in the right middle cerebral artery distribution.

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Stroke may be the presenting manifestation of atrial fibrillation. Paroxysmal atrial fibrillation carries a risk of thromboembolism similar to that associated with chronic atrial fibrillation. Atrial fibrillation is one of the most common causes of stroke in older patients. Moreover, the risk of thromboembolism from atrial fibrillation increases with age. Because of the high frequency of atrial fibrillation among elderly patients with ischemic strokes of embolic appearance, these patients must be exhaustively studied with serial electrocardiograms, Holter monitoring (24–48 hours), and probably prolonged ambulatory heart rhythm monitoring (several days to weeks).7–9

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There are no distinctive radiological features to discriminate atrial fibrillation from other causes of cardiac embolism. Echocardiography is a useful tool to assess the risk of embolism in patients with atrial fibrillation. Embolic risk is increased when the following findings are present (Figure 4-3 and 4-4): ❖ Left atrial thrombus ❖ Left atrial dilatation10,11 ❖ Thrombus in left atrial appendage12,13 ❖ Dense spontaneous echo contrast12,13 ❖ Reduced left atrial appendage peak flow velocities (ⱕ 20 cm/sec)12 ❖ Left ventricular systolic dysfunction11 ❖ Complex aortic arch plaque12,13

Figure 4-3. A 64-year-old man with history of hypertension and paroxysmal atrial fibrillation who had elected not to be treated with oral anticoagulation was transferred to our hospital with diagnosis of acute stroke. (A) Computed tomography scan of the brain showed areas of wedge-shaped cortical infarction in multiple territories, including the posterior division of the left middle cerebral artery, the anterior division of the right middle cerebral artery, and the external border-zone region between the right middle and posterior cerebral arteries. (B) Transesophageal echo view at the level of the midesophagus showing the left atrial appendage obliterated by a thrombus (arrowhead). AV, aortic valve. (C) Closer view of the thrombus (solid arrow) within the left atrial appendage also allows identification of spontaneous echo contrast in the left atrium (open arrow). LA, left atrium; LAA, left atrial appendage. (D) Detail view of the round echodensity located at the entrance of the left atrial appendage, consistent with a thrombus (solid arrow).

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Figure 4-4. Echocardiographic predictors of increased stroke risk in patients with atrial fibrillation. (A) Spontaneous echo contrast or “smoke” (arrow) seen in the left atrium on transesophageal view. (B) Doppler flow velocities measured at the left atrium appendage entrance. Low-amplitude signals (slow velocities) represent decreased left atrial appendage blood flow and indicate predisposition for thrombus formation. (C) Left atrial enlargement seen on apical transthoracic echocardiogram view; the left atrial size in this patient approached that of the left ventricle. (D) Apical four-chamber transthoracic echo view revealing the presence of a left atrial thrombus (arrow). LA, left atrium; LAA, left atrial appendage; LV, left ventricle.

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TEE should always be performed before cardioversion in patients with atrial fibrillation lasting longer than 48 hours or of unknown duration.14 Anticoagulation is clearly indicated for primary and secondary stroke prevention in patients with atrial fibrillation.15 Aspirin should only be used in patients with low risk of thromboembolic complications (i.e., young age, no cardiovascular risk factors, absence of echocardiographic markers of increased embolic risk).15 When anticoagulation is contraindi-

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cated by concurrent conditions, aspirin is prescribed and radiofrequency ablation procedures to restore sinus rhythm permanently are an option. Percutaneous occlusion of the left atrial appendage is being investigated as another alternative for these cases.16 Sick-sinus rhythm (or tachycardia-bradycardia syndrome) is frequently associated with atrial fibrillation in older patients and may therefore increase the risk of stroke (Figure 4-5). This disorder is best treated with insertion of a pacemaker.

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B Figure 4-5. Twenty-four-hour Holter monitor strip of a 63-year-old patient with recent ischemic stroke and sick-sinus syndrome. Note the presence of a fast supraventricular tachycardia (A) and sinus bradycardia (B), the diagnostic hallmark of the tachycardia-bradycardia syndrome.

DILATED CARDIOMYOPATHY

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Figure 4-6. Images illustrating a case of multiple embolic strokes secondary to left ventricular thrombus due to nonischemic dilatated cardiomyopathy. (A) Computed tomography scan of the brain showing bilateral infarctions. (B) Detail of a large left ventricular apical thrombus seen on transthoracic echocardiogram (arrow).

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Patients with dilated left ventricle and severely depressed left ventricular systolic function have considerably increased risk of stroke because of elevated incidence of ventricular thrombus formation (Figure 4-6) and higher risk of atrial fibrillation. The stroke risk is increased regardless of whether the cause of the dilated cardiomyopathy is ischemic or nonischemic.

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Peripartum cardiomyopathy should be considered in patients presenting with stroke during puerperium. Assessment of left ventricular function and evaluation for possible mural or apical clots are best accomplished using transthoracic echocardiography (see Figure 4-6). In patients with associated atrial fibrillation, it is also important to study the left atrial chamber and left atrial appendage (Figure 4-7).

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Figure 4-7. Another example of a patient with ischemic stroke secondary to dilatated cardiomyopathy, in this case associated with atrial fibrillation. (A) Parasternal long axis transthoracic echocardiogram view showing a dilated left ventricle filled with thrombus. Also note the presence of a thrombus attached to the left atrial wall (arrow). (B) Parasternal short axis transthoracic view at the level of the aorta. Two rounded echodensities are seen within the left atrium consistent with thrombi (arrows). AV, aortic valve; LA, left atrium; LV, left ventricle; MV, mitral valve.

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Anticoagulation is generally accepted as the optimal strategy for secondary prevention after a stroke attributed to dilated cardiomyopathy.17 For primary stroke prevention, anticoagulation is only indicated

in patients with documented atrial fibrillation or left ventricular thrombus17 but might be useful in patients without these complicating conditions as well.18

Cardiac Embolism

MYOCARDIAL INFARCTION

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Figure 4-8. A 58-year-old man with history of hypertension and smoking presented to the emergency department with angina and fluent aphasia. (A) Computed tomography scan showed low attenuation changes in the territory of the posterior division of the left middle cerebral artery. (B) Acute left middle cerebral artery branch infarction was confirmed by magnetic resonance imaging (diffusion-weighted sequence shown). (C) Electrocardiogram in the emergency department showed ST elevation in the anterior leads with reciprocal ST depression in the inferior leads in a pattern typical for myocardial infarction of the anterior wall. (D) Detail of the anterior precordial leads showing significant ST elevation in V1 to V3. (E) Apical two-chamber transthoracic echocardiogram view showing a thrombus in the LV apex (arrow).

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The risk of stroke is increased within the first 3 to 4 months after a myocardial infarction, with the highest embolic risk occurring during the first 2 weeks. The increased risk persists after this period in patients with depressed left ventricular function19 or atrial fibrillation. Thus it is important to exclude concurrent myocardial ischemia in all patients presenting with acute ischemic stroke.

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Transmural anterior wall infarctions carry higher risk, but stroke may complicate inferior wall infarctions as well. TTE should be performed to determine whether left ventricular thrombus formation has occurred over dyskinetic wall segments (Figure 4-8). Thrombi with mobile or pedunculated components are most dangerous. Patients with left ventricular apical aneurysms are at particularly high risk of embolism (Figure 4-9).

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Anticoagulation for at least 3 to 6 months is recommended for patients with stroke due to acute myocardial infarction with documented left ventricular mural thrombus.20 In patients with transmural

Figure 4-9. Echocardiographic predictors of increased risk of stroke after a myocardial infarction. (A) Large thrombus (arrow) protruding into the left ventricular cavity from the apex seen on transthoracic echocardiogram. (B) Detailed view showing the large echodensity within the left ventricle consistent with thrombus. (C) Left ventricle apical aneurysm (arrow) following extensive anterior wall myocardial infarction visualized on this apical two-chamber transthoracic echocardiogram view. (D) Transthoracic echocardiogram view after injection of echo contrast. Note the swirling of blood flow in the area corresponding to the left ventricle apical aneurysm (arrow). LA, left atrium; LV, left ventricle.

myocardial infarction but without documented mural thrombus, short-term anticoagulation may be justified if the stroke was attributed to concurrent myocardial ischemia.

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INFECTIVE ENDOCARDITIS Case Vignette A 46-year-old man with recent community-acquired pneumonia and history of diabetes presented with worsening dyspnea. Examination revealed that the patient was confused and febrile, and careful cardiac auscultation denoted a new systolic murmur with characteristics suggestive of mitral regurgitation. Brain imaging showed scattered, small, acute ischemic infarctions in cortical locations. Echocardiography disclosed a vegetation attached to the mitral

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valve (Figure 4-10, F and G), and blood cultures grew Staphylococcus aureus. The patient was successfully treated with vancomycin and rifampin first and later switched to nafcillin with rifampin when susceptibilities proved that the organism was not methicillin-resistant. The patient did not have recurrent episodes of systemic or cerebral embolism, and repeat echocardiography 4 weeks later confirmed resolution of the vegetation.

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Figure 4-10. Diffusion-weighted sequence of brain magnetic resonance imaging showing multiple small lesions (open arrows) (A–C). Contrast enhanced T1-weighted sequence showing rim enhancement of one of the lesions (solid arrow) (D). GRE sequence reveals hemosiderin deposit within the same lesion (solid arrow) (E). Apical four-chamber transthoracic echocardiogram view showing an echodensity attached to the atrial side of the mitral valve (arrow), which corresponds to a vegetation (F). Detailed view of the mitral valve vegetation (arrow) attached to the posterior leaflet of the mitral valve seen on this parasternal long-axis transthoracic echocardiogram view (G). AV, aortic valve; LA, left atrium; MV, mitral valve.

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embolic risk falls substantially.24,25 The risk of stroke may be higher in patients with mitral valve endocarditis than in those with aortic vegetations (Figure 4-11).23

Stroke complicates 10% to 40% of cases of infective endocarditis.21–23 Most strokes occur at presentation or within 48 hours of diagnosis.23,24 After adequate antibiotic therapy is instituted, the

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Figure 4-11. Example of aortic valve endocarditis. (A) Parasternal long axis transthoracic echocardiogram view reveals the presence of a vegetation attached to the aortic valve protruding into the left ventricular cavity (arrow). (B) Detail of the echocardiogram showing the linear echodense vegetation (arrow) and its close association with the aortic valve cusps. AV, aortic valve; LA, left atrium; LV, left ventricle; RV, right ventricle.

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The possibility of infective endocarditis should always be investigated in a patient presenting with stroke and unexplained fever or other signs of systemic infection. Another clinical clue is that patients with infective endocarditis may present with a combination of focal deficits related to the embolic event and signs of more diffuse encephalopathy. TEE is the ideal method to diagnose valvular vegetations. No particular echocardiographic features serve to stratify the degree of embolic risk. Radiological acute ischemic stroke patterns in infective endocarditis are variable, including single cortical lesions, territorial infarctions, disseminated punctuate lesions (Figure 4-10), and infarctions of various sizes in multiple vascular distributions.26 The risk of intracranial hemorrhage is also considerably increased in patients with infective endocarditis (see Chapter 11). It may be caused by hemorrhagic conversion of an ischemic infarction or by rupture of a mycotic aneurysm. Small hemorrhagic components are commonly seen within ischemic infarctions on hemosiderin-sensitive sequences of magnetic resonance imaging (MRI).

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Mycotic aneurysms are typically small and located in the distal circulation; conventional angiography is necessary to exclude their presence because noninvasive angiographic techniques may not be sufficiently sensitive to detect them. When they rupture, they most often produce subarachnoid hemorrhage predominantly around the hemispheric convexity. Antibiotic therapy is the mainstay of treatment. Surgical excision of the vegetation is indicated in patients with recurrent embolic events. Use of anticoagulation is not favored because it does not appear to reduce the risk of embolism22,27 and it increases the risk of hemorrhage.28

PROSTHETIC VALVES ❖

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The radiological patterns of brain infarction caused by embolism from prosthetic valves are quite variable. Multiple or recurrent strokes are not uncommon. TEE provides optimal sensitivity to visualize clots or vegetations over the prosthetic valve (Figure 4-12).

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The high risk of stroke in patients with mechanical prosthetic valves represents an absolute indication for chronic anticoagulation. An international normalized ratio target of 3.0 (2.5–3.5) is recommended for modern metallic prosthetic valves.20 Addition of aspirin is reasonable in patients who had embolic events despite adequate anticoagulation.20 It is generally recommended that patients undergoing placement of bioprosthetic valves be anticoagulated for 3 months. Long-term anticoagulation may

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Figure 4-12. A 42-year-old woman with history of mitral valve replacement presented with a right posterior cerebral artery infarction. Her international normalized ratio was subtherapeutic. (A) Transthoracic echocardiogram showed a vegetation attached to the prosthetic mitral valve on the atrial side (arrow). (B) Detail of the echocardiogram allows visualization of the previously noted vegetation but also discloses a smaller vegetation attached to the anterior leaflet of the prosthetic mitral valve (arrowhead). LA, left atrium; LV, left ventricle; MVal, anterior leaflet of the mitral valve; PMV, prosthetic mitral valve.

be justified in patients with a bioprosthetic valve who had an embolic infarction without other explanation. Patients with prosthetic valves should always receive antibiotic prophylaxis before procedures that may cause transient bacteriemia. In the event of endocarditis, anticoagulation should be continued in patients with metallic valves. In the event of intracranial hemorrhage, anticoagulation may be temporarily interrupted for 1 to 2 weeks with relatively safety.29

NONBACTERIAL THROMBOTIC ENDOCARDITIS

Case Vignette A 42-year-old woman without previous medical problems presented with acute left inferior quadrantanopsia, left hemiparesis, and diffuse petechiae in all limbs. Brain computed tomography (CT) showed high fronto-parietal hypodensities involving the cortex (Figure 4-13, A). Blood studies revealed thrombocytopenia (40,000 per mm3), leukocytosis (30,000 per mm3) and elevated lactate dehydrogenase (5060 U/L). An electrocardiogram disclosed inverted T waves in the inferior leads. Heparin and aspirin were started. Hours after admission, she developed excruciating left flank pain and became confused. Examination showed a pulseless and cold right foot. After four blood cultures were obtained, the patient was empirically started on antibiotics and high-dose dexamethasone. She improved over the following day, with less pain, improved foot temperature, and increasing platelet count. However, she remained confused and exhibited more ecchymotic lesions and subungual splinter hemorrhages (Figure 4-13, B and C). Chest CT revealed large mediastinal lymphadenopathy, and CT of abdomen showed multiple splenic and renal infarcts. Testing for cryoglobulins, antinuclear

antibodies, antiphospholipid antibodies, complement levels, as well as serial blood cultures were negative. Transthoracic echocardiogram (TTE) (Figure 4-13, D) showed a large vegetation attached to the aortic valve, with moderate aortic regurgitation and moderate posterior and apical hypokinesis. The patient underwent aortic valve replacement, and pathological examination revealed marantic vegetations with myxoid degeneration of the removed valve. Stains and cultures of the vegetations were negative. After surgery, she developed bilateral leg ischemia, renal failure, and congestive heart failure due to global left ventricular hypokinesis documented by a new TTE that revealed acceptable function of the prosthetic aortic valve. She expired 7 days after the surgery. Necropsy findings included metastatic adenocarcinoma of unknown primary involving paratracheal nodes and pleura, bilateral kidney and splenic infarctions, congestive hepatomegaly, serosanguineous pleural effusions and ascites, large organizing right cerebral infarcts, and microscopic cerebellar infarcts. The prosthetic valve was covered by multiple vegetations that resulted in partial luminal occlusion.

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A

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Figure 4-13. Computed tomography scan of the brain showing low-attenuation changes consistent with acute infarction in the right frontal lobe (arrows) (A). Splinter hemorrhages were visible under the nails of multiple fingers (B). Areas of ecchymosis and distal ischemia from systemic embolism are illustrated on this picture of the patient’s right foot (C). Parasternal long-axis transthoracic echocardiogram view showing vegetation (arrow) attached to the aortic side of the aortic valve (D). LA, left atrium; LV, left ventricle.

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Nonbacterial thrombotic endocarditis should be suspected in patients with stroke and underlying malignancy or other conditions associated with thrombotic diathesis (such as antiphospholipid antibodies). Emboli may be occult, small and multiple presenting with encephalopathic features, or single and larger manifesting as territorial infarction.30,31 The pattern of acute ischemic lesions associated with nonbacterial thrombotic endocarditis as seen on DWI appears to be less variable than in infective

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cases. The typical pattern consists of numerous infarctions of various sizes distributed across multiple vascular territories.26 TEE is the diagnostic modality of choice to detect the sterile vegetations. However, there are no reliable features to distinguish them from septic vegetations. Anticoagulation is used to prevent embolism. Surgery is a reasonable alternative in patients with severe valvular dysfunction or recurrent embolic events despite anticoagulation.32

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MITRAL STENOSIS AND ANNULAR CALCIFICATION

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Figure 4-14. Illustrations of mitral stenosis and mitral annular calcification. (A) Parasternal long-axis transthoracic echocardiogram view showing the typical findings of rheumatic mitral valve. Note the doming of the anterior leaflet (arrow) and the thickening of its tip (hockey stick appearance). (B) Mitral annular calcification seen as bright linear echodensity (arrow) at the margin of the mitral valve annulus in this apical four-chamber transthoracic echocardiogram view. AV, aortic valve; LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

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Mitral stenosis is often related to rheumatic heart disease (Figure 4-14, A) and may be associated with atrial fibrillation and left atrial thrombus formation. Risk of embolic infarction is elevated and recurrent strokes are not uncommon. Anticoagulation is indicated when atrial fibrillation or left atrial thrombus is documented; warfarin may also be used in the absence of these additional findings in patients with no other apparent causes for the infarction.

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Mitral annular calcification (Figure 4-14, B) has also been associated with higher incidence of ischemic stroke.33 However, it is unclear whether mitral annular calcification directly increases the risk of stroke or represents a marker of other conditions with proven embolic potential (e.g., atrial arrhythmias). TEE is the ideal test to diagnose mitral stenosis and annular calcium deposits.

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ATRIAL MYXOMA

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Figure 4-15. Bilateral embolic strokes in a 54-year-old patient without prominent vascular risk factors whose echocardiogram showed a left atrial myxoma. (A) Diffusion-weighted imaging and (B) fluidattenuated inversion recovery sequences showing the acute and early subacute ischemic infarctions in both frontal lobes. (C) Left atrial echodensity (arrow) seen in this parasternal long-axis transthoracic echocardiogram view. Differential diagnosis for this finding includes thrombus, tumor, and vegetation. (D) Apical four-chamber transthoracic echocardiogram revealing typical appearance and location of a left atrial myxoma (arrow). IAS, interatrial septum; LA, left atrium; LV, left ventricle; MV, mitral valve.

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Ischemic stroke is the most common neurological presentation of atrial myxomas (Figure 4-15).34 The proposed mechanism for the infarctions, which are often multiple, bilateral, and recurrent, is embolism of tumor fragments facilitated by the friable consistency of the mass.

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Strokes typically occur with myxomas of the left atrium but may also be caused by right atrial tumors in patients with patent foramen ovale. Diagnosis is based on echocardiographic visualization, which may also recognize other intracardiac tumors, such as fibroelastomas (Figure 4-16).

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Figure 4-16. Example of patient presenting with sudden dysarthria and mild left hemiparesis who had two small cortical lesions on brain imaging. Echocardiography revealed the coexistent presence of an intracardiac myxoma and a fibroelastoma. (A and B) Apical four-chamber and parasternal long-axis transthoracic echocardiogram views showing a left atrial myxoma (arrows). (C and D) Small echodensity located in the anterior leaflet of mitral valve (arrows). Pathological examination confirmed that this lesion was a fibroelastoma. LA, left atrium; LV, left ventricle; MVal, mitral valve anterior leaflet; MVpl, mitral valve posterior leaflet. ❖

Development of fusiform (“myxomatous”) intracranial aneurysms is an uncommon, delayed complication of embolization from a cardiac myxoma. These aneurysms tend to be multiple.35 They

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may be diagnosed even years after surgical removal of the tumor. Treatment of atrial myxomas and other cardiac tumors is surgical excision.

PATENT FORAMEN OVALE

Case Vignette A 44-year-old woman presented with sudden left-sided weakness and paresthesias and problems with speech articulation. Her symptoms had started after she had tried to lift a heavy box from the floor. Her only risk factors for atherosclerosis were obesity and smoking. Her medical history was otherwise significant for a previous episode of deep venous thrombosis in one leg 3 years before, which was considered spontaneous and had been treated with nearly 6 months of anticoagulation. Brain imaging revealed small cortical infarctions in the posterior right frontal lobe (Figure 4-17, A). Carotid ultrasound was

unrevealing, and ECG showed sinus rhythm. Transthoratic echocardiogram with bubble study disclosed a patent foramen ovale (PFO) (Figure 4-17, B). The right-to-left shunt at rest and exacerbated with Valsalva was subsequently confirmed by transcranial Doppler (Figure 4-17, D–F). Venous Doppler of the lower extremities showed an acute deep venous thrombosis in the right leg (Figure 4-17, C). Hypercoagulability workup was positive for factor V Leiden mutation (heterozygous). The patient was treated with oral anticoagulation and had no stroke recurrences at the last follow-up 32 months later.

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After agitated normal saline solution injection

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Figure 4-17. (A) Diffusion-weighted magnetic resonance imaging showing small areas of acute cortical ischemia in the right hemisphere. (B) Apical four-chamber transthoracic echocardiogram view taken at the time of injection of aerated saline solution through a peripheral vein. Note the complete filling of the right ventricle (RV) and right atrium (RA) with the contrast (arrows) and the passage of microbubbles (arrowheads) to the left-sided chambers through the interatrial septum (IAS), indicating the presence of a patent foramen ovale (PFO). (C) Doppler ultrasound of the right lower extremity revealing a deep venous thrombosis. (D) Baseline transcranial Doppler (TCD) showing the flow in the right middle cerebral artery insonated through the transtemporal window. (E) TCD showing the presence of microembolic signals after the injection of agitated saline on a vein of the arm. (F) Degree of shunting becomes much more prominent when the patient is also asked to perform Valsalva maneuver at the time of the injection.

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PFO associated with atrial septal aneurysm (ASA) is associated with increased incidence of recurrent stroke in young patients (⬍ 55 years old) with cryptogenic cerebral infarctions.36–38 Even in the absence of concomitant ASA, PFO can be responsible for embolic brain infarctions, especially in young patients with deep venous thrombosis or thrombophilia (Figure 4-17). The association of cryptogenic stroke with PFO in older patients (⬎ 55 years of age) is more controversial, but supported by the results of one large study revealed older patients with cryptogenic strokes were 3 times more likely to have a PFO on TEE than patients with stroke of known cause.39 It is important to remember that PFO is a common finding in healthy individuals (prevalence of 25% in a population study).40 In fact, PFO is not an independent risk factor for cerebrovascular events in the general population,41,42 and it has not been consistently found to be associated with increased risk of recurrent stroke among unselected patients with cryptogenic strokes.43 Hence, the influence of PFO on the risk of recurrent stroke remains to be fully defined. In our

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opinion, it is most reasonable to be cautious when ascribing a stroke to PFO, particularly in older patients among whom paroxysmal atrial fibrillation may be difficult to diagnose in the absence of prolonged ambulatory monitoring. PFO-related infarctions are most often small cortical lesions. However, territorial infarctions are possible. There is no radiological lesion pattern that can be considered reliably indicative of PFOrelated strokes.44 The diagnosis of PFO and ASA hinges on the use of echocardiography, particularly TEE (see Figures 4-17, 4-18, 4-19). TEE allows visualization of the PFO, recognition and grading of right-to-left shunt (defined by the appearance of microbubbles in the left atrium within 3 to 5 cardiac cycles following injection of 5 to 10 ml of agitated saline solution into a peripheral vein), and detection of ASA (bulging of the region of the fossa ovalis extending 15 mm or more beyond the plane of the atrial septum). Contrast echocardiography may enhance the sensitivity of the technique.

Figure 4-18. Illustration of atrial septal aneurysm (ASA). (A and B) Apical four-chamber transthoracic echocardiogram views in different parts of the cardiac cycle showing an aneurysmal interatrial septum (IAS). Note the long excursion of the septum, which protrudes into the left atrium (LA) in part A and the right atrium (RA) in part B. LV, left ventricle; RV, right ventricle.

Figure 4-19. Illustration of a patLA

RA

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B

ent foramen ovale (PFO) associated with an atrial septal aneurysm (ASA). (A and B) Transesophageal echocardiogram views of an ASA. Note the doming of the septum (arrows) toward the left atrium (LA). A channel can be identified into the intrarterial septum (IAS) consistent with a PFO (arrowhead). Microbubbles from injection of aerated saline are seen crossing from the RA to the LA.

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Transcranial Doppler (TCD) is also an effective method to diagnose the presence of a right-to-left shunt (Figure 4-17). The shunt is demonstrated by detecting microembolic signals—corresponding to microbubbles—in an intracranial vessel (typically one of the middle cerebral arteries) after infusion of agitated saline in a peripheral vein of the arm. The sensitivity of TCD is comparable that of TEE.45 In fact, we have seen patients with PFO diagnosed by TCD after being missed by TEE because the patients had been too sedated during TEE to perform adequate Valsalva. However, TCD can only prove the existence of a right-to-left shunt rather than a PFO. The degree of shunting can be quantified by TCD,46 but this method does not allow assessment of the characteristics of the PFO itself or presence of an ASA. Hence, TCD and TEE should be considered complementary techniques.47 Use of contrast TCD, and performing

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the test twice using two provocation maneuvers (e.g., coughing and standard Valsalva) may increase the diagnostic sensitivity of the method.48 Larger PFOs may be associated with higher risk of cryptogenic strokes than smaller ones.43,49 Presence of right-to left shunt at rest (as opposed to only with Valsalva maneuver) may also increase the risk for recurrent brain embolism.50 In addition, presence of concomitant ASA correlates with the occurrence of multiple acute DWI lesions, even after controlling for PFO size and degree of right-to-left shunt.51 The optimal treatment of patients with ischemic stroke ascribed to PFO and ASA remains to be established.36 Although there is insufficient evidence to support the use of anticoagulation, most experts favor this approach over antiplatelet therapy. Ongoing trials are testing the value of endovascular closure of PFO.

