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Intracranial Atherosclerosis
Intracranial Atherosclerosis Edited by Jong S Kim, L...
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August 19, 2008
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Intracranial Atherosclerosis
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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Intracranial Atherosclerosis Edited by Jong S Kim Department of Neurology University of Ulsan College of Medicine Asan Medical Center Seoul South Korea
Louis R Caplan Department of Neurology Beth Israel Deaconess Medical Center Boston Massachusetts USA
KS Lawrence Wong Department of Medicine and Therapeutics The Chinese University of Hong Kong Prince Wales Hospital Hong Kong People’s Republic of China
Foreword by Geoffrey A. Donnan Director, National Stroke Research Institute, Melbourne; and President, World Stroke Organization
A John Wiley & Sons, Ltd., Publication
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C 2008 by Blackwell Publishing Ltd This edition first published 2008
Blackwell Publishing was acquired by John Wiley & Sons in February 2007. Blackwell’s publishing program has been merged with Wiley’s global Scientific, Technical and Medical business to form Wiley-Blackwell. Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK Editorial offices: 9600 Garsington Road, Oxford, OX4 2DQ, UK The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK 111 River Street, Hoboken, NJ 07030-5774, USA For details of our global editorial offices, for customer services and for information about how to apply for permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell The right of the author to be identified as the author of this work has been asserted in accordance with the Copyright, Designs and Patents Act 1988. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Designations used by companies to distinguish their products are often claimed as trademarks. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. This publication is designed to provide accurate and authoritative information in regard to the subject matter covered. It is sold on the understanding that the publisher is not engaged in rendering professional services. If professional advice or other expert assistance is required, the services of a competent professional should be sought. The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by physicians for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements for this work. Neither the publisher nor the author shall be liable for any damages arising herefrom. Library of Congress Cataloging-in-Publication Data Intracranial atherosclerosis / edited by Jong S. Kim, Louis R. Caplan, K.S. Lawrence Wong. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4051-7822-8 (hardcover : alk. paper) 1. Cerebral arteriosclerosis. 2. Cerebrovascular disease–Etiology. I. Kim, Jong S. II. Caplan, Louis R. III. Wong, K. S. Lawrence. [DNLM: 1. Intracranial Arteriosclerosis–diagnosis. 2. Intracranial Arterial Diseases–etiology. 3. Intracranial Arteriosclerosis–therapy. WL 355 I6144 2008] RC388.5.I58 2008 616.1 36–dc22 2008023246 A catalogue record for this book is available from the British Library. R Set in 9/11.5 pt Sabon by Aptara Inc., New Delhi, India Printed in Singapore by Fabulous Printers Pte Ltd 1
2008
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Contents
List of contributors, vii Preface, xi Foreward, xiii
Epidemiology and risk factors 1 Anatomy of intracranial arteries, 3 David S Liebeskind and Louis R Caplan 2 Pathologic characteristics, 19 Xiang-Yan Chen and Mark Fisher 3 Epidemiology, 33 Philip Gorelick, Jinghao Han, Yining Huang and KS Lawrence Wong 4 Risk factors, 45 Kazuo Minematsu, Oh Young Bang and Toshiyuki Uehara
Stroke mechanism and clinical consequence 5 Stroke mechanisms, 57 KS Lawrence Wong, Louis R Caplan and Jong S Kim 6 Anterior circulation disorders, 69 Jong S Kim 7 Posterior circulation disorders, 83 Louis R Caplan, Pierre Amarenco and Jong S. Kim 8 Cognitive dysfunction, dementia and emotional disturbances, 100 Jae-Hong Lee, Alex E Roher, Thomas G Beach and Jong S Kim 9 Natural course and prognosis, 113 Juan F Arenillas, Louis R Caplan and KS Lawrence Wong
Diagnostic imaging studies 10 Vascular imaging, 127 Edward Feldman, Harry J Cloft, Mai Nguyen-Huynh and Avean McLaughlin 11 Application of magnetic resonance imaging, 135 Dong-Wha Kang and Jong S Kim 12 Transcranial doppler, 147 Qing Hao, KS Lawrence Wong and Andrei V Alexandrov
v
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CONTENTS
Treatment 13 Antiplatelet therapy, 163 Sun U Kwon and Jong S Kim 14 Anticoagulation, 173 Fadi B Nahab and Marc I Chimowitz 15 Angioplasty and stenting, 181 Wei-Jian Jiang, Dae Chul Suh, Yongjun Wang and Thomas W Leung 16 Surgical therapy, 194 Chang Wan Oh and Jeong Eun Kim 17 Other miscellaneous treatments, 206 Christopher Chen, Jinghao Han and KS Lawrence Wong
Uncommon causes of intracranial arterial disease 18 Immunologic and vasoconstrictive disorders, 217 Min Lou and Louis R. Caplan 19 Arterial dissection, CNS infection and other miscellaneous diseases, 229 Jiann-Shing Jeng and Jong S Kim 20 Moyamoya disease, 246 Susumu Miyamoto, Jun C. Takahashi and Jong S. Kim Index, 259 Colour plates, 160
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List of contributors
Dr Andrei V Alexandrov MD
Dr Xiang-Yan Chen PhD
Department of Neurology University of Alabama at Birmingham Birmingham Alabama USA
Department of Medicine and Therapeutics The Chinese University of Hong Kong Prince Wales Hospital Hong Kong People’s Republic of China
Dr Pierre Amarenco MD
Dr Christopher Chen MD
Department of Neurology and Stroke Centre Bichat Hospital Paris France
Dr Juan F Arenillas MD, PhD Stroke Unit Department of Neurology Hospital Clinico Universitario University of Valladolid Valladolid, Spain
Dr Oh Young Bang MD, PhD Department of Neurology Sungkyunkwan University Samsung Medical Center Seoul South Korea
Department of Pharmacology Yong Loo Lin School of Medicine Singapore
Dr Marc I Chimowitz MBChB MUSC Stroke Center Department of Neurosciences Medical University of South Carolina Charleston South Carolina USA
Dr Harry J Cloft MD, PhD Department of Radiology Mayo Clinic Rochester Minnesota USA
Dr Geoffrey A. Donnan Dr Thomas G Beach MD, PhD Sun Health Research Institute Arizona USA
Dr Louis R Caplan MD Department of Neurology Beth Israel Deaconess Medical Center Boston Massachusetts USA
National Stroke Research Institute Department of Neurology Austin Health Professor of Neurology University of Melbourne World Stroke Organization
Dr Edward Feldman MD Department of Clinical Neurosciences Brown University School of Medicine Providence Rhode Island USA vii
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LIST OF CONTRIBUTORS
Dr Mark Fisher MD
Dr Dong-Wha Kang MD, PhD
Department of Neurology University of California Irvine Medical Center Orange California USA
Department of Neurology University of Ulsan College of Medicine Asan Medical Center Seoul South Korea
Dr Philip Gorelick MD, MPH
Dr Jeong Eun Kim MD, PhD
Department of Neurology and Rehabilitation University of Illinois College of Medicine at Chicago Chicago Illinois USA
Dr Jinghao Han PhD Department of Medicine & Therapeutics Chinese University of Hong Kong Prince of Wales Hospital Hong Kong People’s Republic of China
Dr Qing Hao PhD Department of Medicine & Therapeutics Chinese University of Hong Kong Prince of Wales Hospital Shatin Hong Kong People’s Republic of China
Department of Neurosurgery Seoul National University College of Medicine Seoul South Korea
Dr Jong S Kim MD, PhD Department of Neurology University of Ulsan College of Medicine Asan Medical Center Seoul South Korea
Dr Sun U Kwon MD, PhD Department of Neurology University of Ulsan College of Medicine Asan Medical Center Seoul South Korea
Dr Jae-Hong Lee MD, PhD
Department of Neurology Peking University First Hospital Beijing People’s Republic of China
Department of Neurology University of Ulsan College of Medicine Asan Medical Center Seoul South Korea
Dr Jiann-Shing Jeng MD, PhD
Dr Thomas W Leung MD
Stroke Center and Department of Neurology National Taiwan University College of Medicine Taipei Taiwan
Department of Medicine and Therapeutics The Chinese University of Hong Kong Prince of Wales Hospital Hong Kong People’s Republic of China
Dr Yining Huang MD
Dr Wei-Jian Jiang MD Department of Neurology and Interventional Neuroradiology Beijing Tiantan Hospital The Capital University of Medical Sciences Beijing People’s Republic of China viii
Dr David S Liebeskind MD UCLA Stroke Center and Department of Neurology Los Angeles California USA
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LIST OF CONTRIBUTORS
Dr Min Lou MD Department of Neurology The Second Affiliated Hospital of Zhejiang University School of Medicine Hangzhou Zhejiang People’s Republic of China
Dr Aevan McLaughlin MD Department of Clinical Neurosciences Brown University School of Medicine Providence Rhode Island USA
Dr Kazuo Minematsu MD, PhD Cerebrovascular Division Department of Medicine National Cardiovascular Center Suita City Osaka Japan
Dr Susumu Miyamoto MD, PhD Department of Neurosurgery National Cardiovascular Center Suita Osaka Japan
Dr Fadi B Nahab MD Emory Stroke Center Department of Neurology Emory University School of Medicine Atlanta Georgia USA
Dr Mai Nguyen-Huynh MD Department of Neurology University of San Francisco San Francisco California USA
Dr Chang Wan Oh MD, PhD Department of Neurosurgery