PROXIMAL AORTIC ATHEROSCLEROTIC PLAQUE Case Vignette A 76-year-old man with history of hypertension, hyperlipidemia, smoking, coronary artery disease, peripheral vascular disease with claudication, and previous right carotid endarterectomy for severe, asymptomatic stenosis presented with acute right sided weakness. Examination confirmed the presence of right hemiparesis but also disclosed a left visual field deficit. CT scan of the brain showed cortical infarctions in the left frontal and right occipital lobes (Figure 4-20, A and B). Carotid duplex showed moderate stenosis on the left internal carotid origin and no significant restenosis on the right side. Electrocardiography and cardiac telemetry proved that

the patient was in sinus rhythm. TEE showed extensive aortic arch atherosclerosis including a thick focal plaque with an area of small ulceration on its surface. Although there was no mobile component in the aortic plaque, the patient was treated with oral anticoagulation for 3 months along with low-dose aspirin, high-dose statin, and adjustment in the doses of his antihypertensive agents. The patient recovered favorably with help from rehabilitation services, and repeat TEE 3 months later showed reduction in the size of the larger aortic arch plaque. Warfarin was stopped, and he was continued on aspirin without stroke recurrence.

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Figure 4-20. (A and B) Computed tomography scans of the brain showing bilateral cortical infarctions in the left frontal and right occipital lobes. This combination of infarctions in various arterial territories is a hallmark of embolism from a proximal source. (C) Large atheromatous plaque (5–6 mm in maximal thickness) seen in the aortic arch in this transesophageal echocardiogram view (arrow). (D) Another transesophageal echocardiogram view of the aortic arch revealing diffuse atherosclerotic disease (arrows).

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Complex atherosclerotic plaques (defined by thickness ⬎ 4 mm, presence of ulceration, and/or mobile component) in the proximal aorta (ascending or arch) are associated with an increased risk of embolic stroke (Figure 4-20). This association has been consistently found in several case–control studies.52,53 Among stroke patients referred for evaluation with TEE, the prevalence of complex proximal aortic plaques is 14% to 21%, and the 1-year incidence of stroke is 10% to 12%.54,55 In a population-based study the rate of complex proximal aortic plaques was much lower (2.4%) than in selected populations of stroke patients.56 In this community-based study free of referral bias, there was no association between the presence of complex proximal aortic plaques and the occurrence of embolic strokes over a 5-year follow-up. In the same population, the presence of complex atherosclerotic debris was not associated with the occurrence of cryptogenic strokes.57 However, the low

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number of patients with complex proximal aortic plaques may have undermined the power of the study to test the likelihood of these associations. Aortic atherosclerosis is associated with many other stroke risk factors including hypertension, hyperlipidemia, smoking, hyperhomocysteinemia, elevated serum inflammatory markers, carotid stenosis, coronary artery disease, valvular disease (aortic stenosis, mitral annular calcification), left ventricular hypertrophy, and atrial fibrillation.58 There is some persistent debate in regards to whether proximal aortic debris represents an independent risk of factor for stroke or just a marker for generalized atherosclerosis and cardiovascular disease. Although the lack of association with cryptogenic strokes in the community favors the latter position,59 clinical experience (including iatrogenic cases during invasive procedures), pathological data, and the strikingly increased prevalence of the condition among patients undergoing TEE for stroke of

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unclear cause strongly support the notion that aortic embolism is responsible for embolic strokes.58 TEE is the diagnostic technique of choice to detect and characterize proximal aortic plaques. Although there is a small portion of the ascending aorta near the origin of the innominate artery that may be obscured by the tracheal air column, the rest of the proximal aorta, including the entire arch, is visualized on TEE in great detail. The following ultrasonographic characteristics of the plaque have been shown to correlate with stroke risk: thickness (odds ratio for stroke 13.8 for plaques ⬎ 4 mm thick), mobile elements (usually thrombus), ulceration, and large hypoechoic core (rich lipid content).52 Conversely, plaque calcification (hyperechogenicity) reduced the risk of embolism. The neuroimaging characteristics of strokes caused by aortic embolism are not distinguishable from those of cardioembolic infarction. Before attributing a stroke to aortic embolism, it is important to define the location of the aortic plaque in relation to the main aortic branches. For example, an aortic plaque distal to the takeoff of the innominate branch should not be considered responsible for an infarction in the right middle cerebral artery distribution. Most aortoembolic events are presumed to be caused by atherothrombosis. Embolization of cholesterol crystals from a highly unstable aortic plaque (known as atheroembolism) is a much less common complication, which typically results in ischemia of multiple organs and is often fatal.

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The optimal regimen for secondary stroke prevention in patients with severe aortic arch atheroma has not been firmly established. Aggressive statin therapy should be prescribed on the basis of the benefits documented in a large observational study (59% relative risk reduction in the rate of embolic events)60 and evidence of plaque regression in treated patients.61 There is limited evidence that anticoagulation may be preferable to antiplatelet therapy in these patients;62 a randomized, controlled trial is ongoing. Iatrogenic strokes from aortic embolism (through thromboembolism or atheroembolism) may complicate cardiac catheterization and cardiac bypass surgery. Scraping of a plaque during catheterization, manipulation of the aorta during graft anastomosis, crashing of a plaque during cross-clamping, and direct damage of the plaque and endothelium during cannulation and from the cannula jet flow are possible mechanisms. It is not feasible in practice to discriminate between these mechanisms and air embolism, except when air emboli are seen on acute brain imaging. Careful study of the aortic arch using TEE or intraoperative epiaortic ultrasound is helpful in reducing the risk of perioperative aortoembolic complications.63,64 The option of off-pump bypass surgery in patients with high aortic plaque burden should be considered.65 Prophylactic aortic arch endarterectomy should not be performed because it has been shown to increase the risk of serious embolization.66

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42. Petty GW, Khandheria BK, Meissner I, Whisnant JP, Rocca WA, Christianson TJ, et al. Population-based study of the relationship between patent foramen ovale and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:602–608. 43. Homma S, Sacco RL, Di Tullio MR, Sciacca RR, Mohr JP. Effect of medical treatment in stroke patients with patent foramen ovale: patent foramen ovale in Cryptogenic Stroke Study. Circulation 2002; 105:2625–2631. 44. Jauss M, Wessels T, Trittmacher S, Allendorfer J, Kaps M. Embolic lesion pattern in stroke patients with patent foramen ovale compared with patients lacking an embolic source. Stroke 2006; 37:2159–2161. 45. Belvis R, Leta RG, Marti-Fabregas J, Cocho D, Carreras F, Pons-Llado G, et al. Almost perfect concordance between simultaneous transcranial Doppler and transesophageal echocardiography in the quantification of right-to-left shunts. J Neuroimaging 2006; 16:133–138. 46. Ziai WC, Oh S, Razumovsky AY, Wityk RJ. Quantitation of contrast TCD in patients with and without atrial septal aneurysm. J Neuroimaging 2005; 15:250–253. 47. Droste DW, Schmidt-Rimpler C, Wichter T, Dittrich R, Ritter M, Stypmann J, et al. Right-to-left-shunts detected by transesophageal echocardiography and transcranial Doppler sonography. Cerebrovasc Dis 2004; 17:191–196. 48. Droste DW, Kriete JU, Stypmann J, Castrucci M, Wichter T, Tietje R, et al. Contrast transcranial Doppler ultrasound in the detection of right-to-left shunts: comparison of different procedures and different contrast agents. Stroke 1999; 30:1827–1832. 49. Steiner MM, Di Tullio MR, Rundek T, Gan R, Chen X, Liguori C, et al. Patent foramen ovale size and embolic brain imaging findings among patients with ischemic stroke. Stroke 1998; 29:944–948. 50. De Castro S, Cartoni D, Fiorelli M, Rasura M, Anzini A, Zanette EM, et al. Morphological and functional characteristics of patent foramen ovale and their embolic implications. Stroke 2000; 31:2407–2413. 51. Bonati LH, Kessel-Schaefer A, Linka AZ, Buser P, Wetzel SG, Radue EW, et al. Diffusion-weighted imaging in stroke attributable to patent foramen ovale: significance of concomitant atrial septum aneurysm. Stroke 2006; 37:2030–2034. 52. Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994; 331:1474–1479. 53. Jones EF, Kalman JM, Calafiore P, Tonkin AM, Donnan GA. Proximal aortic atheroma. An independent risk factor for cerebral ischemia. Stroke 1995; 26:218–224. 54. Tunick PA, Rosenzweig BP, Katz ES, Freedberg RS, Perez JL, Kronzon I. High risk for vascular events in patients with protruding aortic atheromas: a prospective study. J Am Coll Cardiol 1994; 23:1085–1090.

55. Atherosclerotic disease of the aortic arch as a risk factor for recurrent ischemic stroke. The French Study of Aortic Plaques in Stroke Group. N Engl J Med 1996; 334:1216–1221. 56. Meissner I, Khandheria BK, Sheps SG, Schwartz GL, Wiebers DO, Whisnant JP, et al. Atherosclerosis of the aorta: risk factor, risk marker, or innocent bystander? A prospective population-based transesophageal echocardiography study. J Am Coll Cardiol 2004; 44:1018–1024. 57. Petty GW, Khandheria BK, Meissner I, Whisnant JP, Rocca WA, Sicks JD, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609–614. 58. Kronzon I, Tunick PA. Aortic atherosclerotic disease and stroke. Circulation 2006; 114:63–75. 59. Petty GW, Khandheria BK, Meissner I, Whisnant JP, Rocca WA, Sicks JD, et al. Population-based study of the relationship between atherosclerotic aortic debris and cerebrovascular ischemic events. Mayo Clin Proc 2006; 81:609–614. 60. Tunick PA, Nayar AC, Goodkin GM, Mirchandani S, Francescone S, Rosenzweig BP, et al. Effect of treatment on the incidence of stroke and other emboli in 519 patients with severe thoracic aortic plaque. Am J Cardiol 2002; 90:1320–1325. 61. Lima JA, Desai MY, Steen H, Warren WP, Gautam S, Lai S. Statin-induced cholesterol lowering and plaque regression after 6 months of magnetic resonance imaging-monitored therapy. Circulation 2004; 19;110: 2336–2341. 62. Ferrari E, Vidal R, Chevallier T, Baudouy M. Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants. J Am Coll Cardiol 1999; 33:1317–1322. 63. Davila-Roman VG, Phillips KJ, Daily BB, Davila RM, Kouchoukos NT, Barzilai B. Intraoperative transesophageal echocardiography and epiaortic ultrasound for assessment of atherosclerosis of the thoracic aorta. J Am Coll Cardiol 1996; 28:942–947. 64. Gold JP, Torres KE, Maldarelli W, Zhuravlev I, Condit D, Wasnick J. Improving outcomes in coronary surgery: the impact of echo-directed aortic cannulation and perioperative hemodynamic management in 500 patients. Ann Thorac Surg 2004; 78:1579–1585. 65. Ascione R, Ghosh A, Reeves BC, Arnold J, Potts M, Shah A, et al. Retinal and cerebral microembolization during coronary artery bypass surgery: a randomized, controlled trial. Circulation 2005; 112:3833–3838. 66. Stern A, Tunick PA, Culliford AT, Lachmann J, Baumann FG, Kanchuger MS, et al. Protruding aortic arch atheromas: risk of stroke during heart surgery with and without aortic arch endarterectomy. Am Heart J 1999; 138(4 Pt 1):746–752.

Chapter

5

Extracranial Large Artery Atherothrombosis Sebastian Koch

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xtracranial atherothrombotic disease is an important cause of stroke, and the management of asymptomatic occlusive disease poses additional challenges and opportunities for stroke prevention. Depending on the population studied, approximately 20% of strokes are attributed to large vessel extracranial disease.1 The prevalence of asymptomatic carotid stenosis greater than 50% stenosis is approximately 3% in the general population.2–4 There is a higher prevalence of extracranial atherosclerotic disease in whites compared with African Americans and other ethnic groups.5,6 The workup of stroke patients requires a careful examination of the extravascular tree to determine vessel pathology and stroke etiology. This investigation must include the carotid bifurcation and vertebral artery origin, which are sites characteristically affected by atherosclerosis. Other forms of extracranial vasculopathy such as arterial dissections typically spare these regions but tend to occur in the distal cervical segments of the carotid and vertebral arteries. Inflammatory extracranial vasculopathies are rare; the most common, Takayasu arteritis, typically affects the origins of the large extracranial vessels as they exit the aortic arch. Understanding how various arterial segments are preferentially affected by different vascular pathologies is often helpful in making an accurate diagnosis of stroke etiology. Diagnostic imaging of the extracranial cerebrovasculature includes ultrasonography, magnetic resonance

(MR), computed tomography (CT), and catheter cerebral angiography. In patients with stroke or transient ischemic attacks (TIA), it is essential to determine the degree of internal carotid artery (ICA) stenosis because this is the most important predictor of stroke recurrence. Symptomatic patients with 50% to 69% and greater than 70% stenosis and asymptomatic patients with stenosis exceeding 60% must be reliably identified because arterial revascularization is typically considered at these cutoff points.

ULTRASONOGRAPHY Ultrasound remains a powerful screening and diagnostic tool in the examination of extracranial carotid and vertebral vessels. It has excellent diagnostic accuracy for carotid stenosis and correlation with the gold standard cerebral catheter angiography. The advantages of ultrasonography include its ease of performance and direct visualization of plaque composition and contour. Determining the exact degree of stenosis remains the single most important goal of extracranial ultrasonography. However, plaque composition is an additional determinant of future stroke risk, particularly in the setting of symptomatic stenosis. Carotid plaques that are hypoechoic (i.e., have a dark intraplaque area), or ulcerated are of 139

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particular concern.7–11 These hypoechoic areas are likely to represent intraplaque hemorrhage, and these plaques should be considered unstable, thus having an increased

thromboembolic potential. The presence of calcifications, in contrast, imparts relative plaque stability, and such plaques are less likely to be symptomatic12 (Figure 5-1).

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C Figure 5-1. (A) Heavily calcified plaque at the internal carotid artery (ICA) origin. The arrows outline an acoustic shadow created by the plaque on the near wall of the artery (top wall on the image shown). The shadow prevents further morphological characterization of the plaque as well as velocity determination within the plaque. This may potentially interfere with determining the true degree of stenosis with ultrasonography and should be recognized as a potential limitation of the study. (B) Hypoechoic plaque. The arrows point to the dark outlines of a circumferential echolucent plaque. Echolucencies are associated with plaque instability. (C) Ulcerated plaque: power Doppler of an ulcerated plaque. The image on the left shows the depth of the ulcer measured at 2.5 mm.

Ultrasonography is technician-dependent and requires considerable skill and expertise. It is typically used as an initial screening tool, and thereby sensitivity is optimized at the expense of specificity—that is, it will tend to overestimate the degree of stenosis resulting in some false-positive results. Therefore a confirmatory test is necessary to improve the overall accuracy of the diagnostic approach.13 Ultrasound is less reliable in identifying carotid stenosis in moderate ranges (between 50% and 69%)14,15 and carotid occlusion.13

Because ultrasonography uses an increase in flow velocities as the main diagnostic criterion, the findings of ultrasonography in the setting of abnormal collateral flow patterns must be carefully interpreted. This situation often arises during insonation of a moderately stenotic plaque in patients with contralateral occlusion or high-grade stenosis. In these cases, ultrasound may overestimate the degree of stenosis of the moderately stenotic plaque,16,17 and the findings on ultrasonography must be cautiously reviewed and confirmed with other imaging modalities.

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It is also important to realize that ultrasonography only visualizes the proximal portion of the carotid artery, and pathology involving the distal cervical segment may be unrecognized.

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Diagnostic accuracy of noninvasive imaging is generally improved if results of ultrasonography and MR or CT angiography are concordant.13

CATHETER CEREBRAL ANGIOGRAPHY MR AND CT ANGIOGRAPHY In general clinical practice, the findings on ultrasonography are often confirmed with an alternate imaging technique. MR and CT angiography have essentially replaced catheter angiography as the confirmatory test. The advantages MR and CT angiography are that they are noninvasive and readily available. The sensitivity and specificity for both techniques exceeds 80% to 90%.13,15,18,19 For the majority of patients, this approach (i.e., ultrasonography and CT/MR angiography combined) will correctly identify the true degree of stenosis. However, it continues to be controversial if noninvasive techniques are reliable enough to make decisions about surgical intervention, particularly if the degree of stenosis is in the moderate (50%–69%) range.15 CT angiography has recently experienced a revival with the advent of multislice detectors and development of sophisticated postimaging software. Advantages of CT over MR angiography lie in its acquisition speed. Even though few data are available with these newer techniques, they are likely to improve further the diagnostic accuracy of CT angiography.19 MR angiography is widely used at present but has some inherent limitations. There is a tendency for overestimation of the degree of stenosis because of sampling error. Therefore MR angiography may be more valuable as a screening tool rather than to confirm that stenosis is actually present.20 The specificity and sensitivity can be improved with gadolinium administration.20,21

Catheter cerebral angiography remains the gold standard in determining the degree of stenosis and identifying surgical candidates. However, even in recent clinical trials, there has been a trend in favor of noninvasive testing, particularly in asymptomatic patients, given the risks of catheter angiography.22 The risk of stroke may be as high as 1.2% in asymptomatic patients; however, other reports have shown a reduced risk of serious complications in general practice.23,24 Less well recognized are subclinical infarcts detected by diffusion-weighted MR imaging after diagnostic cerebral angiography. Such lesions are present in up to 20% of patients and are the result of silent microembolism,25 but might produce subtle neuropsychiatric manifestations that go undetected.

Case Vignette A 75-year-old hypertensive diabetic woman developed right-sided weakness. Extracranial ultrasonography showed a right ICA occlusion and left ICA high-grade stenosis meeting diagnostic criteria for stenosis exceeding 70% of the luminal diameter. MR angiography of the neck showed a high-grade left internal stenosis and confirmed the right internal carotid occlusion. On cerebral angiography, the left carotid stenosis was carefully measured to be 60% (Figure 5-2). The external carotid artery was occluded.

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C Figure 5-2. (A) Ultrasound shows elevation of flow velocities across the plaque with a peak systolic velocity of 279.9 cm/sec. This is suggestive of a high-grade stenosis exceeding 70%. Peak systolic flow velocities are the most reliable and reproducible diagnostic criteria in the determination of the degree of stenosis. (B) A highgrade stenosis is also apparent on magnetic resonance angiography. (C) Cerebral angiography measures the degree of stenosis at 60%.

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The results of ultrasonography must be carefully interpreted in situations in which increased blood flow from collateralization is expected, for example, in this case because of occlusion of the contralateral

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ICA and possibly the ipsilateral external carotid artery. Noninvasive tests may overestimate the degree of stenosis in cases of moderate (50%–69%) narrowing.

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CLINICAL FEATURES OF CAROTID ATHEROTHROMBOSIS

Case Vignette A 76-year-old man with a prior history of hypertension developed three episodes of sudden transient left hand and forearm numbness lasting 10 to 15 minutes over the previous week. His neurological examination showed no abnormalities. A harsh right carotid bruit was heard on neck auscultation. He underwent an emergent carotid ultrasound, which revealed a hypoechoic plaque at the right internal carotid origin

causing high-grade stenosis of the lumen. MR angiography of the neck performed later confirmed these findings (Figure 5-3). He was admitted to a local hospital and placed on antithrombotic therapy. The following morning, he developed left-sided facial droop, dysarthria, and left-arm paralysis. He underwent an emergent endarterectomy and recovered without residual deficits.

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Figure 5-3. (A and B) Longitudinal and axial ultrasound images of a hypoechoic plaque indicated by arrows. ICA, internal carotid artery. (C) Magnetic resonance angiography image confirms a high-grade stenosis.

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This case illustrates the clinical hallmarks of large arterial atherothrombosis: ❖

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High association with TIA compared with other stroke mechanisms Repetitive stereotypical symptoms within the same vascular distribution that are unlikely to occur with cardiac embolism Presence of a bruit, even though the sensitivity and specificity of a carotid bruit for high-grade stenosis is only approximately 60%26 High risk of stroke and hyperacute stroke recurrence after initial presentation. Large arterial disease is the stroke subtype associated with the highest incidence of early stroke recurrence27 Failure of medical therapy to prevent recurrent symptoms and need for early surgical intervention (In fact the benefit of endarterectomy diminishes greatly if performed more than 2 weeks after symptom onset.28)

MECHANISMS OF INFARCTION In extracranial large vessel disease the brain is affected by important pathophysiological events taking place at significant distances. These processes include thromboembolism and the downstream effects of decreased perfusion with increasing degrees of stenosis. These two mechanisms are embolic and hemodynamic.

Atherothrombotic Embolism Artery-to-artery embolism is the most common mechanism of symptoms in large-artery disease. Emboli generated from an unstable carotid plaque may lead to a wide spectrum of symptoms from benign to disabling. These include asymptomatic retinal emboli, transient monocular blindness, retinal arterial infarction, hemispheric TIA, and small or large territorial strokes. Emboli are likely to consist of varying combinations of platelets, cholesterol particles and fibrin.

Case Vignette A 55-year-old smoker underwent a routine ocular examination and was found to have a Hollenhorst plaque in her right eye. She denied any visual symptoms. Carotid ultrasound revealed an ulcerated plaque at

the origin of the right ICA causing no more than 30% to 40% stenosis (Figure 5-4). She was placed on aspirin, and her vascular risk factors were treated intensively.

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Cholesterol emboli are often asymptomatic. Asymptomatic retinal emboli are surprisingly common and have a prevalence of approximately 1% in a general population aged 50 and older.29 Retinal emboli identify a subgroup of patients with asymptomatic atherosclerotic disease who will require aggressive management of vascular risk factors.

Case Vignette

Figure 5-4. Ultrasound image of a low-grade bifurcation stenosis. ICA, internal carotid artery.

A 68 year-old man with history of hypertension, dyslipidemia, and diabetes developed sudden onset of left arm and leg numbness. On examination, he had diminished left-arm sensation and sensory extinction. Brain MRI showed an acute infarct in the right parietal lobe on diffusion-weighted imaging sequence. Fluid-attenuated inversion recovery (FLAIR) showed a prior infarct in right middle cerebral territory (Figure 5-5). Carotid ultrasound and MR angiography revealed high-grade stenosis of the right ICA artery at its origin.

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Figure 5-5. (A) Diffusion-weighted imaging (DWI) showing an acute right parietal infarction. (B) Review of fluid-attenuated inversion recovery images show prior ischemic insult; DW imaging does not demonstrate this infarction to be acute.

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Carotid atherosclerotic disease frequently causes partial territorial infarctions as a consequence of artery-to-artery embolism. Subclinical infarction may be seen in the vascular distribution of the stenotic vessel, suggesting prior asymptomatic embolism. Infarcts related to atherothrombosis are generally smaller than those associated with cardiac embolism,

which tend to generate large emboli and complete territorial infarctions. Even though the degree of carotid stenosis remains the single most important factor in predicting stroke risk in symptomatic patients, certain situations warrant a more careful assessment of carotid disease, as illustrated in the next case vignette.

Case Vignette A 56-year-old man with hypertension and dyslipidemia had a history of two previous strokes in the territory of the left middle cerebral artery. He presented with new onset of right-arm weakness and mild speech difficulties. Brain MRI showed a small acute ischemic stroke in the left frontal lobe. He underwent a careful investigation of his vascular tree and cardiac evaluations including MR angiography of the brain, transthoracic and transesophageal echocardiograms, and Holter monitoring of the cardiac rhythm. All tests failed to reveal the mechanism of his infarction. A carotid ultrasound showed plaque formation in the left carotid bulb, which produced no alteration of

Doppler flow pattern and was estimated to cause no more than 50% stenosis of the luminal diameter (Figure 5-6). Subsequently, he underwent a catheter cerebral angiogram, which confirmed the presence of an ulcerated left carotid bulb plaque, causing no significant stenosis. Given the repetitive nature of his symptoms restricted to a single vascular distribution, it was felt that his symptoms were most likely explained by repeated thromboembolism from the proximal ICA plaque. Consequently, he was treated with left carotid endarterectomy. A hemorrhagic ulcerated plaque was found at the time of the operation. He recovered well from surgery and has been symptom-free for the following 2 years.

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Figure 5-6. (A) Ultrasound of proximal internal carotid artery shows plaque formation in the carotid bulb. The arrows outline the wall of the artery. Velocity measurements do not suggest a high-grade stenosis. (B) Cerebral angiography shows an ulcerated plaque. The arterial wall of the bulb filled with a sizable atheroma is outlined by the arrows, not causing significant luminal stenosis.

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A sizable plaque can develop in the carotid bulb without causing stenosis, as measured by current imaging modalities. In the coronary circulation, the term “plaque burden” refers to the volume of plaque deposition rather than the degree of stenosis as the major determinant of symptoms.30,31 The anatomy of the carotid bulb shows significant variation between individuals. This may lead to a significant atheroma deposition in some individuals who have large bulbous dilatation of the proximal ICA. In these instances, surgical treatment may need to be considered, even though no clear high-grade stenosis is identified. Plaque composition assessed by noninvasive means may not predict well the findings on the pathological sample obtained at the time of endarterectomy.32,33

Alternatively, high-grade stenosis may not require further revascularization, as illustrated in the following case.