Seoul National University Bundang Hospital Seongnam Gyunggi-do South Korea
Dr Alex E Roher MD, PhD Longtine Center for Molecular Biology and Genetics Sun Health Research Institute Sun City Arizona USA
Dr Dae Chul Suh MD, PhD Department of Radiology University of Ulsan College of Medicine Asan Medical Center Seoul South Korea
Dr Jun C Takahashi MD, PhD Department of Neurosurgery National Cardiovascular Center Suita Osaka Japan
Dr Toshiyuki Uehara MD Department of Medicine National Cardiovascular Center Suita City Osaka Japan
Dr Yongjun Wang MD Department of Neurology Beijing Tiantan Hospital Beijing People’s Republic of China
Dr KS Lawrence Wong MD Department of Medicine and Therapeutics The Chinese University of Hong Kong Prince Wales Hospital Hong Kong People’s Republic of China ix
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Preface
It reads in the literature that “extracranial atherosclerosis is an important cause of strokes while intracranial atherosclerosis is uncommon occurrence, accounting for 8–10% of strokes. However, it is more often seen in certain ethnic groups such as Asians, Blacks and Hispanics.” Whenever we read this, we cannot but feel weird. How many Asians, Black people and Hispanics are there in the world? As of March 2008, the world population had reached an estimated 6.65 billion, of which Asia and Africa accounted for over 60 and 12%, respectively, while Europe and North America accounted for only 11 and 8%, respectively. Although the location of cerebral atherosclerosis has not been reliably investigated in some parts of Asia, the dominance of intracranial atherosclerosis is well established in China, which alone comprises 20% of the world population. Therefore, our view is that the quote above should be revised as follows: “Intracranial atherosclerosis is the major cause of strokes worldwide. However, extracranial atherosclerosis is more often seen in certain ethnic groups, such as Caucasians.” Nevertheless, the literature has focused predominantly on extracranial atherosclerosis, largely neglecting intracranial atherosclerosis. Perhaps, there may be no other disease for which there is a greater discrepancy between the coverage of the literature and the real-world incidence than this example. To be sure, there are several reasons for this unusually large discrepancy. First, the literature in modern times has been dominated by scientists from North America and Northern Europe, who naturally focused on their main interest, extracranial atherosclerosis, while information from other countries has received less notice, especially when written in a local language. Second, extracranial carotid atherosclerosis has gained extra interest because endarterectomy has been a gold mine for vascular surgeons. By contrast, intracranial atherosclerosis remains technically inaccessible, attracting little attention from physicians. Finally, while diagnostic tools such as duplex scan can reliably assess the status of extracranial atherosclerosis, there have
been technical limitations to evaluate intracranial vessels until recently. With advances in imaging technologies such as magnetic resonance angiography, computed tomogrpahic angiography and transcranial Doppler, intracranial atherosclerosis is now more easily detected. In addition, advanced magnetic resonance imaging techniques, including diffusion-weighted magnetic resonance imaging, allow us to investigate stroke patterns and pathogenic mechanisms in patients with intracranial atherosclerosis. With the advent of these technologies, there has been a rapid accumulation of research papers that investigate pathology, risk factors, stroke mechanism, clinical syndrome, diagnosis and medical management of intracranial atherosclerosis. Furthermore, there have been remarkable developments in materials and technologies of stenting and angioplasty, while tools that help assess the cerebral perfusion, such as perfusion magnetic resonance imaging, single photon emission computed tomography or positron emission tomography, now enable us to select the patients who would benefit from bypass surgery. The aim of this book is to provide our readers with this ever-increasing knowledge on so far underinvestigated areas of intracranial atherosclerosis. This book, written by more than 30 experts in the field, is the first comprehensive textbook devoted to intracranial atherosclerosis. As such, we expect that this book will be of interest to physicians and researchers in diverse medical fields, including neurology, neurosurgery, radiology and rehabilitation medicine, who take care of stroke patients. Residents and students should also find this book interesting and stimulating. Although we extensively reviewed the currently available knowledge, we think that many important questions still remain to be investigated: Is the pathology of atherosclerosis really different between extraand intracranial arteries? Are the ethnic differences in the location of atherosclerosis related to differences in risk factors, genetic factor or still unknown factors? What would be the best medical therapy for patients with intracranial atherosclerosis? Who are the
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PREFACE
optimal candidates for revascularization therapy, such as angioplasty/stenting or bypass surgery? What is the ultimate clinical outcome in patients with intracranial atherosclerosis? Our hope is that this book will not only guide readers in their clinical practice but also stimulate them to be interested in and to perform research in the field of intracranial atherosclerosis aimed at solving these problems. By doing so, this book will ultimately contribute to the care of patients with intracranial atherosclerosis, the major cause of stroke worldwide.
xii
Finally, we express our sincere appreciation to all the contributors who took time out of their busy schedules to send us manuscripts, and also to Wiley-Blackwell for seeing this book through production. Without their help, this book could not have been brought to light.
Jong S Kim Louis R Caplan KS Lawrence Wong September 2008
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Foreword
The editors have produced a superb book that aggregates for the first time all the information pertaining to intracranial atherosclerosis ranging from anatomy, pathology, and mechanisms through to epidemiology. This is particularly timely, given the recent increase in our understanding of this fascinating aspect of stroke medicine. Because it is a relatively infrequent cause of stroke in the West, probably only about 10%, compared to its major contribution to stroke in Asia (probably 30–60% of all strokes), it has occupied only a minor place in stroke medicine. However, with the emergence of Asia as a major academic driving force, the true place of intracranial atherosclerosis in the pantheon of stroke medicine worldwide is now being appreciated. Increasingly, stroke is being considered as a global problem that needs to be addressed by collaborative initiatives across racial and geographical borders. This book is a good illustration of this approach, with contributions from many different parts of the globe, both East and West. This is very much the philosophy of the World Stroke Organization that has a similar global approach to stroke as a clinical problem together with an awareness that more than half of the worlds’ strokes are occurring in Asian countries. To reduce
the unacceptable burden of stroke one of the major thrusts must be towards understanding stroke mechanisms in Asia so that adequate preventative measures can be instituted. This volume certainly contributes to this endeavor. Interestingly, the extent of the problem of intracranial atherosclerosis and a better understanding of its mechanisms have come up with the more recent advances in neuroimaging, including ultrasound. This book nicely puts this in context and should be a useful reference for those wishing to enter this cutting-edge area of research. No stone is left unturned with a nice chapter on rarer causes of intracranial arterial disease for those confronted with difficult individual cases. Indeed, the book is such that it should be accessible by all those interested in stroke ranging from medical students through to experts in the field. I wish you well in reading this volume. I found it interesting, informative, and addressing an important and emerging area of stroke. I am sure you will find the same. Geoffrey A. Donnan President, World Stroke Organization October 2008
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Colour Plates
Plate 1.1
Plate 1.6
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
1
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CHAPTER 10
A
B
Plate 2.2
A
B
Plate 2.3
Plate 5.2
2
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COLOUR PLATES
Plate 5.4
Plate 6.5
3
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Plate 8.1
Plate 10.1
4
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Plate 11.4
Plate 12.5
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Plate 12.7
High frequency High frequency with irregular amplitude
Low frequency
Low frequency
Post-FFT spectrum
Pre-FFT time domain signal
M FS High frequency High intensity bi-directional low frequency signal
Post-FFT spectrum
Plate 12.8
Low frequency Pre-FFT time domain signal
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COLOUR PLATES
Plate 15.1
7
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CHAPTER 20
Rest
Plate 20.4
8
Acetazolamide i.v.