Case Vignette A 68-year-old man with hypertension was seen at a stroke referral center for a past history of left-sided cortical stroke, which occurred more than 1 year earlier. On follow-up Duplex examination, he was found to have a severely narrowed right ICA with a dampened flow pattern (Figure 5-7). MR angiography suggested occlusion of the right cervical carotid artery. Catheter cerebral angiogram demonstrated a proximal high-grade stenosis with a severely narrowed and collapsed ICA distal to the stenosis. He was deemed to have a functional occlusion and treated with medical therapy.

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Figure 5-7. Extracranial (A) and intracranial (B) cerebral angiogram of a left common carotid artery injection in a patient with near occlusion. The narrowed remaining internal carotid artery is demonstrated by the arrows and contributes little to filling of the ipsilateral middle cerebral artery (top arrow, panel B).

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The diameter of the carotid artery distal to a highgrade stenosis is variable. It may assume nearnormal diameter or be significantly narrowed. Narrowing of the distal carotid artery is also called “string sign” or near occlusion. It is produced by the delayed arrival of contrast distally in the presence of collateral flow to the affected hemisphere.34 Contrary to previous reports suggesting that stroke risk is high in this patient population, recent data suggest that the stroke risk is low on medical therapy, and revascularization may not be necessary.34 The low stroke risk is explained by the reduced blood flow across the tight stenosis, which may fail to dislodge emboli.34,35 The case also demonstrates the difficulties of noninvasive tests in diagnosing complete occlusions and near occlusions in some instances.18

Hemodynamic Infarction Cerebral infarction may also occur as a result of perfusion failure, and the prevalence of hemodynamic mechanisms may have been underestimated.36,37 Such types of infarctions are typically associated with large arterial vessel occlusion or high-grade stenosis. Situations that may lead to changes in cerebral blood flow and perfusion pressure are often precipitating factors. This type of infarction tends to occur in watershed and border-zone areas, that is, the distal irrigation fields between the anterior and

middle cerebral artery (anterior watershed), posterior and middle cerebral artery (posterior watershed), and the medullary penetrating and lenticulostriate arteries of the middle cerebral artery along the lateral and cephalad border of the lateral ventricle (internal border zone).38

Case Vignette An 82-year-old man with history of hypertension and smoking had a documented right carotid occlusion. He presented to the consultation after awakening with leftsided weakness. A careful review of recent symptoms revealed that over the previous 2 to 3 weeks, he had experienced several episodes of lightheadedness and leftsided heaviness after getting up from the bed or a chair; each episode resolved within a few minutes. On several of those occasions, his left arm would shake uncontrollably for several seconds. The day prior to his stroke he had fallen on his left hip. His examination showed left hemiparesis. He had a large hematoma over his left hip. His hematocrit had decreased from 39% (his baseline) to 32%. Brain MRI showed infarction in the deep internal middle cerebral artery watershed distribution, which included the distal irrigation fields of the lenticulostriate and cortical penetrating medullary branches (Figure 5-8). Carotid ultrasound, MR angiography, and CT angiography confirmed occlusion of the ipsilateral ICA.

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ECA

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D Figure 5-8. (A) Diffusion-weighted image of an internal border-zone infarct. The linear stroke pattern is reminiscent of beads on a string. (B) Ultrasound power Doppler shows absence of flow in the right internal carotid artery. ECA, external carotid artery; ICA, internal carotid artery. (C) Postimaging reconstruction of CT angiogram CT delineating the extracerebral and intracerebral vasculature and right internal carotid occlusion (arrow). (D) Axial CT angiography showing absence of contrast in the right internal carotid artery (arrow) consistent with occlusion. The views are used in the postimaging processing to obtain the reconstruction shown in panel C. (E) Magnetic resonance angiography confirms absent distal right internal carotid flow.

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Hemodynamic symptoms in patients with large artery occlusion (or critical stenosis) may be precipitated when coexistent conditions or situations further compromise cerebral perfusion (i.e., orthostatic changes, acute blood loss, nocturnal blood pressure dipping). Another common precipitant factor is the introduction of new antihypertensive treatment. Hemodynamic compromise may be manifested with limb-shaking TIA,39 a rare presentation of cerebral ischemia with positive symptoms rather than negative symptoms (i.e., loss of function). The characteristic pattern of infarction in cases of hemodynamic insufficiency affects the internal border-zone distribution; the resulting infarctions often resemble “beads on a string.” Other symptoms characteristically associated with watershed infarctions include the following: ❖ transcortical motor aphasia—infarction in the anterior watershed area of the dominant hemisphere ❖ transcortical sensory aphasia—infarction of posterior watershed area of the dominant hemisphere ❖ “man-in-the-barrel” distribution of weakness (bi-brachial weakness with preserved leg strength seen with bilateral anterior watershed infarcts).40

TREATMENT Symptomatic Carotid Disease Treatment of atherosclerotic disease comprises careful considerations of medical and surgical therapy. Surgical intervention has to be the primary consideration in symptomatic disease exceeding 70% stenosis because of the high risk of stroke recurrence on medical therapy.23,41 The risk of recurrent stroke on medical therapy is 26% in 2 years and is reduced to 9% with endarterectomy.23,41 The risk of subsequent stroke is greater with increasing degrees of stenosis.

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Surgical therapy must be instituted rapidly because the risk of early reinfarction is high. In fact, the benefit of carotid endarterectomy in stroke prevention is significantly reduced if performed more than 2 weeks from symptom onset.28 In symptomatic carotid disease with 50% to 69% stenosis, the risk of recurrent infarction is lower and the benefit of surgical intervention is more modest.42 Other features such as patient sex, age, and plaque characteristics (ulcerations, intraplaque hemorrhage) may need to be taken into consideration to identify patients at increased risk for stroke recurrence.

Asymptomatic Carotid Artery Stenosis The management of asymptomatic carotid stenosis continues to be a challenge and remains controversial. The risk of first stroke on medical treatment in patients with greater than 60% asymptomatic carotid stenosis is low, approximately 2% annually, and with endarterectomy, it may be reduced to 1%.22,43 Aggressive management of vascular risk factors with newer antithrombotic, antihypertensive, and lipid-lowering agents may have reduced this risk of stroke with medical therapy even further in recent years.22,44,45 Carefully selected asymptomatic patients with greater than 60% stenosis benefit from endarterectomy compared with medical therapy.22,43 The benefits, however, are moderate, were not found for women, and are only evident with a low surgical complications rate of approximately 2%.22,43 Identifying a subgroup of asymptomatic patients that may be at higher risk of stroke would limit intervention to those patients likely to benefit the most and maximize the risk–benefit ratio of surgical intervention. Careful consideration must be given to age, sex, and life expectancy, because the benefits of surgery only become apparent over time. Additional factors that might identify populations at risk for first stroke are not entirely defined but may include presence of asymptomatic microemboli on transcranial Doppler,44,46 asymptomatic infarction in the distribution of the stenosis,47 plaque characteristics (ulcerations and intraplaque hemorrhage),7–11 and impaired vasomotor reactivity.48

Case Vignette An asymptomatic 65-year-old diabetic and hypertensive active man was found to have a carotid bruit. An initial carotid ultrasound suggested a 50% to 60% carotid stenosis. He was followed with serial carotid ultrasonography, and 1 year later, the ultrasound performed in the same laboratory showed progression of the stenosis to 80% to 90%, caused by a larger hypoechoic, ulcerated plaque. This was subsequently confirmed by MR angiography of the neck, and MR angiography of the brain disclosed poor compensatory

collateral flow in the affected hemisphere. Brain MRI showed several cortical FLAIR hyperintensities in the ipsilateral hemisphere, indicating subclinical infarctions. He had several microembolic signals on transcranial Doppler and impaired vasomotor reactivity (Figure 5-9). He was counseled on his future stroke risk as well as risks and benefits of medical versus surgical therapy. His stroke risk was felt to exceed the annual average of 2% generally applied to asymptomatic patients with greater than 60% carotid stenosis.

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cm/s 160 140 120 100 80 60 40 20 0 -20 -40 -60

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Figure 5-9. (A) Fluid-attenuated inversion recovery image showing cortical hyperintensities suggestive of previous subclinical ischemic injury. (B) Transcranial Doppler microembolic signal detected in the middle cerebral artery (arrow). The absence or presence of microembolic signals distal to an asymptomatic stenosis may have important prognostic implications. (C) Vasomotor reactivity study assessing response to inhalation of CO2 (started at first arrow) leading to an increase in flow velocities and hyperventilation (hypocapnia) causing a decrease in flow velocities in the normally functioning middle cerebral artery depicted by the black line. The green line shows the flow in the contralateral middle cerebral artery, which exhibits no significant response to CO2.

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This case illustrates: The need to select asymptomatic patients carefully for carotid revascularization Consideration of clinical factors ❖ relatively young age ❖ lack of medical comorbidities Consideration of ancillary factors that might influence risk of first stroke ❖ Progression of disease,49,50 easily assessed with serial ultrasonography (ideally performed in the same laboratory and using the same equipment) ❖ Presence of microemboli signals ❖ Impaired cerebral vasoreactivity

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Plaque characteristics (i.e., hypoechoic areas, ulcers) Collateral flow pattern Radiological evidence of silent embolic infarctions

Carotid Revascularization New options for revascularization are currently emerging. Carotid endarterectomy is a proven and effective technique with a low complication rate. It will be difficult to improve further on the safety record and durability of carotid endarterectomy. There are,

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however, situations that increase the perioperative complication rate of carotid endarterectomy. Such scenarios include contralateral high-grade stenosis or occlusion, radiation induced carotid stenosis, inaccessible high cervical carotid bifurcation, restenosis after endarterectomy, and medical comorbidities, particularly poor cardiopulmonary status.51 Carotid artery stenting is a treatment option in those settings; however, it is increasingly applied for the treatment of carotid stenosis in general practice. A clear benefit of carotid stenting over carotid endarterectomy has not yet been demonstrated,51–53 and carotid endarterectomy should continue to be considered the

gold standard intervention for the treatment of carotid stenosis.

Case Vignette A 55-year-old man developed an episode of right-arm numbness and weakness. The patient had a prior history of neck radiation for lymphoma. Carotid ultrasonography revealed high-grade left carotid stenosis, which was later confirmed angiographically. The prior history of radiation was considered a relative indication for stent placement rather than endarterectomy (Figure 5-10).

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Figure 5-10. (A) Catheter angiogram showing a long segment of narrowing extending from the proximal to the distal internal carotid artery consistent with radiation induced arteriopathy outlined by arrows. (B and C) Ultrasound B-mode image of carotid stent axial view (B) and longitudinal view (C) identified by arrows. (D) Appearance of stent on cerebral angiography (arrows).

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Accelerated atherosclerosis may occur after radiation therapy in the absence of other vascular risk factors. Radiation-induced lesions tend to involve segments of the carotid artery typically spared by atherosclerosis (i.e., longitudinally extensive segments involved portions of the cervical carotid artery relatively distant from the bulb). Radiation-induced vasculopathy is considered a relative indication for stenting because of the suboptimal results achieved by endarterectomy.

VERTEBRAL ARTERY ATHEROSCLEROSIS Extracranial vertebral atherosclerotic disease remains an underrecognized cause of posterior circulation infarction. Segments typically affected by atherosclerosis are the vertebral artery origin and the proximal few centimeters just distal to the origin. The remaining extracranial segments of the vertebral artery are spared by atherosclerosis. Intracranially, the segments preceding and following origin of the posterior inferior cerebellar artery and the vertebrobasilar junction are typically affected by atherosclerosis.

As in carotid disease, the important mechanisms of infarction are artery-to-artery embolism and hemodynamic mechanisms.54 Hemodynamic mechanisms are further dependent on the patency of the contralateral vertebral artery, which may either be affected by atherosclerosis or congenitally hypoplastic. Vertebral arteries are often incompletely investigated during the evaluation of posterior circulation stroke patients. During ultrasonography, the vertebral artery is often only insonated in its transforaminal segment, and flow is reported as antegrade. Pathology of the vertebral origin is often undetected. The MR and CT imaging protocol for angiography of the neck may also fail to include the vertebral origins unless otherwise specified. The vertebral artery origin may be assessed with ultrasound and CT and MR angiography. However, only a few studies have reported on the diagnostic accuracy of these imaging modalities. A sensitivity of approximately 70% and specificity exceeding 90% has been reported for the diagnosis of proximal vertebral artery disease with ultrasonography compared with the gold standard of cerebral angiography.55,56 A similar sensitivity and specificity has been reported for CT and MR angiography for stenosis of the vertebral artery origin.57–59

Case Vignette A 65-year-old hypertensive man developed recurrent symptoms of vertigo, diplopia, and hemibody numbness. Initial vascular evaluation with ultrasound reported antegrade flow bilaterally in both vertebral arteries insonated in the midcervical area. MR angiography of the neck showed normal vertebral arteries but did not include their most proximal segments. The patient’s

symptoms persisted despite several changes in antithrombotic regimen. Repeated complete vertebral ultrasonography suggested a high-grade vertebral arteryorigin stenosis. This finding was later confirmed by catheter angiography. A stent was placed at the vertebral artery origin, and the patient had no further symptoms (Figure 5-11).

Extracranial Large Artery Atherothrombosis

153

Rt VAO Plaque

B

A

C Figure 5-11. (A) B-mode image showing the proximal vertebral artery including a plaque at the origin (arrow). VAO, vertebral artery origin. (B) Catheter angiography confirms the proximal vertebral artery stenosis. (C) Angiographic result after vertebral origin stent.

❖

❖

Repetitive stereotypical symptoms should be considered highly suspicious of fixed stenosis of a large vessel and demand examination of the entire arterial tree. This case demonstrates the diagnostic difficulties encountered when attempting to examine the vertebral artery by noninvasive methods.

❖

The best management for proximal vertebral artery occlusive disease is not known. Medical treatment, angioplasty and stent placement, or vertebral transposition are treatment options that may be considered.

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References. 1. Sacco RL, Ellenberg JH, Mohr JP, Tatemichi TK, Hier DB, Price TR, Wolf PA. Infarcts of undetermined cause: the NINCDS Stroke Data Bank. Ann Neurol 1989; 25:382–390. 2. Mathiesen EB, Joakimsen O, Bonaa KH. Prevalence of and risk factors associated with carotid artery stenosis: the Tromso Study. Cerebrovasc Dis 2001; 12:44–51. 3. Ghilardi G. Carotid stenotic-obliterative lesions. Distribution in 16,379 subjects 45-75 years of age. Minerva Cardioangiol 1994; 42:345–350. 4. Qureshi AI, Alexandrov AV, Tegeler CH, Hobson RW, Dennis Baker J, Hopkins LN. Guidelines for screening of extracranial carotid artery disease: a statement for healthcare professionals from the multidisciplinary practice guidelines committee of the American Society of Neuroimaging; cosponsored by the Society of Vascular and Interventional Neurology. J Neuroimaging 2007; 17:19–47. 5. Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular disease: A review. Stroke 1986; 17:648–655. 6. Wityk RJ, Lehman D, Klag M, Coresh J, Ahn H, Litt B. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996; 27:1974–1980. 7. Polak JF, Shemanski L, O’Leary DH, Lefkowitz D, Price TR, Savage PJ, et al. Hypoechoic plaque at us of the carotid artery: an independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study. Radiology 1998; 208:649–654. 8. Sterpetti AV, Schultz RD, Feldhaus RJ, Davenport KL, Richardson M, Farina C, Hunter WJ. Ultrasonographic features of carotid plaque and the risk of subsequent neurologic deficits. Surgery 1988; 104:652–660. 9. Russell DA, Wijeyaratne SM, Gough MJ. Changes in carotid plaque echomorphology with time since a neurologic event. J Vasc Surg 2007; 45:367–372. 10. Mathiesen EB, Bonaa KH, Joakimsen O. Echolucent plaques are associated with high risk of ischemic cerebrovascular events in carotid stenosis: the Tromso Study. Circulation. 2001; 103:2171–2175. 11. Bluth EI, Kay D, Merritt CR, Sullivan M, Farr G, Mills NL, et al. Sonographic characterization of carotid plaque: detection of hemorrhage. AJR Am J Roentgenol 1986; 146:1061–1065. 12. Grogan JK, Shaalan WE, Cheng H, Gewertz B, Desai T, Schwarze G, et al. B-mode ultrasonographic characterization of carotid atherosclerotic plaques in symptomatic and asymptomatic patients. J Vasc Surg 2005; 42:435–441. 13. Long A, Lepoutre A, Corbillon, Branchereau A. Critical review of non- or minimally invasive methods (duplex ultrasonography, MR- and CT-angiography) for evaluating stenosis of the proximal internal carotid artery. Eur J Vasc Endovasc Surg 2002; 24:43–52. 14. Kennedy J, Quan H, Ghali WA, Feasby TE. Importance of the imaging modality in decision making about carotid endarterectomy. Neurology 2004; 62:901–904. 15. Wardlaw JM, Chappell FM, Best JJ, Wartolowska K, Berry E. Non-invasive imaging compared with intra-arterial angiography in the diagnosis of symptomatic carotid stenosis: a meta-analysis. Lancet 2006; 367:1503–1512. 16. Heijenbrok-Kal MH, Nederkoorn PJ, Buskens E, van der Graaf Y, Hunink MG. Diagnostic performance of duplex

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Extracranial Large Artery Atherothrombosis 32. Eikelboom BC, Riles TR, Mintzer R, Baumann FG, DeFillip G, Lin J, Imparato AM. Inaccuracy of angiography in the diagnosis of carotid ulceration. Stroke 1983; 14:882–885. 33. Widder B, Paulat K, Hackspacher J, Hamann H, Hutschenreiter S, Kreutzer C, et al. Morphological characterization of carotid artery stenoses by ultrasound duplex scanning. Ultrasound Med Biol 1990; 16:349–354. 34. Rothwell PM, Eliasziw M, Gutnikov SA, Fox AJ, Taylor DW, Mayberg MR, et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet 2003; 361:107–116. 35. Morgenstern LB, Fox AJ, Sharpe BL, Eliasziw M, Barnett HJ, Grotta JC. The risks and benefits of carotid endarterectomy in patients with near occlusion of the carotid artery. North American Symptomatic Carotid Endarterectomy Trial (NASCET) group. Neurology 1997; 48:911–915. 36. Ringelstein EB, Zeumer H, Angelou D. The pathogenesis of strokes from internal carotid artery occlusion. Diagnostic and therapeutical implications. Stroke 1983; 14:867–875. 37. Wodarz R. Watershed infarctions and computed tomography. A topographical study in cases with stenosis or occlusion of the carotid artery. Neuroradiology 1980; 19:245–248. 38. Momjian-Mayor I, Baron J-C. The pathophysiology of watershed infarction in internal carotid artery disease: review of cerebral perfusion studies. Stroke 2005; 36:567–577. 39. Baquis GD, Pessin MS, Scott RM. Limb shaking—a carotid TIA. Stroke 1985; 16:444–448. 40. Sage JI, Van Uitert RL. Man-in-the-barrel syndrome. Neurology 1986; 36:1102–1103. 41. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991; 325:445–453. 42. Endarterectomy for moderate symptomatic carotid stenosis: interim results from the MRC European carotid Surgery Trial. Lancet 1996; 347:1591–1593. 43. Endarterectomy for asymptomatic carotid artery stenosis. Executive committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995; 273:1421–1428. 44. Abbott AL, Chambers BR, Stork JL, Levi CR, Bladin CF, Donnan GA. Embolic signals and prediction of ipsilateral stroke or transient ischemic attack in asymptomatic carotid stenosis: a multicenter prospective cohort study. Stroke 2005; 36:1128–1133. 45. Rothwell PM, Coull AJ, Giles MF, Howard SC, Silver LE, Bull LM, et al. Change in stroke incidence, mortality, case-fatality, severity, and risk factors in Oxfordshire, UK from 1981 to 2004 (Oxford Vascular Study). Lancet 2004; 363:1925–1933. 46. Spence JD, Tamayo A, Lownie SP, Ng WP, Ferguson GG. Absence of microemboli on transcranial Doppler identifies

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low-risk patients with asymptomatic carotid stenosis. Stroke 2005; 36:2373–2378. Tegos TJ, Kalodiki E, Nicolaides AN, Sabetai MM, Stevens JM, Thomas DJ. Brain CT infarction in patients with carotid atheroma. Does it predict a future event? Int Angiol 2001; 20:110–117. Silvestrini M, Vernieri F, Pasqualetti P, Matteis M, Passarelli F, Troisi E, Caltagirone C. Impaired cerebral vasoreactivity and risk of stroke in patients with asymptomatic carotid artery stenosis. JAMA 2000; 283:2122–2127. Olin JW, Fonseca C, Childs MB, Piedmonte MR, Hertzer NR, Young JR. The natural history of asymptomatic moderate internal carotid artery stenosis by duplex ultrasound. Vasc Med 1998; 3:101–108. Rockman CB, Riles TS, Lamparello PJ, Giangola G, Adelman MA, Stone D, et al. Natural history and management of the asymptomatic, moderately stenotic internal carotid artery. J Vasc Surg 1997; 25:423–431. Yadav JS, Wholey MH, Kuntz RE, Fayad P, Katzen BT, Mishkel GJ, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004; 351:1493–1501. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. The Lancet 368:1239–1247. Mas J-L, Chatellier G, Beyssen B, Branchereau A, Moulin T, Becquemin J-P, et al., the EVASI. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 2006; 355:1660–1671. Caplan LR, Wityk RJ, Glass TA, Tapia J, Pazdera L, Chang HM, et al. New England Medical Center Posterior Circulation Registry. Ann Neurol 2004; 56:389–398. de Bray JM, Pasco A, Tranquart F, Papon X, Alecu C, Giraudeau B, et al. Accuracy of color-Doppler in the quantification of proximal vertebral artery stenoses. Cerebrovasc Dis 2001; 11:335–340. Ackerstaff RG, Hoeneveld H, Slowikowski JM, Moll FL, Eikelboom BC, Ludwig JW. Ultrasonic duplex scanning in atherosclerotic disease of the innominate, subclavian and vertebral arteries. A comparative study with angiography. Ultrasound Med Biol 1984; 10:409–418. Farres MT, Grabenwoger F, Magometschnig H, Trattnig S, Heimberger K, Lammer J. Spiral CT angiography: study of stenoses and calcification at the origin of the vertebral artery. Neuroradiology 1996; 38:738–743. Kollias SS, Binkert CA, Ruesch S, Valavanis A. Contrastenhanced MR angiography of the supra-aortic vessels in 24 seconds: a feasibility study. Neuroradiology 1999; 41:391–400. Khan S, Cloud G, Kerry S, Markus HS. Imaging of vertebral artery stenosis: a systematic review. J Neurol Neurosurg Psychiatry 2007; 78:1218–1225.

Chapter

6

Intracranial Atherosclerotic Disease Jose G. Romano

N

arrowing of the large intracranial arteries is a surprisingly common cause of stroke in nonCaucasian populations, and one often overlooked in the evaluation of cerebrovascular patients. Various imaging modalities can effectively interrogate the intracranial vascular tree, at least the large intracranial vessels, to determine the extent of this condition. Although various pathologies can affect intracranial large arteries, including moyamoya disease, sickle cell disease, spasm, and arteritis, the most common cause is atherosclerosis. This chapter reviews the frequency of intracranial atherosclerotic disease, available diagnostic modalities, and treatment options.

reported that between one third and one half of vessels develop worsening stenosis during a mean follow-up of 27 months.5,6 More important, progression of arterial narrowing strongly correlates with development of ischemic symptomatology.6 Therefore, ❖

❖ ❖

Intracranial atherosclerotic disease is responsible for about 10% of all strokes. The risk is higher in non-Caucasian populations. Intracranial disease may coexist with extracranial disease.

MECHANISMS OF CEREBRAL ISCHEMIA EPIDEMIOLOGY AND NATURAL HISTORY In the United States, between 8% and 10% of all strokes are deemed to be due to intracranial atherosclerotic disease.1,2 However, the burden of this condition has clear ethnic differences, affecting Asians, African Americans, and Latinos more than Caucasians. Some reports have cited that as many as 25% of all strokes in Asians are due to intracranial stenosis.3 In addition, intracranial disease may coexist with extracranial disease; 6% of patients with symptomatic extracranial carotid disease have tandem intracranial disease.4 The progression of severity of intracranial stenosis has not been carefully evaluated. Small studies have

The mechanisms by which intracranial arterial disease causes cerebral ischemia are varied and include occlusion of the ostium of a penetrating artery producing a small subcortical (lacunar) stroke, occlusion of multiple penetrators resulting in a large subcortical infarct (such as a striatocapsular stroke), hemodynamic reduction in blood flow with a subsequent watershed stroke, and finally generation of a thrombus on the surface of the plaque with artery-to-artery embolism causing a cortical infarct. Figure 6-1 shows a cortical infarct in a patient with a middle cerebral artery stenosis. Indeed, in the extracranial-intracranial artery bypass surgery trial, 61% of those with middle cerebral artery stenosis had a cortical infarct.7 The role of artery-to-artery embolism in the production of strokes 157

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related to intracranial arterial disease has been confirmed by the finding of microembolic signals during transcranial Doppler (TCD) monitoring of the affected artery. Vessels with microembolic signals tend to be more stenotic and have an increased risk of becoming symptomatic.8

A

The mechanisms of infarction intracranial atherosclerosis are: ❖ ❖ ❖

Penetrating artery occlusion Hemodynamic (“watershed”) ischemia Cortical infarctions from artery-to-artery embolism.

B

C Figure 6-1. A right frontal area of encephalomalacia with surrounding gliosis consistent with a remote infarct is demonstrated on magnetic resonance imaging (A). Magnetic resonance angiography reveals segmental narrowing of the right middle cerebral artery (B), confirmed by catheter angiography (C) where a very proximal M1 segment stenosis and a tandem distal middle cerebral arterial segmental narrowing are noted (arrows).

Intracranial Atherosclerotic Disease

DIAGNOSIS OF INTRACRANIAL ATHEROSCLEROTIC DISEASE

TABLE 6-1. TCD and MRA cutoff parameters to detect ⱖ50% stenosis of large intracranial arteries.