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PART ONE
Epidemiology and risk factors
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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Anatomy of intracranial arteries David S Liebeskind and Louis R Caplan
Comprehensive knowledge of intracranial arterial anatomy forms the basis for consideration of intracranial atherosclerosis. Anatomy defines the location of such neurovascular lesions, delineates the extent and involvement of branching perforators, and consequently determines the effects on downstream perfusion. Anatomy is also intertwined with pathophysiology, as vessel morphology influences hemodynamic variables that promote plaque growth and vessel wall constituents may predispose to atherosclerotic involvement. Once an atherosclerotic plaque has formed, the arterial territories within the brain may shift, reflecting diminished perfusion beyond a stenosis and compensatory collateral flow via anastomoses from adjacent arterial sources.1 Simply stated, the anatomical features of these arteries or pipes and their perforators determine perfusion, penumbra, and the parenchymal consequences of brain ischemia. These intracranial vessels differ in anatomy from other circulatory beds in the heart or periphery, with only limited correlates noted in the comparative anatomy of intracranial arteries across species. Arterial anatomy adds to the complexity of neurological localization, providing a unique classification of neurovascular disorders. Consideration of intracranial arterial anatomy is most germane to clinical management where recognition of particular stroke syndromes influences treatment decisions. Identification of a culprit atherosclerotic lesion also hinges on anatomical details of the case. The historical perspective on characterizing anatomy of the intracranial arteries includes an ironic twist where only marginal advances regarding pathol-
ogy of these arterial segments have been made since the autopsy series performed hundreds of years ago, and angiography reigns as the definitive modality for defining these structures almost a century after its introduction. Pathology related to atherosclerotic involvement of the major intracranial arteries has largely eluded modern imaging techniques because of the small size of these vessels and the orientation of these segments that defy conventional imaging planes. Numerous noninvasive methods have been developed to image intracranial arterial anatomy,2 yet these modern vascular imaging techniques including transcranial Doppler ultrasound (TCD), computed tomographic angiography (CTA), and magnetic resonance angiography (MRA) are not as accurate as the gold standard of conventional or digital subtraction angiography (DSA).3 Recently, the advent of angioplasty and stenting for intracranial atherosclerotic disease has reinforced the importance of DSA, since arterial access is needed for treatment. Noninvasive imaging modalities such as TCD, CTA, and MRA each provide differing information regarding a balance of anatomical information, such as measures of the arterial lumen versus physiological data reflecting flow through a specific arterial segment and distal perfusion. DSA remains the prevailing method for evaluating vascular anatomy in the brain, although modifications such as threedimensional rotational angiography (Fig. 1.1) have allowed for expansion across numerous frames of reference. This introductory chapter considers the vascular anatomy of the major intracranial arterial segments supplying blood flow to the brain, emphasizing
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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CHAPTER 1
longitudinal connections develop, including the vertebral arteries that form with involution of the cervical intersegmental arteries. The embryologic development of the circle of Willis is also important to consider when these segments are recruited to later shunt blood flow due to stenosis or occlusions in the anterior or posterior circulations. Previously hypoplastic segments may be recruited and may progressively enlarge over time, whereas others involute because of disuse. The specific events characterizing the embryologic development of particular intracranial arteries are detailed below.
Fig 1.1 Three-dimensional rotational angiography illustrating the proximal segments of the anterior circulation, including bifurcation of the internal carotid artery (A) into the anterior carotid artery (B) and middle cerebral artery (C).
proximal segments where atherosclerotic lesions or stenoses are often noted. The extracranial segments of these vessels are not discussed and only marginal attention has been devoted to distal branches beyond the primary or secondary intracranial arterial divisions. For each artery, the chapter reviews embryologic development, basic morphology such as orientation and luminal dimensions, functional aspects such as perforators, territories, and collateral anastomoses, and common variants encountered in standard anatomy.