The gold standard method to detect intracranial arterial disease remains conventional catheter angiography. Nonetheless, this procedure is invasive, expensive, and has associated risks.9 Therefore, there is interest in determining the accuracy of available noninvasive tests. The recent Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) study evaluated the role of TCD and magnetic resonance angiography (MRA) in detecting 50% to 99% stenosis of the large intracranial arteries.10 Both TCD and MRA had strong negative predictive values of 86% and 91%, respectively, but the positive predictive values were lower at 36% and 59%. The TCD and MRA criteria for diagnosing 50% to 99% stenosis are outlined in Table 6-1. Data for sensitivity and specificity of computed tomography angiography (CTA) were unavailable from SONIA because of small numbers, but there is information indicating that it has good correlation with angiography, with one report showing a positive predictive value of 93%.11 Therefore, a normal TCD or MRA is a relatively trustworthy indication that there is no significant stenosis, but an abnormal result has a suboptimal predictive value. The relatively low positive predictive value for TCD may be understandable because it is a blind procedure in which the skill of the operator comes into play. The Doppler shift is greatest if the insonation is parallel to the plane of flow; perpendicular

A

159

TCD (mean flow velocity) MCA

100 cm/sec

ICA

90 cm/sec

Vertebral

80 cm/sec

Basilar

80 cm/sec

MRA 50% stenosis or flow gap MRA, magnetic resonance angiography; TCD, transcranial Doppler. (Adapted from Feldmann E, Wilterdink JL, Kosinski A, Lynn M, Chimowitz MI, Sarafin J, et al., Neurology 2007; 68:2099–2106.)

insonation will not detect this Doppler shift and therefore will be unable to detect flow velocity reliably. Figure 6-2 shows an intracranial carotid (cavernous segment) detected by MRA and confirmed by catheter angiography; TCD performed through the orbital window could not detect the increase in flow velocity in this case. However, straight arterial segments may be easier to interrogate by TCD, such as the vertebral, basilar, and M1 segments of the middle cerebral arteries. Figure 6-3 shows a significant basilar stenosis detected by a focal increase in flow velocity on TCD also noted on MRA.

B Figure 6-2. (A) A cavernous segment intracranial carotid stenosis confirmed by catheter angiography (B).

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cm/s

cm/s 340

20

160

18

320 300

140

280

120

260

100

240

80

220 200

60

180 160

40

140

20

120

0

100 80

–20

60

A

–40

40

–60

20

–80

0 8

6

B

Figure 6-3. This patient presented with transient hemianopsia. Transcranial Doppler flow velocity was normal at 60/20 cm/sec (mean flow velocity 33 cm/sec) at 8 cm in depth (A), with increase in flow velocity to 250/100 cm/ sec (mean 150 cm/sec) at 9.4 cm in depth (B). Magnetic resonance angiography (C) reveals significant stenosis with lack of flow enhancement in the junction of the middle and distal third (arrow) of the basilar artery.

If a risky or invasive procedure is planned, then confirmatory conventional angiography is required. However, if medical treatment will not be significantly altered by the test results, it is reasonable to rely on noninvasive diagnostic modalities. As reviewed subsequently, current medical interventions are not optimal, and further research on the valve of revascularization will determine whether it is an effective and safe option; therefore, the relevance of the choice of diagnostic test will be amplified as more therapeutic choices become available.

C

In summary, ❖ TCD, MRA, and CTA are noninvasive methods to detect intracranial stenosis. ❖ TCD and MRA have good negative predictive values (normal in nonstenotic vessels) but less than optimal positive predictive value (abnormal in stenotic arteries) compared with conventional catheter angiography. Early data for CTA is encouraging. ❖ Conventional catheter angiography remains the gold standard for the diagnosis of intracranial stenosis.

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Case Vignette An 84-year-old man presented with vertigo and left hemiparesis. Imaging revealed bilateral upper pontine strokes. MRA showed a flow gap in the distal basilar segment and attenuation of flow in both distal vertebral arteries. The patient was treated with antithrombotics, statin, and antihypertensives. Unfortunately, 3 months

later, he developed a gastrointestinal hemorrhage, hypotension, and new dizziness with worsening left hemiparesis. Angiography revealed occlusion of the mid to upper portions of the basilar artery with filling of the posterior communicating arteries after carotid injections.

A B

C

D

Figure 6-4. Bilateral upper pontine strokes see on diffusion weighted imaging (A) and fluid-attenuated inversion recovery (FLAIR) sequences (B) of the magnetic resonance imaging. The magnetic resonance angiogram (C) showed a flow gap in the distal basilar segment and attenuation of flow in both distal vertebral arteries. Conventional angiography performed 3 months later confirmed revealed basilar artery occlusion; (D) top of the basilar (arrow) is shown filling after the carotid injection through the posterior communicating artery, but the more proximal segment of the basilar artery was occluded.

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MEDICAL THERAPY Symptomatic intracranial arterial disease was, up to recently, commonly treated with anticoagulants. This approach was based on a small case series showing a decrease in mortality in patients with vertebrobasilar symptoms treated with anticoagulants,12 and a subsequent retrospective study of 151 patients treated with either aspirin or warfarin, in which the anticoagulated patients fared better in stroke and death risk.13 Nonetheless, a randomized controlled study was necessary to answer the question adequately. The recently completed Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) study has provided valuable information on the medical treatment of this condition.14 This trial studied patients with a recent stroke or transient ischemic attack (TIA) due to intracranial arterial stenosis (50%–99% reduction of the luminal diameter of a major intracranial vessel) and randomized participants to receive aspirin (1300 mg/d) or warfarin (adjusted to maintain an international normalized ratio of 2–3). There was no difference in the combined primary outcome measure of ischemic stroke, intracerebral hemorrhage, or vascular death between both treatment arms, which occurred at a staggering rate of 22% during the 1.8-year average followup period. Almost two thirds of the events in the combined primary outcome measure were due to recurrent stroke in the territory of the stenotic vessel. Most of the events occurred in the first couple of weeks after randomization. There was a greater than twofold incidence of major hemorrhage or death in the anticoagulated group that led to early termination of the trial. No subgroup of patients in whom warfarin was superior to aspirin was identified.15 Therefore, warfarin appears to be no more effective and riskier than aspirin for secondary stroke prevention in patients with intracranial stenosis. The control of vascular risk factors remains an important aspect of the approach to the patient with intracranial arterial disease. The WASID study demonstrated that greater control of low-density lipoprotein (LDL) to a goal of less than 100 mg/dl reduced the risk of recurrent events. In addition, good control of blood pressure also reduced the risk of stroke recurrence.16 This is important because some clinicians had recommended maintenance of elevated blood pressure to prevent hemodynamic (watershed) events in patients with intracranial disease. The data from WASID show that good blood pressure control, regardless of the degree of stenosis, is indicated for most patients. This recommendation should be individualized, and it does not apply to the very early period after a cerebral ischemic event, but, in general, the Joint National Committee (JNC 7) recommendations for blood pressure management17 should be followed, with no indication to maintain an elevated blood pressure for extended periods of time, except perhaps in the acute period after a stroke.18

WASID also allowed the identification of a group at high risk of recurrent stroke in the territory of the stenotic vessel. High-risk factors included severe stenosis (defined as ⱖ70%), female sex, and enrollment soon after the onset of symptoms.15 The impact of higher degree of stenosis mirrors the experience with extracranial carotid stenosis and is not unexpected. It should be recalled that the large intracranial arteries have a diameter of approximately 3 mm, and thus a 70% stenosis would result in a small residual diameter. Women had an increased risk of stroke recurrence, perhaps because of smaller diameter of their vessels, although hormonal factors might also play a role. The effect of early recruitment into the study as a risk factor for recurrence may be due to recruitment bias, but it is also clear that the early weeks after an event constitute the most vulnerable period. This has led some to suggest that more aggressive antithrombotic therapy for two to four weeks after the stroke might be considered,19 although this approach has not yet been studied in a clinical trial. Interestingly, neither the vessel involved nor the length of the stenosis were shown to predict an increased risk of recurrence. Therefore, anterior circulation and posterior circulation intracranial stenosis should not be viewed differently in regard to risk or treatment considerations. The identification of the high-risk group may permit risk stratification, which would be particularly useful if a risky but effective intervention such as endovascular revascularization became increasingly available. Table 6-2 outlines the risk of recurrence according to degree of stenosis. In summary, ❖

The prognosis of asymptomatic intracranial atherostenosis has not been well defined, but progression is associated with increased risk of stroke. The risk of stroke recurrence after an initial stroke or TIA is approximately 15% in the first year, with most strokes occurring in the territory of the stenotic vessel. Vascular risk factor reduction, particularly LDL and blood pressure reduction, is associated with a decreased risk of recurrence.

❖

❖

TABLE 6-2. Probability of stroke recurrence at 2 years in the territory of the symptomatic vessel in intracranial arterial disease. Risk of recurrence First Event

Stenosis 50%–69%

Stenosis 70%–99%

Stroke

11%

25%

TIA

8%

14%

TIA, transient ischemic attack. (Adapted from Kasner SE, Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, et al., Circulation 2006; 113:555–563.)

Intracranial Atherosclerotic Disease ❖

❖

❖

❖

There is no rationale to maintain an elevated blood pressure during extended periods to prevent stroke recurrence, except perhaps in the acute period after a stroke. Aspirin and warfarin are equally effective in secondary stroke prevention, but anticoagulation is associated with a greater risk of hemorrhage and death. The antithrombotic agents tested to date have been associated with a high risk of recurrence. A high-risk group can be identified: severe stenosis of 70% to 99%, individuals in the first couple of weeks after a cerebral ischemic event, and female sex.

INTERVENTIONAL APPROACHES According to the WASID study, there is a significant risk of stroke recurrence of approximately 15% and of stroke recurrence in the territory of the stenotic vessel of approximately 12% in the first year after the initial symptom, despite antithrombotic therapy in the form of

A

163

aspirin or warfarin.12 This elevated risk has prompted the search for more efficient methods of stroke prevention. Prior surgical interventions such as extracranial to intracranial bypass were unsuccessful in improving outcomes,20 which has led to the consideration of endovascular approaches to treat the stenotic vessel. These interventions include angioplasty and stenting. A number of nonrandomized and controlled series have reported that angioplasty alone is feasible but is often complicated by intimal dissection and plaque disruption, intraluminal thrombus formation, and even vascular rupture.21 Therefore, there is considerable excitement about the use of angioplasty with stenting to avoid these potential complications. The initial experience with stents expanded by balloons at high pressure still raised concerns for plaque disruption and occlusion of penetrating arteries at the level of the stent.21 Technical advances in the stents available and increasing expertise among neurointerventionalists promise to improve outcomes in the near future. Examples of basilar artery and middle cerebral artery angioplasty are illustrated in Figures 6-5 and 6-6.

B

Figure 6-5. This individual presented with right hemiparesis, vertigo, and a right homonymous visual field defect. The diffusion-weighted magnetic resonance imaging (A) shows acute infarcts in the basis pontis and left occipital pole. Brain magnetic resonance angiography shows a basilar artery flow gap suggestive of a significant stenosis (B).

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C

D

E

F

Figure 6-5 cont’d. Cerebral catheter angiography confirmed distal right vertebral and proximal basilar stenosis (C, D) (arrows). Resolution of the basilar stenosis after angioplasty (E, F).

Case Vignette A 74 year old man with dislipidemia and an old right hemispheric stroke due to right middle cerebral artery occlusion presented with spells of transient aphasia and right hemiparesis which recurred in spite of different antithrombotic regimens. Angiography confirmed a high-grade left middle cerebral artery stenosis (Figure 6-6); incidentally, the right middle cerebral artery was occluded. Given the clinical picture and the contralateral middle cerebral artery occlu-

sion, it was decided to proceed with endovascular treatment of the symptomatic lesion. The left middle cerebral artery was treated with angioplasty and stenting with a Wingspan stent with good angiographic results. After the procedure he developed persistent mild aphasia and right hemiparesis. A left capsular infarct in the distribution of the penetrating vessels at the level of the stent was seen on DWI MRI.

Intracranial Atherosclerotic Disease

165

A

B

C

D

Figure 6-6. Three-dimensional angiography showed a high-grade left middle cerebral artery stenosis (arrow) (A). The left middle cerebral artery was treated with angiogplasty and stenting using a Wingspan stent. (B) Radiological improvement after angioplasty and before stent deployment. After the procedure, the patient developed persistent mild aphasia and right hemiparesis. A brain computed tomography scan excluded a hemorrhage but showed the stent in the middle cerebral artery (C). A left capsular infarct in the distribution of the penetrating vessels at the level of the stent was apparent on diffusion weighted imaging (D).

The SSYLVIA study employed a coronary stent in 43 intracranial stenoses with a 30-day risk of stroke in the stented vessel of 6.6% plus a 7.3% subsequent stroke risk for up to 1 year.23 This is actually slightly worse than the risk of stroke with medical therapy.14 These disappointing results led to the development of a new self-expandable stent that presumably causes less plaque disruption. The Wingspan stent was recently approved by the U.S. Food and Drug Administration for intracranial atherosclerotic disease; initial experience with this device has been associated with a 1-year risk of ipsilateral stroke and death of 9.3%.24 It is pos-

sible that this new generation of stents will be helpful for high-risk patients with intracranial arterial disease, but this remains to be proved in a randomized study. In selected cases, many centers are deploying intracranial stents successfully, as illustrated in Figure 6-7. This author believes that, at the present time, intracranial stenting should be reserved for those patients at high risk of recurrent stroke who have failed medical therapy; similar recommendations have recently been put forward.25 Future stent and catheter development, and further evidence about their safety and efficacy, might allow for a more liberal use of this technology.

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B

A

C Figure 6-7. A high-grade right middle cerebral artery stenosis (A) (arrow) was treated endovascularly with a stent (B, arrow). (C) The final outcome with a fully patent stent and no residual stenosis.

In conclusion, ❖

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Endovascular approaches are feasible but can be associated with complications. Self-expanding stents appear to be promising with fewer complications.

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In the absence of randomized studies, endovascular approaches should be reserved for high-risk individuals who have failed medical therapy and should only be deployed by experienced operators. Randomized studies are necessary to assess the efficacy and risk of endovascular interventions.

Intracranial Atherosclerotic Disease

References 1. Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction: the Northern Manhattan Stroke Study. Stroke 1995; 26:14–20. 2. Wityk RJ, Lehman D, Klag M, Coresh J, Ahn H, Litt B. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996; 27:1974–1980. 3. Wong KS, Huang YN, Gao S, Lam WW, Chan YL, Kay R. Intracranial stenosis in Chinese patients with acute stroke. Neurology 1998; 50:812–813. 4. Kappelle LJ, Eliasziw M, Fox AJ, Sharpe BL, Barnett HJM. Importance of intracranial atherosclerotic disease in patients with symptomatic stenosis of the internal carotid artery. Stroke 1999; 30:282–286. 5. Akins PT, Pilgram TK, Cross DT III, Moran CJ. Natural history of stenosis from intracranial atherosclerosis by serial angiography. Stroke 1998; 29:433–438. 6. Arenillas JF, Molina CA, Montaner J, Abilleira S, GonzálezSánchez MA, Álvarez-Sabín J. Progression and clinical recurrence of symptomatic middle cerebral artery stenosis: a long-term follow-up transcranial Doppler ultrasound study. Stroke 2001; 32:2898–2904. 7. Bogousslavsky J, Barnett HJ, Fox AJ, Hachinski VC, Taylor W. Atherosclerotic disease of the middle cerebral artery. Stroke 1986; 17:1112–1120. 8. Gao S, Wong KS, Hansberg T, Lam WWM, Droste DW, Ringelstein EB. Microembolic signal predicts recurrent cerebral ischemic events in acute stroke patients with middle cerebral artery stenosis. Stroke 2004 ;35:2832–2836. 9. Bendszus M, Stoll G. Silent cerebral ischaemia: hidden fingerprints of invasive medical procedures. Lancet Neurol 2006; 5:364–372. 10. Feldmann E, Wilterdink JL, Kosinski A, Lynn M, Chimowitz MI, Sarafin J, et al., and the Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Trial Investigators. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Trial. Neurology 2007; 68:2099–2106. 11. Bash S, Villablanca JP, Jahan R, Duckwiler G, Tillis M, Kidwell C, et al. Intracranial vascular stenosis and occlusive disease: evaluation with CT angiography, MR angiography, and digital subtraction angiography. Am J Neuroradiol 2005; 26:1012–1021. 12. Millikan CH, Siekert RG, Shick RM. Studies in cerebrovascular disease. III. The use of anticoagulant drugs in the treatment of insufficiency or thrombosis within the basilar arterial system. Mayo Clin Proc 1955; 30:116–126. 13. Chimowitz MI, Kokkinos J, Strong J, Brown MB, Levine SR, Silliman S, et al. The Warfarin-Aspirin Symptomatic Intracranial Disease Study. Neurology 1995; 45:1488–1493.

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14. Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, et al., for the Warfarin–Aspirin Symptomatic Intracranial Disease Trial Investigators. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352:1305–1316. 15. Kasner SE, Chimowitz MI, Lynn MJ, Howlett-Smith H, Stern BJ, Hertzberg VS, et al., for the Warfarin–Aspirin Symptomatic Intracranial Disease Trial Investigators. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113:555–563. 16. Chaturvedi S, Turan TN, Lynn MJ, Kasner SE, Romano J, Cotsonis G, et al.; WASID Study Group. Risk factor status and vascular events in patients with symptomatic intracranial stenosis. Neurology 2007; 69:2063–2068. 17. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al.; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560–2572. 18. Adams HP, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. Guidelines for the early management of adults with ischemic stroke. Stroke 2007; 38:1655–1711. 19. Koroshetz WJ. Warfarin, aspirin, and intracranial vascular disease. N Engl J Med 2005; 352:1368–1370. 20. The EC/IC Bypass Study Group. Failure of extracranial– intracranial arterial bypass to reduce the risk of ischemic stroke. Results of an international randomized trial. N Engl J Med 1985;313:1191–1200. 21. Cruz-Flores S, Diamond AL. Angioplasty for intracranial artery stenosis. Cochrane Database Syst Rev 2006; 3: CD004133. DOI: 10.1002/14651858.CD004133.pub2. 22. Jiang WJ, Srivastava T, Gao F, Du B, Dong KH, Xu XT. Perforator stroke after elective stenting of symptomatic intracranial stenosis. Neurology 2006; 66:1868–1872. 23. SSYLVIA Study Investigators. Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA): study results. Stroke 2004; 35:1388– 1392. 24. Bose A, Hartmann M, Henkes H, Liu HM, Teng MM, Szikora I, et al. A novel, self-expanding, nitinol stent in medically refractory intracranial atherosclerotic stenoses: the Wingspan study. Stroke 2007; 38:1531–1537. 25. Hankey GH, Cruz-Flores S, Diamond AL. Angioplasty with or without stenting for intracranial artery stenosis. Stroke. 2006; 37:2858–2859.

Chapter

7

Small Vessel Disease Alejandro A. Rabinstein and Steven J. Resnick

S

mall vessel disease is the less understood of the major mechanisms of cerebral ischemia. This is the case despite its high prevalence in the elderly population, in whom it can present in the form of lacunar strokes, intracerebral hemorrhage, and cognitive decline.1 The seminal work of Dr. C. M. Fisher based on his clinicopathological observations led to the definition of lacunar strokes as small subcortical infarcts measuring between 3 mm and 2 cm and caused by the occlusion of penetrating branches of cerebral arteries.2 He described lipohyalinosis, a hypertensive microvasculopathy, as the main anatomical substrate for the development of lacunar infarctions and also deep cerebral hemorrhages.3 However, he recognized that plaques of atheroma in the parent vessel occluding the origin of the penetrating branch4 and probably microembolism (in patients with structurally normal penetrating branch corresponding to the area of small infarction and a systemic cause of embolism)4 could also produce lacunar strokes. He characterized the classic lacunar syndromes but noted that a number of atypical clinical presentations could also occur. He was then well aware of the

fact that small vessel disease does not constitute a uniform disorder but rather may result from a complex spectrum of conditions with various clinical manifestations. Unfortunately, the conceptualization of lacunar strokes became quite simplified and dogmatic (and therefore untrue) over time. Lacunar infarctions had to manifest with one of the traditional “lacunar syndromes,” they had to be less than 15 mm in size, they only happened in hypertensive patients, and they were always caused by “small vessel disease” (typically understood as lipohyalinosis according to what became known as the “lacunar hypothesis”). However, the advent of brain imaging techniques came to prove that these general assumptions cannot be always applied. First, computed tomography (CT) scan and most recently and especially magnetic resonance imaging (MRI) have reactivated research on this topic by uncovering the real dimension of the intricate disorder we now call small vessel disease to include small subcortical infarctions, microhemorrhages, and white matter changes (also known as leukoaraiosis for the rarefaction of the white matter seen on pathological specimens) (Figure 7-1). 169

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Lacune

Leukoaraiosis

Microhemorrhage

Figure 7-1. The spectrum of small vessel disease.

Longitudinal studies using serial MRI scans are shedding light on the incidence, progression, and severity of cognitive decline in patients with white matter disease. As a consequence, vascular dementia is emerging as a major public health concern.5 Neuroimaging is replacing pathology in the study of the pathophysiology of small vessel strokes, a remarkable indication of progress because small subcortical strokes are not fatal and therefore pathological examinations only allow the examination of chronic lesions. In fact, new theories

defying the preeminence of lipohyalinosis have been postulated to explain the genesis of small subcortical strokes.6,7 Additionally, hemosiderin-sensitive sequences (such as gradient recall echo) allow visualization of areas of microhemorrhage, which were previously impossible to diagnose in vivo.8,9 In this chapter, we attempt to illustrate the contribution of neuroimaging to the understanding of small vessel disease, acknowledging that most is still to be learned in this fascinating field.

SMALL SUBCORTICAL INFARCTIONS

Case Vignette A 78-year-old man with history of hypertension and type 2 diabetes awoke with inability to move his right side. On examination, his blood pressure was 180/98, his pulse was regular, and he had no carotid bruits. He had a dense right hemiparesis with no other associated neurological deficits. Initial CT of scan of the head did not reveal any acute intracranial abnormalities. Brain MRI (Figure 7-2) showed an

acute small subcortical stroke in the posterior limb of the left internal capsule. Carotid ultrasound and cardiac workup were unremarkable. The patient was discharged on antiplatelet therapy, antihypertensives, an adjusted regimen for his diabetes, and a statin. He evolved favorably over the subsequent few months.

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Figure 7-2. Magnetic resonance imaging scan of the brain showing a small subcortical acute ischemic infarction in the posterior limb of the left internal capsule (arrows). Diffusion-weighted imaging and apparent diffusion coefficient map are shown in the upper row. Fluid-attenuated inversion recovery sequence is shown in the lower left. Computed tomography scan 3 days after symptom onset is presented in the lower right.

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Small subcortical infarction is a term that, in our opinion, should be preferred over lacunar infarction when describing findings on brain scans to avoid the pathophysiological implication commonly ascribed to lacunes (i.e., caused by lipohyalinosis). This distinction is pertinent because arterial or cardiac sources of

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embolism are present in 10% to 15% of patients presenting with small subcortical infarctions.10–13 The most common locations of small subcortical infarctions are illustrated in Figure 7-3: putamen, caudate, thalamus, internal capsule, corona radiata, pons, and medulla.

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Figure 7-3. Illustration of the most common locations of small subcortical infarctions. Top row: medullary pyramid (left) and basis pontis (right). Middle row: cerebral peduncle (left) and thalamus (right). Lower row: internal capsule (left) and corona radiata (right). All infarctions are shown on diffusion-weighted imaging sequence of magnetic resonance imaging scan.

Small Vessel Disease ❖

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MRI is the modality of choice for the diagnosis of small subcortical infarctions, especially early after symptom onset.14,15 However, CT scans can also provide useful information to help determine the underlying mechanisms of stroke and the extent of the necessary workup.16 For example, in our experience, when a small subcortical infarction is seen on CT scan in a patient presenting with classical lacunar syndrome and no evidence of atrial fibrillation, the yield of transesophageal echocardiogram is low.17 Diffusion-weighted imaging (DWI) sequence is particularly useful for various reasons: ❖ It allows confirmation of small subcortical infarctions in patients presenting with lacunar syndrome.14,15,18 ❖ It precisely depicts the exact subcortical location of the infarction.19

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It differentiates between small subcortical infarctions and larger striatocapsular infarcts.20 It may identify otherwise unsuspected embolic stroke patterns in up to one third of patients with lacunar presentations.21,22 Sometimes DWI discloses an embolic mechanism by showing coexistent small cortical lesions in conjunction with a small subcortical infarction.10 It identifies acute from chronic subcortical infarctions.23 Small subcortical infarcts seen acutely on DWI can later be visualized on T2-weighted imaging and fluid-attenuated inversion recovery (FLAIR) as well as on CT scan (Figure 7-4). However, timing of the infarctions in patients with multiple subcortical lesions is often possible only by using DWI during the acute phase.

Figure 7-4. Another example of a small subcortical infarction (arrow) presenting with pure motor syndrome, but the images shown were obtained 10 days after symptom onset, thus representing a later phase of evolution of the ischemic lesion. Notice bright signal on diffusion-weighted imaging (top left) with corresponding high diffusion coefficient (increased signal intensity) on the apparent diffusion coefficient map (top right). Fluid-attenuated inversion recovery (lower left) clearly delineates the hyperintense lesion, which is also visible on the T1-weighted sequence as an area of hypointensity (lower right).

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LACUNAR SYNDROMES Case Vignette A 72-year-old obese woman with history of hypertension and metabolic syndrome presented with acute onset of right-sided numbness and weakness. Symptoms had started the day before, but she had not come to the emergency department because they had fluctuated in severity to the point that a few times she felt almost back to normal. However, over the previous 6 to 8 hours before her arrival to the emergency department, her deficits had

become constant. Examination demonstrated right hemiparesis and hypoesthesia without associated cortical signs. Brain imaging confirmed the clinical suspicion that the patient had a small subcortical stroke (Figure 7-5) that had presented with an initially stuttering course. Her deficits improved over the following days, and she had nondisabling residual motor and sensory sequelae 3 months later.

Figure 7-5. Small subcortical infarction in the posterior limb of the left internal capsule (arrow) showing restricted diffusion on diffusion-weighted imaging (top left) and apparent diffusion coefficient map (top right). T2-weighted sequence is shown on the lower left and computed tomography scan on the lower right.

Small Vessel Disease ❖

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The classical lacunar syndromes are the following: ❖ Pure motor hemiparesis ❖ Pure sensory stroke ❖ Sensorimotor stroke ❖ Ataxia hemiparesis ❖ Dysarthria—“clumsy hand syndrome” Traditional lacunar syndromes are reliable predictors of small subcortical infarctions on brain imaging.18,19 The correlation between traditional lacunar syndromes and specific anatomical locations is limited.19 For instance, pure motor hemiparesis can be due to lesions in the posterior limb of the internal capsule, basis pontis, corona radiata, or medial medulla. It is important to recognize that small subcortical infarctions can have atypical presentations, including facial sparing, dysarthria with facial palsy, isolated dysarthria, isolated hemiataxia, horizontal gaze palsy

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(affecting the contralateral III or VI nerves; causing transient internuclear ophthalmoplegia or oneand-a-half syndrome), abulia and paresis of vertical gaze, transient subcortical aphasia, and hemichoreahemiballismus, among many other clinical manifestation.2,24 Neuroimaging is crucial to recognize the site and mechanism of infarction in these cases.24 Certain indistinguishable clinical syndromes can correspond to various mechanisms that can be discriminated with brain imaging. One of the best examples of this situation is illustrated by Figure 7-6. A small subcortical infarction in the basis pontis and a paramedian pontine infarction can have the same clinical manifestations (typically ataxia hemiparesis). However, their radiological appearance reliably differentiates the two and predicts the presence of basilar atherosclerosis in patients with paramedian pontine lesions.

Figure 7-6. Top row: small infarction in the left basis pontis ascribed to penetrating artery disease (diffusion-weighted imaging on the left and T2-weighted sequence on the right, infarction signaled by open arrows). Lower row: left paramedian pontine infarction (shown on T2-weighted magnetic resonance imaging scan on the left, lesion pointed by arrowhead) related to the occlusion of the paramedian penetrating artery due to an atherosclerotic plaque in the basilar artery, as indicated by magnetic resonance angiography (right, solid arrow). Both patients had presented with a combination of right ataxia and hemiparesis.

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Most small subcortical infarctions are actually asymptomatic. However, these silent infarctions are far from benign because their accumulation over

time leads to gait dysfunction, cognitive decline, and eventually dementia.5

STRIATOCAPSULAR INFARCTIONS

Figure 7-7. Fluid-attenuated inversion recovery magnetic resonance imaging showing an example of a striatocapsular infarction (arrows). Notice the extension of the lesion into the corona radiata.

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Striatocapsular infarctions are larger lesions than lacunes and involve the internal capsule and corpus striatum, sometimes extending into the corona radiate (Figure 7-7). They correspond to the territory of more than one and often several penetrating branches. The mechanism may be occlusion of a single common stem from which these branches arise or microatheromatosis of the parent vessel (horizontal segment of the middle cerebral artery). Embolic sources may be encountered slightly more often than in patients with small subcortical infarctions. These infarctions are symptomatic, and atypical subcortical manifestations are common. When differentiating small subcortical infarcts from striatocapsular lesions, one should be mindful that DWI may overestimate the final size of subcortical strokes.25

CAPSULAR WARNING SYNDROME ❖

Small subcortical and striatocapsular infarctions share the distinctive feature that they can present in a “stuttering” fashion, with deficits fluctuating or

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progressing over hours and less often even days before becoming fully established (as illustrated by the case shown in Figure 7-5).26,27 This clinical presentation is not restricted to capsular infarctions and can be also seen in patients with small strokes in other locations, such as the pons.28 Thus brain imaging is necessary to define reliably the topography of the lesion. MRI obtained during the acute phase may demonstrate growth of a lesion on serial DWI and discrepancies between the size of lesions on DWI and FLAIR while clinical deficits are still fluctuating or progressing.29 The pathophysiology of this phenomenon is debated. Intermittent or worsening hypoperfusion in the territory of the penetrating artery, intermittent peri-infarct depolarizations, and endothelial failure with progressive extravasation of blood components have been postulated as possible mechanisms.6,29 The latter hypothesis appeared to be supported by an autopsy study that reported evidence of perivascular edema in lesions resembling “incomplete” lacunar infarctions.30

Small Vessel Disease

MULTIPLE LACUNAR INFARCTIONS

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Figure 7-8. Computed tomography scan of the brain revealing bilateral small subcortical infarctions (arrowheads) and extensive periventricular and deep white matter changes (arrows) in a patient who presented for evaluation of progressive cognitive impairment and dysbasia.

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Multiple bilateral lacunes (Figure 7-8) can produce a fairly characteristic clinical syndrome manifested by executive dysfunction with slowing of mental and motor processes, gait disturbance with small steps, hesitancy and apraxia, and urinary incontinence. Pseudo-bulbar palsy, abulic-apathetic depression, focal motor or sensory deficits, and extrapyramidal signs may also occur. Notably, most but not all patients with multiple discrete lacunes provide a history of recurrent strokes and stepwise decline. Often, patients with severe subcortical ischemic disease tend to have confluent areas of white matter disease (leukoaraiosis) rather than multiple discrete lesions (Figure 7-9). Ischemic white matter disease is a progressive disorder (see Figure 7-9). Progression is greater in the deep white matter and anterior subcortical regions.31 The degree of progression is associated with the initial severity of subcortical ischemic changes and the presence of vascular risk factors.32

Figure 7-9. Multiple examples of patients with worsening degrees of ischemic white matter disease, from isolated discrete lesions to confluent extensive leukoaraiosis, as seen on fluid-attenuated inversion recovery sequence of magnetic resonance imaging.

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Nomenclature is confusing when describing these disorders. Subcortical arteriosclerotic encephalopathy (also known as Binswanger’s disease despite the questionable resemblance of modern descriptions of this condition with the original report by Otto Binswanger in 1894)33 is a commonly used term, but its definition in the literature is far from uniform. Actually, the most accepted pathological and radiological correlate of subcortical arteriosclerotic encephalopathy in more recent classifications is diffuse white matter changes rather than multiple lacunes.34 Pathologically, the most severe cases of multiple lacunar infarctions have been classified as lacunar state (état lacunaire of Pierre Marie). These cases are commonly associated with dementia and for some

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authors constitute the pathological substrate for true multi-infarct dementia. Small subcortical infarctions in the deep gray nuclei appear to correlate much better with cognitive decline than small white matter infarctions.35 We ascribe to the use of the comprehensive term “subcortical ischemic vascular disease”36 to describe the clinicoradiological syndrome involving cognitive decline affecting predominantly executive functions, dysbasia, upper motor neuron signs, and bladder incontinence and associated with multiple lacunar infarctions, more diffuse and confluent white matter changes, or both. In practice, neuroimaging (especially MRI) is crucial in establishing this diagnosis.

SILENT INFARCTIONS, WHITE MATTER DISEASE, AND DEMENTIA Case Vignette A 78-year-old woman with treated hypertension was brought to the neurological consultation by the family because of concerns about cognitive decline. The patient was a retired teacher who had been excellent at multitasking, but over the previous couple of years, she had been noticed to have increasing difficulties performing regular chores at her house. She only acknowledged some

difficulties with concentration. In addition, both she and her family reported worsening gait balance. On examination, the patient had fairly pronounced cognitive problems, particularly on executive functions. Her gait was frankly apraxic. Although she denied ever having had a stroke, MRI of her brain revealed extensive white matter changes indicative of subcortical ischemia (Figure 7-10).

Figure 7-10. Fluid-attenuated inversion recovery sequence of brain magnetic resonance imaging disclosing extensive and confluent white matter hypertintensities in an elderly patient with diagnosis of vascular dementia.

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Silent brain infarctions and white matter changes increase the risk of dementia in the elderly population.5,37 To some degree, the type of cognitive difficulties can be fairly reliably predicted by the location of ischemia on MRI: thalamic infarcts are predominantly associated with memory

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loss and nonthalamic infarcts with psychomotor slowing.5 The volume of white matter hyperintensities (often collectively referred to as leukoaraiosis) on T2weighted or FLAIR sequences of MRI correlate with decreased cognitive performance in populations of

Small Vessel Disease

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nondemented subjects.38 Furthermore, extensive white matter changes have a negative impact on executive performance in patients with documented lacunar strokes,39 and the degree of white matter hyperintensities is independently related to poststroke cognitive decline.40 However, in individual cases, the severity of white matter disease on neuroimaging may not

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correlate with the degree of cognitive and functional deficits. The coexistence of underlying Alzheimer’s disease pathology in patients with more cognitive impairment may explain this apparent discrepancy between radiological and clinical findings.41 The extent of white matter disease is much better visualized with MRI than CT scan (Figure 7-11).

Figure 7-11. Comparison of computed tomography (CT) scan and magnetic resonance imaging (MRI) in a patient with subcortical ischemic changes. CT scan is shown on the top row; notice on the left image the good delineation of a chronic left thalamic lacune, small lesion in the right subinsular region, and decreased attenuation of the white matter surrounding the frontal horns of the lateral ventricles. However, the right image clearly underestimates the degree of white matter disease in the corona radiata, which is much better visualized on the fluid-attenuated inversion recovery sequence of the MRI (lower right).

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It may be important to discriminate the degree of periventricular versus subcortical white matter changes. There is some evidence that periventricular white matter changes may be less detrimental than deep subcortical or more superficial white matter lesions.42 The clinician should always personally review the MRI scan when trying to interpret the contribution

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of white matter changes to the clinical status of a patient. Outside of study protocols applying strict grading criteria, the description of the severity of white matter changes is subjective and often deceiving. White matter hyperintensities are also associated with increased risk of future stroke independently of traditional vascular risk factors.43,44

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MICROHEMORRHAGES

Figure 7-12. Fluid-attenuated inversion recovery sequence showing fairly advanced periventricular and deep white matter disease (left) and gradient recall echo sequence revealing bilateral silent microhemorrhages in the region of the basal ganglia (right, arrows).

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Microhemorrhages, typically asymptomatic and only recognizable using hemosiderin-sensitive MRI sequences (e.g., gradient recall echo (GRE)), can be seen in up to 20% of patients with small subcortical infarctions and white matter changes (Figure 7-12).45,46 The prevalence of microhemorrhages is significantly lower in patients with cortical infarctions.45,46 The presence and number of microhemorrhages correlates with the severity of white matter hyperintensities.45,46 Additionally the association of

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References 1. Benavente O, White CL, Roldan AM. Small vessel strokes. Curr Cardiol Rep 2005; 7:23–28. 2. Fisher CM. Lacunar strokes and infarcts: a review. Neurology 1982; 32:871–876. 3. Fisher CM. The arterial lesions underlying lacunes. Acta Neuropathol (Berl) 1968; 12:1–15. 4. Fisher CM. Capsular infarcts: the underlying vascular lesions. Arch Neurol 1979; 36:65–73. 5. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003; 348:1215–1222. 6. Wardlaw JM. What causes lacunar stroke? J Neurol Neurosurg Psychiatry 2005; 76:617–619. 7. Wardlaw JM, Sandercock PA, Dennis MS, Starr J. Is breakdown of the blood–brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 2003; 34:806–812. 8. Wardlaw JM, Lewis SC, Keir SL, Dennis MS, Shenkin S. Cerebral microbleeds are associated with lacunar stroke defined clinically and radiologically, independently of white matter lesions. Stroke 2006; 37:2633–2636. 9. Kato H, Izumiyama M, Izumiyama K, Takahashi A, Itoyama Y. Silent cerebral microbleeds on T2*-weighted MRI:

10.

11.

12.

13.

14.

15.

microhemorrhages with lacunar strokes has been found to be independent of the presence of white matter lesions.46 Thus, small subcortical infarctions, white matter hyperintensities, and microhemorrhages should be considered part of a spectrum of disorders of the cerebral microcirculation (see Figure 7-1). Clinical expressions may include ischemic strokes, intracerebral hemorrhage, and gradual cognitive decline.

correlation with stroke subtype, stroke recurrence, and leukoaraiosis. Stroke 2002; 33:1536–1540. Ay H, Oliveira-Filho J, Buonanno FS, Ezzeddine M, Schaefer PW, Rordorf G, et al. Diffusion-weighted imaging identifies a subset of lacunar infarction associated with embolic source. Stroke 1999; 30:2644–2650. Mead GE, Lewis SC, Wardlaw JM, Dennis MS, Warlow CP. Severe ipsilateral carotid stenosis and middle cerebral artery disease in lacunar ischaemic stroke: innocent bystanders? J Neurol 2002; 249:266–271. Tejada J, Diez-Tejedor E, Hernandez-Echebarria L, Balboa O. Does a relationship exist between carotid stenosis and lacunar infarction? Stroke 2003; 34: 1404–1409. Arboix A, Padilla I, Massons J, Garcia-Eroles L, Comes E, Targa C. Clinical study of 222 patients with pure motor stroke. J Neurol Neurosurg Psychiatry 2001; 71:239–242. Hommel M, Besson G, Le Bas JF, Gaio JM, Pollak P, Borgel F, et al. Prospective study of lacunar infarction using magnetic resonance imaging. Stroke 1990; 21:546–554. Rajajee V, Kidwell C, Starkman S, Ovbiagele B, Alger J, Villablanca P, et al. Diagnosis of lacunar infarcts within 6 hours of onset by clinical and CT criteria versus MRI. J Neuroimaging 2008; 18:66–72.

Small Vessel Disease 16. Mead GE, Lewis SC, Wardlaw JM, Dennis MS, Warlow CP. Should computed tomography appearance of lacunar stroke influence patient management? J Neurol Neurosurg Psychiatry 1999; 67:682–684. 17. Rabinstein AA, Chirinos JA, Fernandez FR, Zambrano JP. Is TEE useful in patients with small subcortical strokes? Eur J Neurol 2006; 13:522–527. 18. Lindgren A, Staaf G, Geijer B, Brockstedt S, Stahlberg F, Holtas S, et al. Clinical lacunar syndromes as predictors of lacunar infarcts. A comparison of acute clinical lacunar syndromes and findings on diffusion-weighted MRI. Acta Neurol Scand 2000; 101:128–134. 19. Schonewille WJ, Tuhrim S, Singer MB, Atlas SW. Diffusion-weighted MRI in acute lacunar syndromes. A clinical-radiological correlation study. Stroke 1999; 30:2066–2069. 20. Jung S, Hwang SH, Kwon SB, Yu KH, Lee BC. The clinicoradiologic properties of deep small basal ganglia infarction: lacune or small striatocapsular infarction? J Neurol Sci 2005; 238:47–52. 21. Wessels T, Rottger C, Jauss M, Kaps M, Traupe H, Stolz E. Identification of embolic stroke patterns by diffusionweighted MRI in clinically defined lacunar stroke syndromes. Stroke 2005; 36:757–761. 22. Gerraty RP, Parsons MW, Barber PA, Darby DG, Desmond PM, Tress BM, et al. Examining the lacunar hypothesis with diffusion and perfusion magnetic resonance imaging. Stroke 2002; 33:2019–2024. 23. Oliveira-Filho J, Ay H, Schaefer PW, Buonanno FS, Chang Y, Gonzalez RG, et al. Diffusion-weighted magnetic resonance imaging identifies the “clinically relevant” small-penetrator infarcts. Arch Neurol 2000; 57:1009–1014. 24. Arboix A, Lopez-Grau M, Casasnovas C, Garcia-Eroles L, Massons J, Balcells M. Clinical study of 39 patients with atypical lacunar syndrome. J Neurol Neurosurg Psychiatry 2006; 77:381–384. 25. Cho AH, Kang DW, Kwon SU, Kim JS. Is 15 mm size criterion for lacunar infarction still valid? A study on strictly subcortical middle cerebral artery territory infarction using diffusion-weighted MRI. Cerebrovasc Dis 2006; 23:14–19. 26. Steinke W, Ley SC. Lacunar stroke is the major cause of progressive motor deficits. Stroke 2002; 33:1510–1516. 27. Donnan GA, O’Malley HM, Quang L, Hurley S, Bladin PF. The capsular warning syndrome: pathogenesis and clinical features. Neurology 1993; 43:957–962. 28. Benito-Leon J, Alvarez-Linera J, Porta-Etessam J. Detection of acute pontine infarction by diffusion-weighted MRI in capsular warning syndrome. Cerebrovasc Dis 2001; 11:350–351. 29. Staaf G, Geijer B, Lindgren A, Norrving B. Diffusionweighted MRI findings in patients with capsular warning syndrome. Cerebrovasc Dis 2004; 17:1–8. 30. Lammie GA, Brannan F, Wardlaw JM. Incomplete lacunar infarction (Type Ib lacunes). Acta Neuropathol (Berl) 1998; 96:163–171. 31. Sachdev P, Wen W, Chen X, Brodaty H. Progression of white matter hyperintensities in elderly individuals over 3 years. Neurology 2007; 68:214–222.

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32. Gouw AA, van der Flier WM, Fazekas F, van Straaten EC, Pantoni L, Poggesi A, et al. Progression of white matter hyperintensities and incidence of new lacunes over a 3-year period. The Leukoaraiosis and Disability Study. Stroke 2008. 33. Roman GC. On the history of lacunes, etat criblé, and the white matter lesions of vascular dementia. Cerebrovasc Dis 2002; 13(2 Suppl):1–6. 34. Erkinjuntti T, Inzitari D, Pantoni L, Wallin A, Scheltens P, Rockwood K, et al. Research criteria for subcortical vascular dementia in clinical trials. J Neural Transm Suppl 2000; 59:23–30. 35. Gold G, Kovari E, Herrmann FR, Canuto A, Hof PR, Michel JP, et al. Cognitive consequences of thalamic, basal ganglia, and deep white matter lacunes in brain aging and dementia. Stroke 2005; 36:1184–1188. 36. Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui HC. Subcortical ischaemic vascular dementia. Lancet Neurol 2002; 1:426–436. 37. Longstreth WT Jr, Bernick C, Manolio TA, Bryan N, Jungreis CA, Price TR. Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study. Arch Neurol 1998; 55:1217–1225. 38. Au R, Massaro JM, Wolf PA, Young ME, Beiser A, Seshadri S, et al. Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study. Arch Neurol 2006; 63:246–250. 39. Wen HM, Mok VC, Fan YH, Lam WW, Tang WK, Wong A, et al. Effect of white matter changes on cognitive impairment in patients with lacunar infarcts. Stroke 2004; 35:1826–1830. 40. Jokinen H, Kalska H, Mantyla R, Ylikoski R, Hietanen M, Pohjasvaara T, et al. White matter hyperintensities as a predictor of neuropsychological deficits post-stroke. J Neurol Neurosurg Psychiatry 2005; 76:1229–1233. 41. Burns JM, Church JA, Johnson DK, Xiong C, Marcus D, Fotenos AF, et al. White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease. Arch Neurol 2005; 62:1870–1876. 42. Smith CD, Snowdon DA, Wang H, Markesbery WR. White matter volumes and periventricular white matter hyperintensities in aging and dementia. Neurology 2000; 54:838–842. 43. Vermeer SE, Hollander M, van Dijk EJ, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and white matter lesions increase stroke risk in the general population: the Rotterdam Scan Study. Stroke 2003; 34:1126–1129. 44. Kuller LH, Longstreth WT Jr, Arnold AM, Bernick C, Bryan RN, Beauchamp NJ Jr. White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke 2004; 35:1821–1825. 45. Kato H, Izumiyama M, Izumiyama K, Takahashi A, Itoyama Y. Silent cerebral microbleeds on T2*-weighted MRI: correlation with stroke subtype, stroke recurrence, and leukoaraiosis. Stroke 2002; 33:1536–1540. 46. Wardlaw JM, Lewis SC, Keir SL, Dennis MS, Shenkin S. Cerebral microbleeds are associated with lacunar stroke defined clinically and radiologically, independently of white matter lesions. Stroke 2006; 37:2633–2636.

Chapter

8

Uncommon Causes of Stroke Alejandro A. Rabinstein and Steven J. Resnick

I

maging can be invaluable when evaluating patients with stroke of unknown cause. Sometimes it provides the diagnosis, and sometimes clues to guide additional investigations. This chapter illustrates some of the many infrequent causes of stroke and highlights the ways in which neuroimaging can contribute to their identification. For a more comprehensive review on the topic of uncommon causes of stroke, the reader is referred to a monograph edited by Caplan and Bogousslavsky.1 The stroke etiologies and mechanisms described in this chapter are seldom encountered in practice.

Suspicion is often based on clinical presentation, associated semiological signs, or systemic manifestations. Imaging studies may be crucial to confirm previously suspected uncommon causes. But it may also bring into consideration potential causes that had not been entertained in the differential diagnosis until the imaging findings shed new light on the case. Examples of this situation include spontaneous dissections, different forms of vasculitis, CADASIL, and MELAS among others.

CERVICOCRANIAL ARTERIAL DISSECTIONS

Case Vignette A 41-year-old man with history of smoking and amphetamine use presented to the emergency department with acute confusion, right gaze preference, left homonymous hemianopia, left hemiplegia (involving face, arm, and leg) and marked left-sided neglect. Three hours before the onset of these deficits, he had complained of severe headache and had tried to go to sleep. Upon awakening, the neurological deficits were established. Computed tomography

(CT) scan showed a hyperdense sign in the top of the internal carotid and middle cerebral arteries (Figure 8-1, A–B). The patient was emergently taken to the angiographic suite, and a catheter angiogram revealed occlusion of the right internal carotid artery 1.5 to 2 cm beyond its origin (Figure 8-1, E). No revascularization therapy was attempted because of the site of the occlusion, acceptable collateral pathways (the anterior communicating artery and posterior Continued 183

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communicating arteries were open), and because the patient started seizing and had to be rapidly transferred to the intensive care unit for anticonvulsive treatment. His blood pressure was augmented with fluids and vasopressors, but he developed a large stroke in the middle cerebral artery territory, as shown on the magnetic resonance

imaging (MRI) scan performed within 24 hours of admission (Figure 8-1, C–D). He recovered well but was still moderately disabled at 3-month follow-up. At that time, a magnetic resonance angiogram (MRA) showed persistent occlusion of the right internal carotid artery (Figure 8-1, F).

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Figure 8-1. (A) Nonenhanced head computed tomography scan showing a hyperdense vessel sign in the top of the right internal carotid artery (arrow). (B) This sign extends into the horizontal segment of the right middle cerebral artery (arrow). (C) Diffusion-weighted sequence of the magnetic resonance showing a large area of bright signal in the territory of the right middle cerebral artery (apparent diffusion coefficient map showed corresponding dark signal in that region, indicating restricted diffusion from cellular edema due to acute ischemia). (D) Fluid-attenuated inversion recovery sequence shows early signs of cortical ischemia in the right hemisphere. (E) Digital substraction angiography displaying tapering and occlusion of the right internal carotid artery1.5 to 2 cm above its origin (arrow). (F) Magnetic resonance angiography 3 months later demonstrating persistent occlusion of the vessel (arrow).

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Uncommon Causes of Stroke ❖

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Dissections represent one of the most common causes of ischemic stroke in the young (under age 45).2 They should be suspected in trauma patients presenting with focal neurological symptoms or Horner’s sign (due to damage of the sympathetic plexus surrounding the carotid wall). However, many cases occur in the absence of obvious precipitating injury. In fact, in these “spontaneous” cases, it is not uncommon to identify minor trauma or predisposing activities (such as chiropractic maneuvers, roller-coaster rides, certain sports, or other factors associated with sudden or prolonged hyperextension or extension/ torsion of the neck). Abnormalities of connective tissue, particularly elastic fibers, have been documented in ultrastructural analysis of skin biopsies of patients with spontaneous dissections.3 Conditions disrupting the integrity of the connective tissue in the arterial wall predispose to dissection; these include fibromuscular dysplasia (discussed later in the chapter), Marfan syndrome, Ehlers-Danlos type III, and alpha-1 antitrypsin deficiency, among others.4–6 Familial cases have also been reported.7,8

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Headache and neck pain preceding or accompanying the symptoms and signs of brain ischemia should raise suspicion for arterial dissection.9 Most dissections affect the extracranial portions of the internal carotid and vertebral arteries (Figures 8-1 and 8-2). Carotid dissections most often occur 1.5 to 2 cm above the carotid bifurcation (different from atherosclerosis, which characteristically affects the carotid bulb) and usually end at the skull base, before the artery penetrates the petrous bone. Vertebral artery dissections typically affect the V3 segment, originating at the C1–C2 level as the artery leaves the transverse foramen of the axis and makes its turn to enter the intracranial compartment.2,10 Dissections may affect multiple cervical vessels simultaneously in 15% of cases. MRI and MRA of the neck are the best imaging modalities for the diagnosis of cervical artery dissections (Figure 8-3).11–14 CT angiograms are also useful for the noninvasive detection of arterial dissections (Figure 8-4), particularly in the emergency setting.

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Uncommon Causes of Stroke

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Figure 8-2. Illustrations of various cases of arterial dissection involving the carotid (A–C) and vertebral arteries (D–F) as depicted by conventional angiography. (A) Luminal tapering and string sign (arrow). (B) Luminal tapering and occlusion (arrow). (C) Luminal tapering and string sign followed by functional occlusion (arrow). (D) Vertebral artery dissection with pseudo-aneurysm (arrowhead), small intimal flap (open arrow) and double lumen (solid arrow). (E and F) Additional examples of vertebral artery pseudo-aneurysms after dissections (arrows).