Embryology The arteries of the central nervous system originate from mesenchymal elements that coalesce to form channels that cover the surface of the neural tube. Over time, certain channels persist and enlarge to become principal conduits whereas others involute. A single ventral median artery forms, with paired or symmetrical branches that spread out in a circumferential pattern over the surface. A segmental pattern of blood flow predominates the 4- to 12-mm human embryo stage, arising from the branchial arches. Intracranial blood flow at this stage is distributed by the primitive trigeminal, otic or acoustic, and hypoglossal arteries. Early arterial blood flow is centripetal, extending from the periphery to the center. Beyond the 12-mm stage, 4
Arterial wall The majority of anatomical descriptions consider the cerebral vasculature as a mere conduit to supply and return blood through the brain, yet these vascular channels play an active role in the regulation of blood flow in the brain. The proximal segments of the intracranial arteries distribute flow to specific areas of the brain to match metabolic demand during development and for years thereafter. Cerebral perfusion depends on intraluminal pressure and downstream resistance. Because arterial blood pressure is so readily measured and commonly employed as a principal vital sign, the presumption is that cerebral blood flow is principally mediated by blood pressure. Most of the pressure head or arterial pressure gradient is lost before blood flow reaches the terminal branches feeding the cortical surface and deep regions of the brain. Resistance is directly modulated by these proximal arterial circuits and their vessel wall constituents, in addition to other biophysical factors and metabolic orchestration within the intracranial compartment. Unlike the peripheral vasculature, where precapillary sphincters mediate pressure gradients, the cerebral circulation lacks such structures and pressure gradients are modified in the arteries and arterioles of the brain. Flow is also readily shunted or equilibrated via unique anastomotic structures such as the circle of Willis. These features underscore the importance of recognizing the unique role of the proximal arterial circulation in the brain, not just as pipes for flow distribution, but as active physiological elements in metabolic homeostasis. The structural characteristics in the vessel wall that enable such functional capacity are therefore an important anatomical aspect to consider.
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ANATOMY OF INTRACRANIAL ARTERIES
Several features distinguish intracranial arteries from arteries of similar caliber elsewhere in the body. Arteries in the brain have a well-developed internal elastic lamina with only a minimal degree of elastic fibers scattered in the media.4 Unlike arteries elsewhere throughout the body, the intracranial arteries do not have an external elastic lamina. Other distinctive features of the intracranial arteries include the presence of tight endothelial junctions with a relative paucity of pinocytic vesicles, and differing distribution of enzymes within the vessel wall. The adventitial layer is typically thin compared with the systemic arteries. In general, the cerebral arteries have a smaller wall-tolumen ratio than arteries elsewhere in the body.5 Overall, the intimal layer accounts for about 17% of total vessel wall thickness, with the media constituting 52% and adventitia only 31%.6,7 The arterial lumen is defined by the adjacent architecture of the vessel wall. Cerebral endothelial cells with tight junctions form a critical element of the blood–brain barrier.8 These endothelial cells are not fenestrated and the tight junctions bestow only selective permeability to this boundary, preventing exchange of numerous substances. This boundary is often referred to as the “blood–brain barrier.” Under pathophysiologic conditions, this selective permeability boundary may be deranged.9 The number of endocytotic vesicles is also limited compared with the endothelial lining of other vascular beds. Cerebral endothelial cells have a high concentration of mitochondria, denoting their active metabolic role and, possibly, their vulnerability to ischemia.10 Endothelial cells in cerebral arteries and arterioles play an active role in the regulation of hemodynamics. This capacity is partially related to the expression of a wide array of vasoactive substances, including endothelin and nitric oxide.11 The internal elastic lamina of intracranial arteries is fenestrated, with holes that vary in size according to the arterial segment.12 Beyond the endothelial layer, the cerebral arteries have protuberances at distal branching sites that also modulate flow. These structures have been variably defined as intimal cushions, bifurcation pads, or subendothelial protuberances. Underneath the luminal surface, these structures contain groups of smooth muscle cells arranged in irregular fashion, with intertwined collagenous fibrils and are encompassed by the split internal elastic membrane.13 Although the exact role of these structures in titration of arterial pressure has not been fully