Uncommon Causes of Stroke

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Figure 8-3. Examples of arterial dissection diagnosed by magnetic resonance imaging and angiography. (A) Cervical left internal carotid artery tapering and occlusion due to dissection. (B) Axial T1-weighted sequence with fat saturation of the same patient showing a hyperintense crescent sign caused by an eccentric intramural thrombus (arrow). (C) Another example of intramural thrombus seen on fat saturated, T1-weighted axial cuts. (D) Magnified picture of the same finding (arrow).

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Figure 8-4. Diagnosis of arterial dissection by computed tomography angiography (CTA). (A) Computed tomography scan showing a hyperdense left middle cerebral artery sign (arrow). (B) Diffusion-weighted imaging sequence of magnetic resonance imaging showing an area of bright signal on the left striatocapsular region. (C) Apparent diffusion coefficient showing low signal in the same region, thus confirming restricted diffusion from acute infarction. (D) Source images of the CTA showing lack of contrast flow in most of the lumen of the left carotid artery, with a residual eccentric segment of patent lumen (arrow). (E) Three-dimensional reconstruction of the CTA depicting the left carotid dissection causing tapering and occlusion of the lumen (arrow). (F) Isolated CTA of the left carotid artery clearly demonstrating the flamelike dissection and occlusion of the vessel (arrow).

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The angiographic signs of cervical artery dissections are listed in Table 8-1. These changes can be seen on MRA, CT angiography (CTA), or catheter digital subtraction angiography. Angiography of the intracranial vessels allows identification of dissections extending into the intracranial compartment and intracranial pseudoaneurysms (see Figure 8-2). Some consider the presence of these findings a relative contraindica-

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tion for anticoagulation (used by many practitioners to prevent embolic infarctions after dissections, although never formally studied for this particular indication). However, subarachnoid hemorrhage typically occurs at the time of formation of dissecting aneurysms. The risk of this complication subsequently appears to be very low.15 MRI of the neck should include thin cuts of fatsuppressed T1-weighted sequence to allow the

Uncommon Causes of Stroke

TABLE 8-1. Angiographic signs of cervical artery dissections.

upon presentation, this simple test can be used for subsequent monitoring. The most common pattern of ischemia in patients with carotid artery dissection is that of multiple acute brain infarctions (suggestive of embolism), often involving cortical and watershed areas.19 In cases of vertebral artery dissection the pattern of acute multiple brain infarctions also predominates (Figure 8-5), affecting the terminal branches of the basilar artery. More than a third of patients present signs of ischemia in the cerebellar border-zone distribution. Pontine ischemia is less common after vertebral artery dissections than with atherosclerosis of this vessel, and isolated small thalamic infarctions appear to be distinctly uncommon with both mechanisms of large-vessel vertebrobasilar disease.20

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Tapered luminal narrowing (string sign) With stenosis With occlusion

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Pseudo-aneurysm (segmental dilatations) Oval segmental dilatation of the lumen Extraluminal pouch Small dilatation at the end of a string sign Intimal flap* Double lumen High carotid stenosis or occlusion * Usually only seen on catheter angiography but sometimes noted on thin axial cuts of magnetic resonance imaging scans.

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identification of the intramural hematoma (see Figure 8-3). It appears as a hyperintense signal, which may be eccentric (as a crescent) or concentric (as a doughnut), and widens the external diameter of the vessel. This sequence may also permit visualization of an intimal flap (generally seen as a thin, curvilinear, hypointense signal change between the true and a false lumen). Flow void may be normal, narrowed (eccentrically or concentrically), or absent. However, loss of flow void in these cases does not necessarily represent vessel occlusion, because very slow flow may cause signal loss in a patent vessel. There is some evidence that concentric intramural hematomas may be associated with higher risk of brain ischemia, whereas eccentric intramural hematomas might tend to cause more nonischemic clinical signs (such as Horner’s syndrome).16 Catheter digital subtraction angiography may occasionally demonstrate signs of dissection (particularly small intimal flaps) in patients with no definite abnormalities on MRI/MRA of the neck. Thus it may be reasonable to perform catheter angiography in selected cases when the clinical suspicion of dissection is high but the diagnosis could not be confirmed by noninvasive modalities. In these situations, the yield of catheter angiography may be higher for vertebral artery dissections.13 Ultrasound may be useful for the diagnosis and monitoring of extracranial carotid artery dissection. It is reliable to demonstrate the narrowing or occlusion of the vessel lumen (except when its location is too high). Intramural thrombus and intimal flap may occasionally be recognized by their increased echogenicity (but the sensitivity of ultrasound to detect these abnormalities is low).17,18 When stenosis or occlusion was seen on ultrasound

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Figure 8-5. A 35-year-old woman with chronic headaches and neck pain following an automobile accident presented to the emergency department with acute right-sided neck pain, dizziness, dysarthria, and dysphagia. Her neck had been manipulated by a chiropractor the day before. Magnetic resonance imaging showed acute areas of ischemia in the right cerebellar hemisphere, scattered across the territories of the posterior-inferior and anterior-inferior cerebellar arteries (diffusion-weighted imaging sequence [A and B], infarctions signaled by arrows). Magnetic resonance angiography with gadolinium revealed right vertebral artery occlusion in its V3 segment from a dissection (C, arrow). Notice that the distal portion of the V4 segment is filled from retrograde flow. The patient recovered well despite persistent vessel occlusion on repeat imaging 4 months later.

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Uncommon Causes of Stroke

In cases of arterial occlusion, recanalization is possible within the first few weeks, and it may be more common in the vertebral arteries.21 Thus, follow-up imaging is indicated in these patients. We typically recommend repeating imaging of the neck 8 to 12 weeks after a documented dissection with compromise of the vessel lumen. Cervical aneurysms formed as a consequence of arterial dissections tend to be persistent, but their prognosis is benign.22–24

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Intracranial dissections are uncommon. Most commonly affected locations are the V4 segment of the vertebral artery and the supraclinoid carotid artery. Middle cerebral and basilar artery dissections are exceptional. Intracranial dissections may present with subarachnoid hemorrhage, which is not infrequently fatal. Recurrence of dissections are possible, but the risk is low,25–27 particularly after the first two months.28,29

AORTIC DISSECTIONS

Figure 8-6. A 65-year-old hypertensive man presented to the emergency department with complaints of severe chest pain radiating to the back. On examination, he was confused and dysarthric. He had mild left hemiparesis. Aortic dissection was suspected on chest X-ray and confirmed by noninvasive angiography. (A) Diffusion-weighted sequence of brain magnetic resonance imaging revealed bilateral scattered areas of acute ischemia predominantly (but not exclusively) located in the external watershed distributions of both cerebral hemispheres; the pattern was considered most consistent with an embolic shower from a proximal source. (B) Magnetic resonance angiography (MRA) of the aortic arch revealed a large aortic aneurysm with preservation of the cervical branches. (C) Another view of the MRA of the chest showing the double lumen at the level of the aortic arch and descending thoracic aorta (arrow). (D) Axial cut of the computed tomography scan allows clear visualization of the aortic double lumen (arrow). (E) MRA of the abdominal aorta disclosing extension of the dissection and double lumen into the left iliac artery. (F) Axial image of the MRA at the level of the upper renal poles.

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Uncommon Causes of Stroke ❖

Aortic arch dissection may cause ischemic brain infarctions by generating emboli or, most commonly, affecting the cervical arteries. However, this complication is uncommon. Aortic dissection must be suspected in patients presenting with stroke who complain of severe chest pain radiating to the back or the neck. These patients may be hemodynamically unstable. However,

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painless aortic dissections in patients presenting with cerebral ischemia may go initially unrecognized; asymmetric pulses or aortic murmur may be useful clues in these instances.30 The diagnosis of thoracic aortic dissection can be reliably established by noninvasive angiography (MRA or CTA) (Figure 8-6) and even by ultrasound (Figure 8-7).

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The stroke pattern varies according to the mechanism of infarction. Aortic embolism may result in bilateral infarctions (Figures 8-6 and 8-7) and may involve anterior and posterior circulation territories. Extension of dissection may also provoke brain ischemia from artery-to-artery-

Figure 8-7. Another example of stroke caused by aortic dissection. Notice bilateral strokes on fluidattenuated inversion recovery (A) with a right posterior frontal infarction of embolic appearance (arrow) and small areas of ischemia in the internal watershed of both hemispheres (arrowheads). The aortic arch aneurysm was diagnosed by magnetic resonance angiography (B). Ultrasound clearly showed the presence of a double lumen (C and D, arrows).

embolism, but in this case the infarctions will be confined to the territory of the affected cervical vessel. If the dissection causes severe narrowing or occlusion of the cervical vessels, hemodynamic infarctions in watershed distributions may occur.

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Uncommon Causes of Stroke

FIBROMUSCULAR DYSPLASIA

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Figure 8-8. Illustrations of fibromuscular dysplasia on conventional angiography. Notice the string-ofbeads appearance across long segments of cervical carotid and vertebral arteries (A–C, arrows). (D) A case of intracranial involvement with associated stenosis of the M1 segment of the right middle cerebral artery (arrow).

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Fibromuscular dysplasia (FMD) is a systemic arteriopathy involving the craniocervical, splanchnic, and renal vessels. Pathological findings consist of rings of fibrous tissue (from dysplastic smooth muscle) in the tunica media alternating with areas of medial thickening and disrupted elastic lamina. As a result, the lumen has narrower and wider areas along the affected segments, leading to the characteristic angiographic appearance of a “string of beads” (Figure 8-8). FMD predominantly affects the distal extracranial segments of the vertebral and carotid arteries. Intracranial involvement is observed less frequently (Figure 8-8, D), mostly in the petrous and cavernous segments of the internal carotid arteries. The diagnosis may be suspected on Duplex ultrasound but is confirmed by angiography. Although the string-of-beads pattern represents the hallmark of the condition, other presenting features may include relatively long areas of tubular stenosis,

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diverticular dilatations, or fusiform aneurysmatic formations.31 Spontaneous dissections are more common in these patients, and this mechanism constitutes the most solidly proven association with an increased risk of stroke.6,32 Recurrent dissections may occur more commonly in patients with FMD.33 Catheterization of affected vessels should be performed cautiously and only when indispensable because the risk of iatrogenic dissection is elevated in these cases.

DOLICHOECTASIA ❖

Arterial dolichoectasia, a dilatative angiopathy with predilection for intracranial vessels, may affect the carotid and vertebrobasilar systems. Its etiology is unclear, but it has been reported to be associated with traditional vascular risk factors

Uncommon Causes of Stroke

(older age, male sex, hypertension, and history of myocardial infarction), although not with carotid atherosclerosis.34 Intracranial artery dolichoectasia is also associated with enlargement of the descending thoracic aorta, suggesting that the vasculopathy is not restricted to intracranial vessels.35 It can produce symptoms from compression of adjacent structures, ischemia (typically in distributions of penetrating arteries or, in the case of vertebrobasilar dolichoectasia [Figure 8-9] in the

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territory of the posterior cerebral arteries), or rupture with intraparenchymal or subarachnoid hemorrhage.36–40 It has also been associated with increased incidence of pathologically proved small vessel disease.41 Risk of recurrent ischemic infarctions is elevated.40 The diagnosis can be surmised from the dilatated and elongated flow voids on CT and MRI of the brain, but it is confirmed by noninvasive angiographic studies. Conventional angiography is rarely necessary except in cases of hemorrhage.

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Figure 8-9. A 69-year-old man who con-

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sulted for progressive symptoms of brainstem dysfunction. (A) Nonenhanced head computed tomography scan showed marked dilatation of the vertebrobasilar system with calcification of the vessel walls (arrow). (B) Magnetic resonance angiography confirmed the diagnosis of vertebrobasilar dolichoectasia with an associated thrombosed fusiform aneurysm arising from the left vertebrobasilar junction (arrow). (C) Sagittal T1-weighted sequence shows the brainstem compression by the thrombosed aneurysmatic formation (arrow). (D) Axial T2-weighted sequence provides a different view of the compressive vessel dilatation (arrow). (E) Magnified view of the magnetic resonance angiography of the vertebrobasilar system; notice elongation and dilatation of the vessels and faint visualization of the fusiform aneurysm (arrow).

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MOYAMOYA

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Figure 8-10. A 22-year-old woman without history of hypertension who presented with massive intraventricular hemorrhage and left basal ganglia hematoma on computed tomography scan (A). Digital substraction angiography revealed occlusion of the supraclinoid left internal carotid artery with the typical moyamoya pattern of collateralization (arrows) (B and C).

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The term “moyamoya” (which translates from Japanese as “hazy puff of smoke”) identifies an angiographic pattern of collateralization that occurs following progressive, severe narrowing (often culminating in occlusion) of the supraclinoid segments of the internal carotid arteries and proximal branches of the circle of Willis (Figure 8-10). Moyamoya disease is a nonatherosclerotic, noninflammatory vasculopathy that occurs predominantly in patients of Japanese ancestry,42,43 in whom it was initially described. However, it may also affect other ethnic groups.44–49 The etiopathogenesis of moyamoya disease is unknown; occurrence of familial cases argues for a genetic contribution. Japanese cases present in childhood with ischemic infarctions and in adulthood with brain hemorrhages. In Occidental patients, ischemia predominates and, although the natural history of the condition may be more benign than in Asian cases,44 the risk of recurrent ischemic strokes is high.47 Angiographic findings of moyamoya can also be seen in patients with advanced intracranial athero-

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sclerosis, radiation-induced vasculopathy, sickle cell disease, meningitis, systemic vasculitis, and cocaine use.50–53 Although these cases may be classified as moyamoya syndrome or moyamoya phenomenon, they should not be confused with cases of moyamoya disease. The diagnosis is made angiographically. However, brain imaging may suggest the diagnosis by disclosing multiple flow voids in the basal ganglia on CT scan or T1-weighted sequence, appearing as dots that enhance after contrast is administered. Sulci appear bright on FLAIR because of engorgement of pial vessels. Areas of ischemic infarction may be multiple and typically distributed in deep or watershed regions. DWI is helpful in distinguishing acute versus chronic lesions. Hemorrhages tend to be ganglionic or intraventricular (Figure 8-10). Although the diagnosis can be established with noninvasive angiograms, performing catheter digital substraction angiography is advisable to define the extent of the disease with certainty. It allows optimal visualization of the areas of arterial narrowing/

Uncommon Causes of Stroke

occlusion and the collateral arborization (deep lenticulostriate and thalamoperforator vessels, which appear earlier and produce the moyamoya pattern, and transdural connections between external and internal carotid artery branches, which develop later). Digital substraction angiography is indispens-

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able for preoperative planning when surgery is contemplated. It may also disclose the presence of intracranial aneurysms because patients with moyamoya have a higher incidence of these vascular anomalies (in fact, lenticulostriate artery aneurysms can be seen in these patients).54

CADASIL

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Figure 8-11. Various examples

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of patients with different stages of CADASIL seen on fluid-attenuated inversion recovery sequence of magnetic resonance imaging. (A) More scattered distribution of lesions in a less advanced case. (B) Early predominance of involvement of the anterior temporal lobes. (C) Confluent white matter lesions in a more advanced case. (D) Extensive temporal involvement late in the disease.

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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an autosomal dominant disorder caused by a mutation in the NOTCH3 gene. It is characterized by migraines, recurrent strokes, psychiatric symptoms, and rapidly progressive dementia.55 The disease process affects primarily the vascular smooth muscle cells with predilection for the arterioles of the brain. Although the diagnosis requires genetic confirmation, brain imaging is extremely valuable to evaluate this diagnosis. Brain MRI shows multiple subcortical infarctions with diffuse leukoencephalopathy (Figure 8-11), findings that progress over time. Pre-

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dominant involvement of the anterior temporal lobes is characteristic, although lesions are also common in the frontal-parietal white matter and external capsule.56–58 Lesions tend to become confluent over time, particularly in the temporal poles.57 Intracerebral hemorrhages can also occur, although they are very infrequent.59 Microhemorrhages on T2*/GRE sequence are probably more common, especially when patients are also hypertensive and diabetic.60 Electron microscopy examination of skin biopsy specimens searching for extracellular granular osmiophilic material in the tunica media of small blood vessels may also be useful to screen for this disorder.61

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MELAS

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Figure 8-12. Illustrations of diagnostic imaging features of MELAS. (A and B) Typical lesions of MELAS in the parietal, occipital, and temporal cortex on fluid-attenuated inversion recovery (FLAIR) sequence of magnetic resonance imaging (arrows). (C) Another case of MELAS with bright cortical areas on diffusion-weighted imaging (arrows) that corresponded to a normal signal on apparent diffusion coefficient; notice absence of signal abnormalities on FLAIR (D). (E and F) A third patient with diagnosis of MELAS exemplifying the characteristic finding lactate doublet peak on MRS (arrows) despite normal FLAIR appearance.

Uncommon Causes of Stroke ❖

Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is an inherited mitochondrial DNA disorder that manifests with cortical lesions resembling infarctions. However, these lesions extend across vascular territories and exhibit migration over time (they resolve and then recur in the same or different location).62 Lesions are more common in the parieto-occipital regions (including cortex normally perfused by the middle and posterior cerebral arteries) but may involve the temporal lobes and basal ganglia (Figure 8-12, A and B). They are most often multiple, and their size is variable. Initially they show an inflammatory appearance with gyriform swelling and compression of sulci. Subcortical white matter may be involved or spared. On MRI, these acute lesions are bright on DWI (Figure 8-12, C) but often normal on apparent diffusion coefficient (ADC; distinguishing them from true infarctions),63 hyperintense on T2-weighted imaging and FLAIR, and frequently enhance with contrast. GRE rarely shows evidence of microhemorrhage.64

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Angiograms prove absence of arterial narrowing or occlusions and may suggest luxury perfusion. Indeed, perfusion scans confirm the presence of hyperperfusion in the areas of acute involvement.65 As lesions evolve, signs of laminar necrosis may be seen. In the chronic stage, neuroimaging may demonstrate cortical atrophy, atrophy of deep gray nuclei, and multifocal hyperintensities on T2 and FLAIR sequences in the deep white matter and basal ganglia. Multivoxel MR spectroscopy (MRS) is enormously valuable to substantiate the diagnosis of MELAS. Acute lesions have a characteristic lactate “doublet” peak resonating at 1.3 ppm when spectra is acquired with short echo time (TE; 35 msec; Figure 8-12, E) and inversion of the lactate peak when a long TE (136–144 msec) is used.66 MRS abnormalities may precede changes on DWI.67 Neuronal hyperexcitability (often associated with local epileptiform discharges) has been proposed as the underlying mechanism exacerbating energy failure and inducing inflammatory changes and local acidosis followed by neuronal death in the acute brain lesions of patients with MELAS.68,69

REVERSIBLE CEREBRAL VASOCONSTRICTION

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Figure 8-13. A 32-year-old woman who developed severe headache and confusion 2 weeks after delivering her second child. Magnetic resonance imaging showed acute ischemia in the internal watershed distribution of both cerebral hemispheres, as shown on diffusion-weighted imaging (A) and apparent diffusion coefficient (B) (arrows). Magnetic resonance angiography disclosed severe vasospasm on both supraclinoid internal carotid arteries and M1, M2, A1, and A2 segments (arrows) (C). Digital substraction angiography confirmed the diagnosis of severe vasospasm (arrows); right carotid injection shown (D). Symptoms resolved within days and follow-up angiography 2 weeks later was normal.

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This form of angiopathy, often referred to as CallFleming syndrome,70 is caused by transient, reversible vasoconstriction of the arteries of the circle of Willis and their branches.71 It is most commonly encountered in women during early puerperium, but a similar disorder may be observed in late pregnancy. Additional causes of reversible cerebral vasoconstriction include migraine, subarachnoid hemorrhage, drugs (ergot derivatives; sympathomimetics such as decongestants, appetite suppressants, cocaine, and amphetamines; serotoninergic agents such as triptans), and, rarely, carotid endarterectomy.71 However, not all of these conditions may produce vasospasm by the same mechanism; it is very likely that the pathophysiology of cerebral vasospasm after aneurysmal subarachnoid hemorrhage differs substantially from the vasoconstriction seen in postpartum or with migraines.

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Brain imaging typically demonstrates small, multifocal areas of infarction in the posterior head regions or watershed distributions (Figure 8-13, A and B). Sparing of the calcarine cortex and medial occipital lobes differentiates these infarctions from those produced by embolism.72 Perfusion scans may reveal large areas of hypoperfusion. Serial brain imaging may show additional areas of ischemia before the vasculopathy subsides. Angiography indicates the diagnosis by disclosing multifocal areas of arterial narrowing and dilatation during the acute phase (Figure 8-13, C and D) with subsequent resolution (over days or weeks). Large and medium-sized arteries are most often affected. Noninvasive angiographic studies (MRA, CTA) may be useful, but conventional catheter angiography remains the best method to certify the diagnosis. Transcranial Doppler may be used to monitor disease progression.

HYPERCOAGULABILITY

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Figure 8-14. A 42-year-old man with a past medical history remarkable only for an unprovoked deep venous thrombosis in the right leg 2 years earlier presented to the emergency department after an episode of transient left-sided weakness. Examination revealed a left visual field deficit to confrontation. (A) Magnetic resonance imaging showed a right parieto-occipital acute infarction in the middle and posterior cerebral arteries watershed territory (arrow). Magnetic resonance angiography disclosed an occlusion of the right supraclinoid internal carotid artery. Comprehensive stroke workup revealed high titers of anticardiolipin antibodies (immunoglobulins M and IG). Patent foramen ovale was excluded by transesophageal echocardiogram and transcranial Doppler with injection of agitated saline.

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In general, strokes related to thrombophilia do not have a distinctive radiological pattern. In patients with hypercoagulable conditions, brain infarctions may be due to arterial occlusions (mostly embolic,

but thrombosis in situ is also possible) (Figure 8-14) or venous thrombosis. Lesions are often multiple or recurrent and tend not to be restricted to a single vascular territory.

Uncommon Causes of Stroke

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Figure 8-15. Example of multifocal stroke in a patient with thrombotic thrombocytopenic purpura. (A) Fluid-attenuated inversion recovery sequence of magnetic resonance imaging showing bilateral subcortical and left parasagittal cortical strokes (arrows). (B) Peripheral smear revealing the characteristic schistocytes (arrow).

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Thrombotic thrombocytopenic purpura (TTP) is a hematological disorder with multisystemic manifestations that include fever, thrombocytopenia, cutaneous purpura, microangiopathic hemolytic anemia (with formation of schistocytes in the peripheral blood), neurological symptoms, and renal dysfunction. Patients may have headaches, confusion, depressed level of consciousness, seizures, and focal deficits with or without brain infarctions or hemorrhage. TTP may cause strokes by inducing thrombosis or vascular and rheological changes with flow restriction. Thrombosis may cause small subcortical or cortical infarcts (Figure 8-15),73 territorial infarctions, or even massive strokes.74 Compromised perfusion due to intravascular hemolysis and arterial narrowing (which has been documented to be reversible)75 produces watershed infarctions. Apart from brain infarctions, patients with TTP can have reversible radiological changes, often consistent with the pattern of reversible posterior encephalopathy syndrome in patients with severe hypertension and renal failure.76 Extensive brainstem involvement is possible in these cases.77 Reversibility of radiological brain lesions is associated with better prognosis for recovery,78 although small persistent lesions may be seen in patients who recover well.79

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TABLE 8-2. Differential diagnosis of cerebral vasculitis. Primary central nervous system angiitis Susac’s syndrome Cogan’s syndrome Eale’s disease Systemic noninfectious vasculitis Giant cell arteritis Takayasu arteritis Systemic lupus erythematosus Polyarteritis nodosa Microscopic polyangiitis Wegener’s disease Churg-Strauss’ disease Sarcoidosis Beçhet’s disease Infectious vasculitis Bacterial (tuberculosis, bacterial meningitis, syphilis) Viral (VZV, CMV, HIV,* etc.) Fungal (cryptococosis, aspergillosis, mucormycosis, candidiasis etc.) Parasitic (cysticercosis) Radiation Drugs of abuse (cocaine, amphetamines)†

VASCULITIS

Tumors and proliferative disorders‡ Infiltrating angiocentric lymphoma

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Cerebral vasculitis may result from multiple causes. Main categories are primary, autoimmune reactions, infections, and radiation (Table 8-2). Patients with vasculitis may present with ischemic or hemorrhagic strokes but most often have preceding headaches, personality changes, alterations in level and content of consciousness, and signs of meningeal inflammation or increased intracranial pressure.

Lymphomatoid granulomatosis CMV, cytomegalovirus; HIV, human immunodeficiency virus, VZV, varicella zoster virus. * Most cases are related to a small vessel vasculopathy, which does not include major perivascular or intravascular inflammatory infiltrates (hence, not strictly a vasculitis).80 † Many of these cases may be caused by acute, severe vasoconstriction. ‡ Questionable if this truly can be considered within the category of vasculitis.

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Angiograms are the most helpful imaging modality in patients with suspected vasculitis. The distinctive imaging feature of vasculitis cases as a group is the visualization of multifocal areas of segmental luminal narrowing and dilatation (vascular beading). The type, size, and location of the blood vessels involved vary with each specific entity. Brain imaging may show cortical and subcortical ischemic lesions of different sizes and often distributed across different vascular territories. CT scan is relatively insensitive to detect ischemic changes related to vasculitis, but it may show multi-

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focal areas of decreased attenuation in patients with multiple larger infarctions. Its value is much greater in cases with hemorrhage. Contrast enhancement may be seen in some lesions (or the leptomeninges in cases associated with meningitis) after iodine administration. MRI can demonstrate the parenchymal lesions in greater detail. DWI allows discrimination of acute lesions. T2* GRE may show microhemorrhages. Gadolinium-T1 sequence can reveal patchy areas of enhancement.