elucidated, it appears that these structures help alter flow via fluid shear stress mechanisms. Fluid shear stress is a critical physiological variable both in the development of atherosclerosis and in compensatory arteriogenesis.14,15 A circumferential orientation of the smooth muscle cells at branching sites may be related to titration of arterial inflow resistance by acting via a sphincter-like mechanism. In normal intracranial arteries, smooth muscle cells make up 72% of the media, whereas this composition is radically altered under pathophysiologic conditions such as intracranial atherosclerosis or chronic hypertension.4 Age-related changes are found in the composition of the media. Autonomic nerves located in the tunica adventitia have connections with these subendothelial structures via intercellular smooth muscle cell contacts. Within the media, smooth muscle cells are generally oriented in a pattern circumferential to the lumen except at bifurcations.6 Adjacent collagen and elastin fibers run perpendicular to the smooth muscle layer or in parallel with the long axis of the vessel. The thin medial layer of intracranial arteries compared with systemic vessels is thought to be related to compliance differences associated with surrounding cerebrospinal fluid. The number of smooth muscle cell layers within the media diminishes distally. A basement membrane associated with the adjacent smooth muscle cells forms the framework for adjoining layers of the intima and adventitia. Nerve fibers approach the media from the adventitial layer. Within the adventitia, loose connective tissue surrounds autonomic nerve fibers and all vessel wall structures are enclosed by spindle-shaped fibrocytes. Once beyond the dura mater, the intracranial arteries have no vasa vasorum. The external surface of the intracranial arteries in these regions is in direct contact with surrounding cerebrospinal fluid. A rete vasorum in the adventitia is permeable to large proteins, allowing ingress or exchange with cerebrospinal fluid in the subarachnoid space.16 Characteristics of the intracranial arterial wall in humans typically consider the proximal intracranial arteries such as the middle cerebral artery (MCA) separately from much smaller intracerebral or pial arterioles. As the internal carotid artery (ICA) courses distally, there is progressive disappearance of the external elastic lamina. The MCA is a terminal continuation of the ICA with a gradual change in blood vessel wall characteristics of histopathology. The relative 5
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CHAPTER 1
amounts of intima, media, and adventitia in the MCA are less than the equivalent amount per vessel size in the more proximal ICA. The MCA internal elastic lamina is thicker and partially fenestrated. Compared with similar sized extracranial arteries, the MCAs have less adventitia with less elastic tissue and few perivascular supporting structures, including an absence of vasa vasorum.17
Internal carotid artery Each ICA supplies approximately 40% of total perfusion to the brain. The ICA develops from the third primitive aortic arch. The distal cervical segment of the ICA arises from the junction of the distal aspect of this third primitive aortic arch with the dorsal aorta. The ICA arises from the common carotid artery in the neck, extending into the head at the skull base via the carotid canal (Fig. 1.2). There are three named segments of the intracranial ICA, including petrous, cavernous, and supraclinoid segments (Fig. 1.3). The petrous ICA extends for about 25–35 mm anteromedially from the skull base to the cavernous sinus.18 The shape of the petrous ICA varies depending on the development of the surrounding bony structures skull. Along this course, it bends anterior to the tympanic cavity near the apex of the petrous bone and traverses the posterior aspect of the foramen lacerum. The ICA crosses the membranes of the cavernous sinus, winding anteriorly and superomedially, then ascending vertically in a groove along the sphenoid bone and then passing along the medial aspect of the anterior clinoid process. On exiting the cavernous sinus, the ICA extends through the meninges to become the supraclinoid segment. The cavernous ICA typically averages 39 mm in length. The supraclinoid or cerebral ICA bends posteriorly and laterally between the oculomotor (III) and optic (II) nerves. Because of this sinuous course of the ICA, the cavernous and supraclinoid segments are often collectively referred to as the carotid siphon. Beyond the supraclinoid segment, the ICA terminates at the bifurcation into the anterior carotid artery (ACA) and MCA. This bifurcation is often referred to as the “carotid T” because of its shape or the “top-of-the carotid” because of its location. Along the course of the intracranial ICA, branching progressively increases with more distal locations.19 6
Fig 1.2 Gadolinium-enhanced magnetic resonance angiography depicting the course of the right internal carotid artery (ICA) from its extracranial origin at the carotid bifurcation (A), through the carotid canal at the skull base (B), to become the intracranial ICA (C).
Fig 1.3 Line drawing of the intracranial internal carotid artery, depicting the petrous (A), cavernous (B), and supraclinoid (C) segments.