Primary Central Nervous System Angiitis

Case Vignette A 53-year-old man with history of biopsy-proved primary central nervous system (CNS) angiitis was transferred from another hospital because of recurrent strokelike episodes. His neurological symptoms had started 3 years earlier when he developed severe headaches and some degree of confusion. MRI of the brain showed scattered subcortical lesions, and his cerebrospinal fluid had inflammatory features (125 cells/mm3 with lymphocytic predominance and normal cell morphology, protein level of 112 mg/dl with normal) glucose content. Double substraction angiography (DSA) revealed multifocal irregularities in large and smaller intracranial arteries. Brain biopsy confirmed the diagnosis of CNS vasculitis. Extensive workup for infection, tumor, and systemic vasculitis was negative. The patient was treated with intravenous corticosteroids with good clinical response. He remained asymptomatic on prednisone until 2.5 months before the current hospitalization when he developed acute dysarthria and left hemiparesis. Brain imaging disclosed a new right subcortical stroke, and noninvasive angiography showed increased signs of vasculitis. The dose of

prednisone was increased, but the patient continued to worsen. His attention span declined, and he became more irritable. Over the following 3 months, he had two more episodes of increased dysarthria and incoordination. A third event prompted the hospitalization. MRI of the brain at that time showed a new area of acute ischemia in the right corona radiata (Figure 8-16, A and B). DSA displayed extensive arterial beading in all major intracranial arteries (Figure 8-16, C and D). Despite high-dose intravenous steroids, the patient’s level of alertness worsened over the subsequent week. On the seventh hospital day, he was found stuporous and required intubation for airway protection. He appeared to have a new right hemiparesis. Repeat MRI of the brain showed enlargement of the area of ischemia on the right hemisphere and a new, larger ischemic infarction on the left hemisphere (Figure 8-16, E and F). He was treated with a pulse dose of cyclophosphamide without response. Plasma exchange was also tried unsuccessfully. He became comatose, and after failure to improve over the following 10 days, his family requested withdrawal of life support.

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Figure 8-16. (A) Diffusion-weighted imaging (DWI) sequence of magnetic resonance imaging (MRI) showing an area of acute ischemia in the right corona radiata. (B) Fluid-attenuated inversion recovery (FLAIR) sequence of MRI revealing the acute right hemispheric stroke but also disclosing previous areas of contralateral infarction. (C) Digital substraction angiography (DSA), right carotid injection, illustrating the extensive vasculitic changes (arrows). (D) Magnified view of the same DSA allowing better visualization of the vascular irregularities (arrows). (E) Repeat DWI after major clinical decline showing extension of the area of right hemispheric ischemia with a new, large infarction on the left hemisphere. (F) Repeat FLAIR displaying the extensive bilateral infarctions.

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Primary or isolated CNS angiitis is a rare form of vasculitis that exclusively affects small and middle-sized arteries and veins of the brain, spinal cord, and leptomeninges. Pathological examination most often demonstrates nonspecific mononuclear infiltration of vessel walls associated with variable degrees of granulomatous formation and necrosis. Cases with predominant involvement of small vessels present with severe headaches and encephalopathy. Primary CNS angiitis mainly affecting medium-sized vessels is more likely to present with stroke.81

Figure 8-17. Additional examples of primary central nervous system vasculitis on cerebral angiography. Notice multifocal areas of arterial beading, some indicated by small arrows.

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Brain imaging features are highly variable. Multiple small cortical and subcortical infarctions, often with contrast enhancement, are most characteristic and suggest small vessel inflammation.82,83 Similar lesions may be seen in the spinal cord.82,84 Territorial infarctions indicate medium-sized vessel disease.81 Even benign cases often have abnormalities on brain MRI at presentation.85 Intracranial hemorrhages are uncommon. Digital substraction angiography indicates the diagnosis by showing multifocal stenoses and dilatations (beading or sausage-like appearance) with possible areas of occlusions (Figures 8-16 and 8-17).86

Uncommon Causes of Stroke ❖

Angiograms can be negative in patients with biopsy-proved primary CNS angiitis.86 Conversely, typical angiographic abnormalities may be seen in patients with negative biopsies and proved alternative diagnosis.87 Brain and leptomeningeal biopsy establishes the diagnosis of primary CNS angiitis with certainty when it demonstrates signs of vascular inflammation or necrosis. However, biopsy can be negative in some cases with typical angiographic findings and clear response to immunosuppressants.83 Obtaining the biopsy specimen from abnormal areas on MRI increases the yield of the pathological examination.83 Findings on brain and vascular imaging have prognostic implications. Outcome is worse in patients with cerebral infarctions and large vessel involvement.83 Conversely, patients with prominent

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gadolinium-enhanced brain lesions or marked meningeal enhancement have better prognosis.83,88 The histological pattern of positive biopsy specimens (granulomatous, lymphocytic, or necrotizing) does not appear to determine prognosis.83 However, patients with suspected CNS angiitis but negative biopsy may have a relatively favorable outcome regardless of whether immunosuppressants are used.89 A benign form of primary CNS angiitis has been reported (benign angiopathy of the nervous system)85 characterized by striking angiographic findings but prompt reversibility with less intensive immunosuppression; however, it remains unclear whether this condition truly represents a benign variant of primary CNS angiitis or is rather a different entity altogether (e.g., some of these cases might be a form of reversible cerebral vasoconstriction syndrome) (Figure 8-18).

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Figure 8-18. A 52-year-old woman presented for evaluation of thunderclap headache. Initial computed tomography (CT) scan performed at a local center was reportedly negative, and the patient was prescribed sumatriptan. The headache continued, and she became slightly confused before consulting us for a second opinion. Repeat CT scan of the brain revealed subarachnoid hemorrhage in the left frontal sulci. The hemorrhage was visualized more clearly on the fluid-attenuated inversion recovery sequence of magnetic resonance imaging (A). (B) Digital substraction angiography (DSA) disclosed diffuse arterial irregularities (beading and sausage-like changes). Three-dimensional angiogram allowed optimal depiction of the changes (C). The patient had been recently started on a serotonin-reuptake inhibitor for depression and had smoked marihuana before symptom onset. She had no signs of systemic vasculitis. Cerebrospinal fluid showed elevated red blood cells (1925 cells/mm3) with xanthochromia, mild mononuclear pleocytosis (25 cells/mm3) and elevated protein content (87 mg/dL). A second DSA 1 week later was unchanged. We concluded that it was not possible to discriminate between a benign presentation of primary central nervous system vasculitis and reversible cerebral vasoconstriction syndrome. Brain and meningeal biopsy was contemplated, but instead the patient was treated with prednisone and verapamil for 3 months, at which time the DSA was repeated. The headache subsided over the following 2 weeks. This third DSA showed full resolution of the vascular irregularities. The patient has remained asymptomatic following tapering and discontinuation of prednisone.

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Giant Cell (Temporal) Arteritis

Figure 8-19. A 65-year-old woman with severe headaches, fatigue, early morning stiffness, and jaw claudication presented with recurrent episodes of transient dysarthria, diplopia, and left-arm incoordination. Temporal arteries were hypertrophic and pulseless. Sedimentation rate and C-reactive protein were markedly elevated. Brain magnetic resonance imaging was unremarkable, but magnetic resonance angiography indicated multifocal areas of intracranial stenosis. Illustrative DSA findings are shown. (A) Left vertebral injection, anteroposterior view, revealing severe stenosis of the distal left vertebral artery near its junction with the basilar artery (arrow). (B) Left carotid injection, lateral view, discloses severe areas of stenosis of the supraclinoid carotid artery (arrow). (C) The distal left vertebral stenosis was considered responsible for the patient’s symptoms, and it was treated with angioplasty and stenting with good angiographic result (arrow). After the intervention, the patient did not have recurrent transient ischemic attacks. Treatment with prednisone led to nearresolution of the headache and systemic symptoms.

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Giant cell arteritis (also known as temporal arteritis for its characteristic involvement of the superficial temporal arteries) is a systemic vasculitis of mediumsized and large arteries that affects older adults and elderly patients. The cardinal clinical features of giant cell arteritis are headache, polymyalgia rheumatica, and jaw claudication. Anorexia and malaise are common. The most feared complications are ischemic optic neuropathy, which may result in blindness, and brain infarctions.90 Accelerated sedimentation rate and elevation of Creactive protein strongly support the suspicion of giant cell arteritis. However, temporal artery biopsy is indispensable to make the diagnosis of giant cell arteritis. Typical pathological changes are granulomatous formation (with Langhans giant cells) causing smooth muscle fiber necrosis in the tunica

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media and destruction of the elastic lamina.91 These changes may be segmental; thus small biopsy samples may lead to false-negative results.92 Strokes are most often caused by involvement of the extradural vertebral and carotid arteries; a relative preference for the vertebral arteries is reflected in a greater frequency of occipital and brainstem infarctions. Artery-to-artery embolism and hemodynamic compromise are the most likely immediate mechanisms for the infarctions. Strokes are often multifocal and bilateral. Arterial occlusions are uncommon but may occur.93 Intracranial arteritis is less frequent, but its occurrence has been reported94,95 and is well illustrated by our case (Figure 8-19). Angiography, particularly DSA, can demonstrate lumen irregularities in the most severely involved vessel segments. Special attention should be focused

Uncommon Causes of Stroke

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on the distal extracranial vertebral arteries. Areas of severe stenosis can be treated with angioplasty and stenting (Figure 8-19). Ultrasound (color duplex imaging with frequencies of 5–15 MHz) may be helpful in the diagnosis of temporal arteritis. Indicative findings are the “halo sign” (dark halo around the lumen of the artery likely due to edema of the vessel wall)96,97 and stenosis or occlusion of the temporal artery.97 However, the ultrasonographic results are only

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reliable when examined with the pretest probability of the diagnosis taken into account.97 Ultrasound is best used as a screening test to decide whether to proceed with temporal artery biopsy in suspected cases. Giant cell arteritis is associated with an increased risk for the development of aortic aneurysm.98 Consequently, screening for aortic aneurysms with appropriate imaging studies is advisable in these patients.

SUSAC’S Syndrome

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Figure 8-20. This 36-year-old woman presented for evaluation of subacute headaches, behavioral changes, and cognitive impairment. Six months before, she had been diagnosed with right sudden sensorineural hearing loss. Magnetic resonance imaging of the brain showed multifocal white matter lesions best visualized on fluid-attenuated inversion recovery sequence (A–C, open arrows). Preferential callosal involvement with enhancement is observed on the post-gadolinium sagittal T1-weighted sequence (D, solid arrow).

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This microangiopathic syndrome, first described and most comprehensively delineated by Susac,99,100 manifests with a combination of bilateral sensorineural hearing loss, visual disturbances from retinal artery branch occlusions, and encephalopathy from small brain infarctions (headaches, personality changes, cognitive decline). It is also known as retinocochleocerebral arteriolopathy.101 The disease predominates in young women. Cause is unknown but favorable effects observed after administration of immunomodulatory therapy (steroids, immunoglobulin) suggest an autoimmune (probably inflammatory) mechanism.102 The natural evolution of the disorder is characterized by symptomatic flare-ups followed by remissions over a few years, after which the disease tends to subside. However, delayed manifestations are possible (especially retinal infarctions).103 Brain MRI shows multiple small infarctions in the subcortical white matter characteristically

affecting the corpus callosum (Figure 8-20).104 Central callosal fibers are most vulnerable and lesions may appear linear (spokes) or rounded (snow balls). Additional locations of involvement include cortex and deep gray nuclei. Acute lesions may enhance and exhibit restricted diffusion; chronic lesions are hypointense on T1weighted imaging (referred to as T1 holes). Leptomeningeal enhancement may be seen in up to one third of cases.104

Infectious Vasculitis ❖

Bacterial meningitis rarely causes cerebrovascular complications. Arterial thrombosis may result in cortical infarctions, but cortical vein thrombosis should also be considered in those cases. More proximal branches of the circle of Willis may also be involved with uncontrolled, advanced infection (Figure 8-21).

Uncommon Causes of Stroke

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Figure 8-21. Patient with severe bacterial

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meningitis caused by Staphylococcus aureus who developed right hemiparesis during his hospitalization. (A) Computed tomography scan showing acute ischemic changes on the right temporal lobe (arrow). (B and C) Diffusion-weighted imaging and apparent diffusion coefficient map reveal that the ischemia involves most of the cortical territory supplied by the right middle cerebral artery (arrows). (D and E) Post-gadolinium T1-weighted sequence displays extensive leptomeningeal enhancement with increased uptake in the right insular area affected by the acute stroke. (F) Magnetic resonance angiography discloses severe stenosis of the right supraclinoid internal carotid artery, A1 and M1 segments (arrows). (G) Digital substraction angiography (right carotid injection, frontal view) confirms the arterial stenosis (arrow) (upper corner shows the left anterior circulation with less severe involvement). (H) Lateral view of the right carotid injection illustrating the paucity of filling in the terminal carotid branches.

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may be ischemic or hemorrhagic.105–108 Most ischemic infarctions are located in the territory of multiple penetrating branches (Figure 8-22), and consequently they are better seen on MRI.106 Recurrences occur in most severe cases.107

Central nervous system infection by tuberculosis produces a proliferative and exudative meningitis that preferentially affects the base of the brain. Thus the inflammation may involve the arteries of the circle of Willis, especially in children.105 Strokes

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Figure 8-22. Example of tuberculous meningitis complicated with ischemic infarction. (A) Noncontrast computed tomography scan showing signs of swelling of the right hemisphere, particularly in the insular region (open arrow) and subtle low attenuation changes of the head of the caudate (solid arrow). (B) Diffusion-weighted imaging sequence of the magnetic resonance imaging confirms the suspicion of acute stroke in the right basal ganglia (solid arrow) (apparent diffusion coefficient map demonstrated low diffusion coefficient in this area). (C and D) Axial and sagittal views of the post-gadolinium T1-weighted sequence display marked enhancement in the right Sylvian region (arrows) caused by the meningitis.

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Varicella zoster virus is the most common viral infection causing strokes. Most often, they complicate varicella in children.109 In adults, strokes from varicella zoster virus may be seen more frequently in HIV-infected patients.110,111 Medium-sized

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intracranial vessels are affected by narrowing or occlusion (Figure 8-23). Cryptococcal meningitis may be associated with ischemic infarctions in patients with HIV (Figure 8-24), but this complication is rare.

Uncommon Causes of Stroke

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Aspergillosis is the fungal infection with higher risk of cerebrovascular complications, ischemic and hemorrhagic, which are often devastating112 (Figure 8-25). Transplant recipients are predisposed to develop

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Figure 8-23. A 34-year-old woman with AIDS who presented with acute dysarthria, diplopia, and ataxia. (A) Magnetic resonance imaging scan of the brain showed an acute stroke in the right pons (arrow). Fluidattenuated inversion recovery sequence is shown. Lesion exhibited restricted diffusion on diffusionweighted imaging and apparent diffusion coefficient map. (B) Digital substraction angiography reveals severe stenosis of the vertebrobasilar junction and critical stenosis of the midbasilar artery (arrows). Polymerase chain reaction of the cerebrospinal fluid was positive for VHZ.

Figure 8-24. A 38-year-old patient with AIDS presented with fever, headaches, and confusion. On examination, he had mild left hemiparesis. Magnetic resonance imaging (MRI) scan of the brain revealed a focus of restricted diffusion on the right corona radiata, (A) diffusion-weighted imaging and (B) apparent diffusion coefficient map. Cerebrospinal fluid contained a very elevated protein level, mononuclear pleocytosis, and hypoglycorrhachia. India ink smear and cryptococcal antigen testing were positive, indicating Cryptococcus neoformans infection. Despite treatment with amphotericin B and flucytosine, the patient continued to worsen, became unresponsive, and developed bilateral extensor posturing. Repeat MRI of the brain showed marked extension of the bilateral subcortical lesions (C: fluid-attenuated inversion recovery sequence) with multifocal areas of enhancement (D: T1weighted sequence).

invasive aspergillosis. Direct invasion of the arterial wall by the fungus can be pathologically demonstrated in these cases.113 Hemorrhages may result from aneurysm formation and rupture.

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Figure 8-25. A 56-year-old man with diabetes and previous kidney-pancreas transplantation on long-term immunosuppression developed new headache, malaise, neck stiffness, and dizziness over 3 to 4 weeks. Upon hospitalization to another hospital, he was febrile, and soon after admission he became suddenly hemiparetic on the left side. Computed tomography scan of the brain performed at that time revealed multifocal infarctions. Cerebrospinal fluid had predominantly neutrophilic pleocytosis, and the patient was started on a broad regimen of antimicrobials, including antifungal agents. Nonetheless, the patient continued to worsen and became progressively less responsive, prompting transfer to our institution. On our first examination, he was unresponsive and had right third nerve palsy, absent right corneal reflex, and left hemiplegia. Magnetic resonance imaging of the brain disclosed multiple infarctions, involving the right mid and upper brainstem and cerebral hemispheres. Some of these lesions are illustrated by the fluidattenuated inversion recovery images (A and B). Transesophageal echocardiogram did not shown any vegetations. Digital substraction angiography revealed changes suggestive of vasculitis with occlusion of the right superior cerebellar artery (C, arrow) and irregularities in several arterial segments, including the supraclinoid right internal carotid artery (D, arrow). A sample from a sphenoid sinus biopsy contained abundant hyphae, and Aspergillus fumigatus grew from the cultures of the material. Despite aggressive antifungal therapy, the patient remained comatose and subsequently developed bilateral extensor posturing. Repeat computed tomography scan showed massive hemorrhagic lesions with hydrocephalus (E and F). Family requested withdrawal of life support. Brain necropsy confirmed the diagnosis of invasive aspergillosis with widespread vascular invasion and destruction (G and H).

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HIV VASCULOPATHY

Figure 8-26. A 34-year-old man

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with HIV infection and no vascular risk factors was brought by a friend to the emergency department 1 day after acute onset of slurred speech and difficulty controlling his left arm. He denied recreational drug use, and his toxicological screen was negative. On examination, he exhibited dysarthria, perseveration, and apraxia of the left arm. (A) Computed tomography scan of the brain revealed a right caudate infarction (arrow). (B) Brain magnetic resonance imaging scan confirmed the ischemic lesion but also showed an aneurysm in the anterior communicating artery region (arrowhead). (C) Magnetic resonance angiography of the intracranial circulation disclosed only possible narrowing of the right A1 segment (arrow) and the incidental, small saccular anterior communicating artery aneurysm (arrowhead).

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Severely immunodepressed HIV-infected patients often have strokes related to uncommon mechanisms, including infectious vasculitis (from concurrent opportunistic infections) and hypercoagulability.111 In addition, HIV-infected patients may develop subcortical areas of ischemia from disease involving the microcirculation in the absence of traditional vascular risk factors (Figure 8-26).80 Accelerated atherosclerosis might also occur in patients treated with highly active antiretroviral therapy (especially with regimens containing protease inhibitors) who develop metabolic syndrome.80 However, the impact of this potential complication on the stroke risk of the HIV population remains to be established. Pathological studies have shown the presence of small vessel wall thickening, perivascular space dilatation, rarefaction and pigment deposition with vessel wall mineralization, and occasional perivascular inflammatory cell infiltrates without definitive

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evidence of vasculitis.114 This form of vasculopathy could represent the structural substrate to explain the impairment in cerebrovascular reactivity that has been documented in HIV-infected patients.115 Histologically proved cases of isolated central nervous system vasculitis in HIV-infected patients without opportunistic infectious or tumors are rare; the pathogenic role of HIV in these patients has not been clarified.116 A form of cerebral aneurysmal arteriopathy has been observed in the major vessels of the circle of Willis of HIV-infected children.117–119 These aneurysmal dilatations are seen in conjunction with medial fibrosis, intimal hyperplasia, and vascular occlusion, leading to areas of infarction. Inflammation involving the vasa vasorum and leading to vessel wall ischemia120 and transendothelial migration of HIV-infected monocytes121 have been quoted as potential mechanisms for the production of these aneurysms.

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RADIATION-INDUCED VASCULOPATHY

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Figure 8-27. A 62-year-old woman consulted for evaluation of recurrent episodes of sudden, transient gait imbalance. The duration of the spells ranged between a few minutes and close to 1 hour. She had undergone craniocervical radiation 7 years before for treatment of nasopharyngeal carcinoma. Her vascular risk factors were previous smoking and treated hyperlipidemia. Brain magnetic resonance imaging scan revealed only a chronic small cerebellar infarction and scattered small areas of T2 hyperintensity in both cerebral hemispheres. Magnetic resonance angiography (MRA) of the neck (A) showed stenosis of the proximal cervical left vertebral artery (short arrow), severe stenosis of the midcervical left vertebral artery (long arrow), and a diminutive right vertebral artery throughout its course. MRA of the intracranial circulation (B) showed severe tapering of the basilar artery (arrow). There were also less severe changes affecting the distal cervical and petrous segments of both carotid arteries. MRA of the head and neck preceding radiation therapy proved that all the areas of stenosis had developed since that time.

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Radiation therapy to the neck and head can damage cervical and intracranial vessels, producing luminal stenosis and ischemia.122–124 Accelerated atherosclerosis is responsible for this complication.123,125 The interval between radiation and onset of ischemic symptoms is typically several years.125,126 It is therefore prudent to monitor patients who have undergone neck radiation with periodic carotid ultrasounds.127 Radiation-induced vascular lesions tend to be long and multiple. Tandem lesions and multiple vessel involvement are commonly seen (Figure 8-27). Moyamoya syndrome may develop in patients with severe intracranial carotid disease after radiation of brain tumors at a young age.124,126 Brain infarctions may be caused by arterial-arterial embolism or hemodynamic insufficiency due to critical stenosis or occlusion. Territorial or borderzone infarctions predominate, but small subcortical strokes can also be seen in these patients. History of radiation is an important factor when counseling patients with carotid disease. Carotid endarterectomy is associated with higher risk of complications (stroke, cranial nerve injury, restenosis, wound infection) in patients with radiation -induced vasculopathy.128 Fibrosis obliterating the surgical plane, long lesions exceeding the usual parameters of endarterectomy, and poor tissue healing may explain this increased risk. Thus carotid stenting has been proposed as a valuable alternative in these cases.129 However, late symptomatic occlusions may occur after stenting,130 and treated patients must be monitored rigorously after the procedure.

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STROKES FROM SUBSTANCE ABUSE

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C Figure 8-28. A 46-year-old man was brought to the emergency department by a friend because of frank behavioral changes. He appeared intoxicated and was quite restless. He could not move the legs to command. (A) Computed tomography scan showed bilateral frontal infarctions with a small hemorrhagic component on the left side. (B) Magnetic resonance imaging confirmed bilateral frontal strokes as illustrated by the fluid-attenuated inversion recovery sequence. (C) Magnetic resonance angiography of the brain showed vasospasm of both anterior and middle cerebral arteries. Toxicological screen was positive for amphetamines.

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Intracranial vasculitis from abuse of cocaine or amphetamines is not infrequently suspected on the basis of angiographic changes. However, histologically confirmed cases are rare in the literature.131–136 Most cases may actually be due to acute, severe (reversible) cerebral vasoconstriction (Figure 8-28).133,137,138

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Ischemic and hemorrhagic strokes may occur, and they may also coexist. Every vascular distribution may be involved, and strokes may affect cerebral hemispheres, cerebellum, spinal cord, and retina.

214

Uncommon Causes of Stroke

SICKLE CELL DISEASE

Figure 8-29. A 14-year-old African American girl with documented sickle cell disease since childhood and poor compliance with exchange transfusions presented with exacerbation of previous left-sided weakness due to a recurrent stroke in the margin of a previous ischemic lesion. (A) Diffusion-weighted imaging showing a small, bright signal identifying the new ischemic lesion (arrow). (B) Fluid-attenuated inversion recovery sequence showing the chronic bilateral areas of ischemia following a watershed distribution. (C) Magnetic resonance angiography displays poor visualization of major intracranial branches at the level of the circle of Willis; notice the formation of moyamoya collaterals (arrow). (D) Transcranial Doppler disclosed very elevated blood flow velocities in the right M1 segment.

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A

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Sickle cell disease (SCD) is a major cause of stroke in children and adolescents. The risk is much higher in children homozygous for the sickle cell gene mutation (SCD-SS).139 Ischemic strokes predominate in childhood and intracerebral hemorrhages in young adults.139 SCD may produce ischemic infarctions by various mechanisms, including vasculopathy of cervical or major intracranial vessels. Compromise of blood in large intracranial vessels may induce a form of moyamoya syndrome (Figure 8-29).140 Patients with moyamoya collaterals have increased risk of recurrent strokes.140 Location and size of the infarctions are also variable.141 Territorial infarctions tend to affect preferentially the middle cerebral artery distribution, but any territory may be affected. Border-zone infarctions can also occur. Small deep ischemic strokes are quite common in the basal ganglia and deep white matter. Border-zone and small infarctions are often asymptomatic. The prevalence of these silent brain lesions on brain MRI exceeds 20% in SCD populations.142

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Finding on TCD of time-averaged mean blood flow velocities greater than 200 cm/sec in the internal or middle cerebral arteries predicts markedly increased risk of stroke (Figure 8-29).143,144 Thus TCD monitoring is advisable in children with SCD, especially if they have anemia, high percentage of sickle hemoglobin, high white blood cell count, hypertension, evidence of brain lesions on imaging scans, or history of chest crisis.139,142 The degree of elevation of blood flow velocities should guide the intensity of TCD monitoring (i.e., shorter intervals between studies in patients with higher velocities).145 Periodic blood transfusions to maintain the sickle hemoglobin less than 30% of the total hemoglobin are effective in reducing the risk of stroke in patients with elevated TCD velocities.144 Chronic transfusions are necessary. Consequently, iron overload and alloimmunization are important transfusion-related risks. Unfortunately, discontinuation of periodic transfusions guided by improved results on TCD monitoring was not found to be a safe practice.146,147

Uncommon Causes of Stroke

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Uncommon Causes of Stroke 138. Kaufman MJ, Levin JM, Ross MH, Lange N, Rose SL, Kukes TJ, et al. Cocaine-induced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA 1998; 279:376–380. 139. Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998; 91:288–294. 140. Dobson SR, Holden KR, Nietert PJ, Cure JK, Laver JH, Disco D, et al. Moyamoya syndrome in childhood sickle cell disease: a predictive factor for recurrent cerebrovascular events. Blood 2002; 99:3144–3150. 141. Adams RJ, Nichols FT, McKie V, McKie K, Milner P, Gammal TE. Cerebral infarction in sickle cell anemia: mechanism based on CT and MRI. Neurology 1988; 38:1012–1017. 142. Adams RJ. Stroke prevention and treatment in sickle cell disease. Arch Neurol 2001; 58:565–568.

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143. Adams R, McKie V, Nichols F, Carl E, Zhang DL, McKie K, et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med 1992; 326: 605–610. 144. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998; 339:5–11. 145. Wang WC. The pathophysiology, prevention, and treatment of stroke in sickle cell disease. Curr Opin Hematol 2007; 14:191–197. 146. Adams RJ, Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med 2005; 353:2769–2778. 147. Hankins JS, Fortner GL, McCarville MB, Smeltzer MP, Wang WC, Li CS, et al. The natural history of conditional transcranial Doppler flow velocities in children with sickle cell anaemia. Br J Haematol 2008; 142:94–99.

Chapter

9

Spinal Cord Infarction Alejandro A. Rabinstein and Steven J. Resnick

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pinal cord infarction remains the less well-studied form of acute ischemic stroke. Although several useful studies describing the clinical and radiological features of spinal cord infarction have been published and the characteristics of the presenting syndrome are fairly well known, its risk factors (apart from aortic dissection and aortic surgery), area of maximal cord involvement, and prognosis are insufficiently understood. Furthermore, it remains a condition with no proven effective treatment. Magnetic resonance imaging (MRI) allows documentation of spinal cord infarction. However, the true sensitivity of MRI for the early diagnosis of spinal cord ischemia is not well established. Imaging the cord is also important to exclude other causes of acute spinal cord syndrome such as cord compression (from displaced discs, epidural hematomas or abscesses, intradural extramedullary tumors, etc.), spinal cord hemorrhage, dural arteriovenous fistula, multiple sclerosis, neuromyelitis optica, infectious myelitis (e.g., West Nile virus), transverse myelitis (most often negative on early imaging), spinal cord contusion, or intramedullary tumors.1–3 MRI cannot be replaced by any other imaging modality for assessment of spinal cord infarction and exclusion of its differential diagnoses.

VASCULAR ANATOMY OF THE SPINAL CORD The spinal cord is supplied by three main arteries: the anterior spinal artery and the two smaller posterior spinal arteries. The anterior spinal artery is located along the ventral midline of the cord and supplies the anterior two thirds (often closer to the anterior 75%) of the cord tissue. The posterior spinal arteries lie on each side of the posterior aspect of the cord and supply its posterior third (or 25%). Thus the anterior, central, and lateral regions of the cord are irrigated by the anterior spinal artery and the dorsal horns and columns receive blood from the ipsilateral posterior spinal artery. An internal watershed area can be found in the central cord between small penetrating branches from the anterior and posterior spinal arteries. Branches from the three spinal arteries encircle the surface of the cord forming a fine pial plexus with multiple anastomosis (known as the vaso corona). The anterior spinal artery receives blood from the vertebral arteries in the cervical region and from radicular arteries in the thoracic and lumbar regions. Often two branches arising from each vertebral artery join at the upper cervical level to form the anterior spinal artery; however, many anatomical variations exist 221

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and these branches may arise from the posterior inferior cerebellar arteries or from cervical segmental branches. Just a few radicular arteries are responsible for the blood supply to the spinal arteries at the thoracolumbar level. They stem from segmental branches of the aorta (posterior intercostal and lumbar branches), which reach the intervertebral foramina and divide into the anterior and posterior radicular arteries. The largest radicular artery is the arteria radicularis magna of Adamkiewicz (or main anterior radicular artery), which most commonly arises on the left from T9 to T12

but occasionally can be positioned on the right (17% of cases) and arise anywhere from T5 to L4. Between the lower cervical and the mid- to lower thoracic levels, there are usually just two or three small radicular branches supplying this long segment of the cord. Hence the midthoracic area is traditionally considered a watershed territory at high risk for ischemia from hypoperfusion.4,5 Yet most cases of documented spinal cord ischemia do not occur in this area.6–8 Figures 9-1 and 9-2 illustrate the normal vascular anatomy of the spinal cord.

Anterior sulcal artery

Vertebral artery

Posterior spinal artery Posterior medullary artery

Cervical radicular artery

Anterior radicular artery Posterior radicular artery Cervicothoracic T1

Anterior spinal artery

Great radicular artery

Aorta Intercostal artery T11 T7 Thoracic radicular artery

Radicularis magna (artery of Adamkiewicz)

Aorta Thoracolumbar

Figure 9-2. Axial view of the normal vascular anatomy of the spinal cord. L1

Sacral S1

Figure 9-1. Longitudinal view of the normal vascular anatomy of the spinal cord.

Intercostal artery T12

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Case Vignette A 52-year-old woman with history of ovarian cancer in remission and no previous vascular disease presented with sudden onset of bilateral leg weakness. She had acute back pain initially, but it was short lasting. There was no loss of sphincter control. In the emergency department, she had flaccid paraplegia and leg areflexia. On sensory examination, she had decreased superficial pain and temperature sensation in both legs, but there was no sensory level detected in the trunk. Proprioception was normal. Computed tomography (CT) angiogram of chest and abdomen excluded aortic dissection but disclosed diffuse atherosclerotic changes throughout the descending aorta.

MRI of the thoracolumbar spine revealed changes consistent with acute spinal cord ischemia from T11 to the tip of the conus medullaris (Figure 9-3). She was treated with interventions to optimize blood pressure, intravenous dexamethasone, and lumbar drainage. Over the following 48 hours, her sensation in the legs became nearly normal, but she only regained minimal motor function (some activation of hip flexors). She developed signs of neurogenic bladder and bowel. Comprehensive vascular evaluation uncovered no other mechanisms for the spinal cord ischemia other than aortic atherosclerosis. Three months later, her neurological condition remained unchanged.

Figure 9-3. Magnetic resonance imaging (MRI) scan of the thoracolumbar spine showing signs of acute spinal cord ischemia. Sagittal T2 fast spin echo sequence (upper left panel) demonstrates hyperintense signal and cord enlargement in the affected area (T11 to conus). Axial cut at the T12 level shows high signal intensity in the territory of the anterior spinal artery, more prominent in the ventral gray matter (upper right panel). Diffusion-weighted imaging (DWI) confirms the acuity of the lesion by revealing diffusion restriction (lower left panel). Post-gadolinium T1 fat-saturated sequence shows modest enhancement of the lesion on a repeat MRI scan 5 days after the onset of deficits (lower right panel).

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The presentation of spinal cord infarction depends on the underlying cause, the level of ischemic injury, and the extent of the infarction. Multiple risk factors and etiologies have been associated with the occurrence of spinal cord ischemia.2,4 Aortic disease (atherosclerosis, dissection) and aortic surgery (repair of thoracoabdominal aortic aneurysm) are the most common causes of spinal cord ischemia.4–9 Severe hypotension, especially that due to cardiocirculatory arrest, may also produce spinal cord ischemia,4,7,8 but this complication is infrequent. Presence of multiple vascular risk factors (hypertension, smoking, hypercholesterolemia, diabetes mellitus, previous vascular events) appears to increase the risk of spinal cord infarction.6,7 Many cases remain classified as cryptogenic.4,6–9 Anterior spinal artery infarction, exemplified by the previous vignette, is the most frequent form of spinal cord ischemia.4,6,7,9 It typically presents with sudden flaccid paralysis (paraplegia or quadriplegia according to the level of the lesion), areflexia, loss of spinothalamic sensory modalities (pain and temperature), and autonomic deficits (such as atonic urinary bladder, paralytic ileus, and abolished sphincter tone) below the level of the lesion.4 Posterior column sensory modalities (vibration and proprioception) are preserved, resulting in dissociated sensory loss. Back or radicular pain may be severe at the site of infarction, but this is an inconsistent symptom. After the phase of acute spinal shock, pyramidal signs (spasticity, hyperreflexia, Babinski signs, clonus) supervene. Other clinical syndromes are encountered more infrequently. Posterior spinal artery territory infarction causes selective loss of proprioception or of all sensory modalities (due to dorsal horn involvement) with relative preservation of motor function.10 Deficits are often asymmetric. Posterior spinal artery ischemia is uncommon because of the extensive collateral network in the dorsal cord. Transverse cord infarction presents with flaccid weakness, and loss of all sensory modalities and autonomic control below the level of the lesion. Local pain or hyperesthesia is often reported at the level of the infarction. When unilateral or asymmetric, it may resemble the BrownSequard syndrome. This pattern of infarction is seen after severe systemic hypotension or spine trauma. Similar causes may result in centrospinal infarction, which affects the cord gray matter and manifests with persistent lower motor neuron weakness and dissociated loss of pain and temperature in a segmental distribution. When the injury is partially reversible (often seen with trauma), the legs recover motor function and the arms remain weaker distally more than proximally in a pattern that is often referred to as “man-in-the-barrel” syndrome.

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Ischemia most often involves the thoracolumbar region, followed by the cervical area (often in its higher portion).6–8 Contrary to what would be expected on the basis of purely anatomical grounds, the epicenter of the infarction is rarely in the midthoracic region. MRI signs of spinal cord ischemia are best seen on T2-weighted sequence. It shows “pencil-like” hyperintensities on sagittal views, often associated with cord enlargement (see Figure 9-3, upper left).8 Preferential involvement of the ventral gray matter often gives the appearance of “owl eyes” on axial views (see Figure 9-3, upper right).2,11 Changes may be asymmetric, but they are typically bilateral.8 Increased bone marrow signal may indicate concurrent bone infarction.12,13 T1-weighted images are rarely diagnostic. When visible, lesions have decreased signal intensity. Subtle hemorrhagic components have been infrequently reported.8 Enhancement on post-gadolinium images may appear early but are most commonly visible a few days after the onset of symptoms (see Figure 9-3, lower right). Diffusion-weighted imaging (DWI) may be a valuable addition to T2-weighted sequence in the detection of acute spinal cord ischemia (see Figure 9-3, lower left). In most cases with restricted diffusion, T2 hyperintensities are also seen,14 but a few cases with diffusion abnormality in the absence of T2 changes have been reported.15,16 The shortest interval between onset of symptoms of spinal cord ischemia and documented diffusion abnormalities reported thus far has been 3 hours (later than in brain ischemia). Pseudo-normalization of the apparent diffusion coefficient (ADC) occurs after only 7 days (earlier than in brain ischemia).17 Multishot, interleaved echo planar imaging may be less susceptible to image distortion and offer better spatial resolution than single-shot echo planar imaging and fast spin echo DWI.14,18,19 The sensitivity of MRI for the diagnosis of spinal cord ischemia is not well established. In a consecutive series of 54 patients with acute spinal cord syndrome who underwent MRI within 45 days of symptom onset (median, 1 day), imaging was diagnostic in only 45% of cases.7 However, DWI was obtained in only five of the patients, and many of the cases included in this series had mild deficits at presentation. In another study of 28 consecutive patients examined with MRI (not including DWI) within 10 days of clinical onset, MRI was diagnostic in 24 cases (86%).6 Delayed MRI remained negative even after contrast administration in the four cases with lack of ischemic changes on initial MRI. Other published series did not examine patients consecutively, and therefore selection bias could explain the high sensitivity of

Spinal Cord Infarction

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MRI in these reports.8,9,14,16 In our experience, the sensitivity of MRI is often seriously compromised by motion, pulsatility, and susceptibility artifacts. Angiography is usually not performed in patients with suspected or documented spinal cord ischemia, unless it is presumed to be related to a vascular malformation (dural arteriovenous fistula). Selective

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catheterization of radicular arteries is technically difficult and may be complicated with vessel injury or occlusion. Noninvasive angiography (most often magnetic resonance angiography) is sometimes used to exclude concomitant vascular anomalies,20 but the diagnostic accuracy of this study remains undetermined.

Case Vignette A 74-year-old man with history of severe peripheral vascular disease requiring bilateral iliac-to-femoral artery bypass surgery was admitted to the hospital for surgical repair of an enlarging thoracoabdominal aneurysm. A cerebrospinal drainage catheter was inserted before the initiation of the vascular surgery. The surgery was completed without apparent complications. However, following surgery the patient was noticed to be paraplegic. Neurological examination showed dense flaccid paraparesis with minimal movement of the toes as the only preserved motor function. No definitive sensory level was noted. MRI of the spine

on postoperative day 2 was severely limited by motion artifact. A repeat MRI of the spine obtained 10 days after surgery (Figure 9-4) confirmed the presence of spinal cord infarction extending from T10–11 to the conus. The patient experienced no neurological recovery and was discharged 2 weeks later with persistent paraplegia, neurogenic bladder and bowel, and medications to control his severe back pain. He died 2 months after discharge in a nursing home from suspected pulmonary embolism (his preventive regimen of anticoagulation had been stopped after an episode of melena).

Figure 9-4. Sagittal T2-weighted fast spin echo sequence showing high-intensity signal extending from T10–11 to the conus; severe scoliosis only allows partial visualization of the length of the thoracic cord (left panel). Axial cut demonstrates predominant involvement of the anterior cord (right panel).

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Postoperative paraplegia from spinal cord ischemia is a well-recognized complication of thoracic aortic surgery, with an incidence between 10% and 30% depending on the type and emergency of the surgery.5,21 Preoperative spinal angiography, intraoperative evoked potentials, and perioperative use of lumbar drains may decrease the risk of spinal cord ischemia.5,21–24

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Cerebrospinal fluid drainage is the best studied strategy for the prevention of paraplegia after surgical repair of thoracic and thoracoabdominal aneurysms. In a meta-analysis of randomized controlled studies and cohort studies with a control group, the pooled odds ratio for development of paraplegia in the cerebrospinal drainage group was 0.3 (i.e., 70% reduction in the risk of the neurological complication).21 Cerebrospinal fluid drainage can be

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combined with other preventive strategies such as regional spinal cord hypothermia with epidural cooling,25 administration of naloxone,22 or distal aortic perfusion.24 Extended duration of cerebrospinal fluid drainage (for up to 100 hours) may confer additional protection.23 Hemorrhagic complications related to the placement of the lumbar drain may occur rarely, and they may be extremely difficult to recognize promptly.26 When patients are paraplegic upon awakening following aortic surgery, MRI can confirm the diagnosis in a timely manner and allow for adequate management of blood pressure to maximize perfusion to the cord.

MANAGEMENT AND PROGNOSIS ❖

Unfortunately, radiological confirmation of the diagnosis of spinal cord ischemia does not open major therapeutic opportunities. In postsurgical cases, as mentioned earlier, blood pressure should be supported to maximize cord perfusion. In nonperioperative cases, the options are even more limited. When the systemic blood pressure is low, it should be improved. Isolated cases of improvement of initially severe deficits after emergency placement of a

References 1. Brinar VV, Habek M, Brinar M, Malojcic B, Boban M. The differential diagnosis of acute transverse myelitis. Clin Neurol Neurosurg 2006; 108:278–283. 2. Fortuna A, Ferrante L, Acqui M, Trillo G. Spinal cord ischemia diagnosed by MRI. Case report and review of the literature. J Neuroradiol 1995; 22:115–122. 3. Fukui MB, Swarnkar AS, Williams RL. Acute spontaneous spinal epidural hematomas. AJNR Am J Neuroradiol 1999; 20:1365–1372. 4. Cheshire WP, Santos CC, Massey EW, Howard JF Jr. Spinal cord infarction: etiology and outcome. Neurology 1996; 47:321–330. 5. Shamji MF, Maziak DE, Shamji FM, Ginsberg RJ, Pon R. Circulation of the spinal cord: an important consideration for thoracic surgeons. Ann Thorac Surg 2003; 76:315–321. 6. Masson C, Pruvo JP, Meder JF, Cordonnier C, Touze E, De La Sayette V, et al. Spinal cord infarction: clinical and magnetic resonance imaging findings and short term outcome. J Neurol Neurosurg Psychiatry 2004; 75: 1431–1435. 7. Nedeltchev K, Loher TJ, Stepper F, Arnold M, Schroth G, Mattle HP, et al. Long-term outcome of acute spinal cord ischemia syndrome. Stroke 2004; 35:560–565. 8. Weidauer S, Nichtweiss M, Lanfermann H, Zanella FE. Spinal cord infarction: MR imaging and clinical features in 16 cases. Neuroradiology 2002; 44:851–857.

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lumbar drain have been reported,27 and we tend to try this intervention when the diagnosis is made shortly after symptom onset. The value of corticosteroids has not been tested; although large doses of dexamethasone are sometimes administered extrapolating an approach validated for acute spinal cord trauma, we believe there is no solid rationale for the use of steroids in patients with nontraumatic spinal cord infarction. It is clear that more severe deficits at presentation portend worse long-term prognosis for functional recovery.4,6,7 In particular, patients with complete or nearly complete motor and sensory loss (American Spinal Injury Association [ASIA] Grades A and B), bladder dysfunction, or abolished proprioception in addition to paraplegia (indicating complete transverse ischemia) predict unfavorable long-term outcome.6,7 However, the prognosis of spinal cord infarction in patients with more benign presentations may be much more favorable.7,9 Even some patients with severe impairment at onset but without signs of complete transverse cord infarction may achieve substantial recovery.6 Other than initial severity of deficits, prognostic factors are unknown. In particular, the impact of imaging findings on prognosis for recovery remains to be adequately studied.

9. Novy J, Carruzzo A, Maeder P, Bogousslavsky J. Spinal cord ischemia: clinical and imaging patterns, pathogenesis, and outcomes in 27 patients. Arch Neurol 2006; 63:1113–1120. 10. Mascalchi M, Cosottini M, Ferrito G, Salvi F, Nencini P, Quilici N. Posterior spinal artery infarct. AJNR Am J Neuroradiol 1998; 19:361–363. 11. Mawad ME, Rivera V, Crawford S, Ramirez A, Breitbach W. Spinal cord ischemia after resection of thoracoabdominal aortic aneurysms: MR findings in 24 patients. AJNR Am J Neuroradiol 1990; 11:987–991. 12. Faig J, Busse O, Salbeck R. Vertebral body infarction as a confirmatory sign of spinal cord ischemic stroke: report of three cases and review of the literature. Stroke 1998; 29:239–243. 13. Suzuki T, Kawaguchi S, Takebayashi T, Yokogushi K, Takada J, Yamashita T. Vertebral body ischemia in the posterior spinal artery syndrome: case report and review of the literature. Spine 2003; 28:E260–E264. 14. Thurnher MM, Bammer R. Diffusion-weighted MR imaging (DWI) in spinal cord ischemia. Neuroradiology 2006; 48:795–801. 15. Fujikawa A, Tsuchiya K, Takeuchi S, Hachiya J. Diffusionweighted MR imaging in acute spinal cord ischemia. Eur Radiol 2004; 14:2076–2078. 16. Loher TJ, Bassetti CL, Lovblad KO, Stepper FP, Sturzenegger M, Kiefer C, et al. Diffusion-weighted MRI in acute spinal cord ischaemia. Neuroradiology 2003; 45:557–561.

Spinal Cord Infarction 17. Kuker W, Weller M, Klose U, Krapf H, Dichgans J, Nagele T. Diffusion-weighted MRI of spinal cord infarction—high resolution imaging and time course of diffusion abnormality. J Neurol 2004; 251:818–824. 18. Bammer R, Augustin M, Prokesch RW, Stollberger R, Fazekas F. Diffusion-weighted imaging of the spinal cord: interleaved echo-planar imaging is superior to fast spinecho. J Magn Reson Imaging 2002; 15:364–373. 19. Zhang J, Huan Y, Qian Y, Sun L, Ge Y. Multishot diffusionweighted imaging features in spinal cord infarction. J Spinal Disord Tech 2005; 18:277–282. 20. Bowen BC, Saraf-Lavi E, Pattany PM. MR angiography of the spine: update. Magn Reson Imaging Clin N Am 2003; 11:559–584. 21. Cina CS, Abouzahr L, Arena GO, Lagana A, Devereaux PJ, Farrokhyar F. Cerebrospinal fluid drainage to prevent paraplegia during thoracic and thoracoabdominal aortic aneurysm surgery: a systematic review and meta-analysis. J Vasc Surg 2004; 40:36–44. 22. Acher CW, Wynn MM, Hoch JR, Popic P, Archibald J, Turnipseed WD. Combined use of cerebral spinal fluid drainage and naloxone reduces the risk of paraplegia in

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thoracoabdominal aneurysm repair. J Vasc Surg 1994; 19:236–246. Fleck TM, Koinig H, Moidl R, Czerny M, Hamilton C, Schifferer A, et al. Improved outcome in thoracoabdominal aortic aneurysm repair: the role of cerebrospinal fluid drainage. Neurocrit Care 2005; 2:11–16. Safi HJ, Hess KR, Randel M, Iliopoulos DC, Baldwin JC, Mootha RK, et al. Cerebrospinal fluid drainage and distal aortic perfusion: reducing neurologic complications in repair of thoracoabdominal aortic aneurysm types I and II. J Vasc Surg 1996; 23:223–228. Cambria RP, Davison JK, Carter C, Brewster DC, Chang Y, Clark KA, et al. Epidural cooling for spinal cord protection during thoracoabdominal aneurysm repair: a five-year experience. J Vasc Surg 2000; 31:1093–1102. Weaver KD, Wiseman DB, Farber M, Ewend MG, Marston W, Keagy BA. Complications of lumbar drainage after thoracoabdominal aortic aneurysm repair. J Vasc Surg 2001; 34:623–627. Blacker DJ, Wijdicks EF, Ramakrishna G. Resolution of severe paraplegia due to aortic dissection after CSF drainage. Neurology 2003; 61:142–143.

Chapter

10

Spontaneous Intraparenchymal Hemorrhage Alejandro A. Rabinstein and Steven J. Resnick

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he ability to image the brain using computed tomography (CT) and magnetic resonance imaging (MRI) has greatly enhanced our understanding of intraparenchymal hemorrhages (IPH) in the central nervous system. Before the advent of these modalities, the diagnosis of IPH was based on clinical presentation and indirect angiographic findings. Certainty could only be reached at the time of necropsy. CT and MRI now provide us with means to characterize the hematoma size, its location, and its effect on adjacent structures. Furthermore, they allow us to follow the evolution of the hematomas and taught us that these lesions are highly dynamic and have a dangerous tendency to expand early after their development.1,2 Brott et al. reported substantial hematoma growth (greater than one third of the baseline volume) in 26% of patients within 1 hour of the initial CT scan and in an additional 12% within the first 20 hours among patients presenting for emergency evaluation within 3 hours of symptom onset.1 The cause responsible for the production of the hematoma can often be gleaned from brain imaging,

such as in cases of associated tumors and vascular anomalies. Timing and adequacy of interventions may be guided by serial imaging, as is often the case with progressive hydrocephalus requiring ventriculostomy or expanding cerebellar hemorrhages demanding surgical evacuation. Various radiological features predict functional outcome after IPH. Hematoma volume greater than 60 cc, pronounced midline shift, infratentorial location, presence of hydrocephalus, and intraventricular hemorrhage have been shown to be prognosticators of death or poor recovery.3,4 Because hematoma volume carries such remarkable prognostic weight, it is essential to be familiar with the pragmatic technique used to estimate volume on the basis of CT scan appearance. This technique, known as the ABC/2 method and reliably validated in the literature, is simply based on the measurement of the three maximal diameters of the hematoma.5 It is illustrated on Figure 10-1. This measurement method can be applied using axial cuts of MRI sequences, but MRI-based measurements may lead to overestimation of lesion size.6

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Figure 10-1. An estimation of hematoma volume (cc) can be calculated with the formula (A ⫻ B ⫻ C)/2.5 First, identify the slice with the largest area of intracerebral hematoma. A represents the longest diameter (cm) to be measured in the slice showing the largest hematoma size. B represents the longest diameter (cm) perpendicular to A. C represents the height of the hematoma, calculated by multiplying the number of slices involved by the slice thickness (cm). To measure the number of slices involved, comparisons should be made to the largest diameter slice using percentages: if the diameter of the hematoma in the slice is greater than 75% of the largest diameter in the scan, that slice is counted as one full slice; if the diameter of the hematoma in the slice is between 25% and 75% of the largest diameter in the scan, that slice is counted as half, if the diameter is less than 25% of the largest diameter, the slice is not counted. The figure exemplifies how hematoma volume can be estimated. Slice 5 was identified as the largest area of intracerebral hematoma. The longest diameter (A) is measured as 6.5 cm. The longest perpendicular diameter (B) is 5.5 cm. C can be measured by calculating the slice thickness (0.5 cm) by the number of slices involved (10) (0.5 ⫻ 10⫽5). Slices 1, 2, and 16 were not counted because the diameter of the hematoma in those slices was less than 25% of the largest diameter in the scan. Slices 3, 9, 12, 13, 14, 15 were counted as half (total of 3); slices 4, 5, 6, 7, 8, 10, 11 were counted as one (total of 7). Values A(6.5) ⫻ B(5.5) ⫻ C(5) were then multiplied and divided by 2 to reach an estimated volume of 89 cc.

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Traditionally, CT scan was considered the modality of choice for the diagnosis of hyperacute IPH.7 However, MRI has now been shown to be as accurate as CT scan for the detection of acute hematomas and offers greater sensitivity for the recognition and temporal staging of chronic hemorrhages.8–10 Susceptibilityweighted sequences, such as gradient-recalled echo

(GRE) T2*-weighted imaging, are particularly useful for the detection of acute hemorrhage. GRE also allows optimal visualization of chronic hemorrhages and microhemorrhages. Figure 10-2 depicts how changes in MRI appearance help determine the age of intraparenchymal hemorrhage.

MRI STAGES OF HEMORRHAGE Clinical stage Biochemical form Hemoglobin stage

Hyperacute