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The petrous segment gives rise to the caroticotympanic artery, supplying the tympanic cavity, and the pterygoid or vidian branch passing through the pterygoid canal.18 This vidian artery anastomoses with the internal maxillary artery. On occasion, the persistent stapedial branch of the petrous segment traverses a bony canal and continues as the middle meningeal artery.18 The cavernous portion, however, has far more tributaries including the meningohypophyseal trunk, the anterior meningeal artery, the artery to the inferior portion of the cavernous sinus, and the ophthalmic artery. The meningohypophyseal trunk further subdivides into diminutive branches that include the basal and marginal (artery of Bernasconi and Cassinari20 ) tentorial arteries, the inferior hypophyseal artery, and the dorsal meningeal artery. The inferolateral trunk arises from the inferolateral aspect of the cavernous ICA, supplying many small branches to the tentorium and trigeminal (V) nerve divisions. Collateral anastomoses between the ICA and the external carotid artery (ECA) are formed by the inferolateral trunk extending to the internal maxillary artery. The supraclinoid ICA also has numerous branches including the superior hypophyseal perforators to the anterior pituitary and stalk, posterior communicating artery (PCoA), and anterior choroidal artery (AChA) before bifurcating into the ACA and MCA.21 The two ACAs connect through the anterior communicating artery (ACoA) thus joining the left and right carotid circulations. The PCoA extends posteriorly to connect with the primary segment of the posterior cerebral artery, allowing collateral flow to pass between the anterior and posterior circulations.1 This vascular network, referred to as the circle of Willis (Fig. 1.4), plays a critical role in shunting blood flow between adjacent territories in the brain. At its origin, the PCoA often has a widened segment referred to as the infundibulum. The PCoA passes ventral to the optic tract, with perforators that supply the optic tract, posterior aspect of the chiasm, posterior hypothalamus, and anterior and ventral nuclei of the thalamus. In 15% of individuals, this vessel continues distally as the posterior cerebral artery.22,23 Great variability may be noted in the caliber of the PCoA, ranging from less than 1 mm to greater than 2 mm. The anatomy of the PCoA differs in various populations and in clinical conditions associated with ischemia.23,24 Hypoplasia or absence of the PCoA is
Fig 1.4 Line drawing of anastomotic connections at the circle of Willis, including the anterior communicating artery (A), the proximal or A1 segment of the anterior carotid artery (B), the posterior communicating artery (C), and the proximal or P1 segment of the posterior cerebral artery (D).
found in a minority of cases at autopsy, with bilateral hypoplasia in only 0.25% of individuals.22 The configuration and size of the PCoA also differs between rates gleaned from autopsy studies and angiography series. There are numerous variant configurations of the ICA, including its rare absence or hypoplasia. The amount of blood volume supplied to distal structures can vary depending on the caliber of the terminal ICA. The course of the ICA sometimes varies, coursing through the middle ear or bending towards the midline in a configuration termed kissing ICAs at the cavernous segments. Anomalous origins of the posterior fossa arteries from the ICA, including the superior cerebellar artery (SCA), anterior inferior cerebellar artery (AICA), or posterior inferior cerebellar artery (PICA), may also occur. Persistent fetal connections to the posterior circulation may involve the PCoA, trigeminal, otic or acoustic, hypoglossal, and proatlantal intersegmental arteries. The persistent trigeminal artery is the most common persistent embryonic connection (85%), arising from the cavernous ICA and joining the upper basilar artery.25 The persistent otic artery is very rare, connecting the petrous ICA with the basilar artery inferior to AICA. The persistent hypoglossal connects the distal cervical ICA with 7
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the distal vertebral artery. Intercavernous ICA collaterals may also allow for blood to flow laterally to either hemisphere.
Anterior choroidal artery The AChA arises from the posterior aspect of the ICA, about 2–4 mm distal to the origin of the PCoA and about 5 mm proximal to the carotid terminus.26 The AChA is relatively small, yet serves as an important landmark in delineating important structures at angiography.27 There are two segments of the AChA, including the cisternal and plexal segments. The AChA may have a single origin or may consist of several smaller vessels (4% of individuals).26,28 The AChA arises from the MCA or PCoA in 2–11% of individuals.28 Complete absence of the AChA has also been reported.27 The external diameter of this vessel is often only 0.5–1 mm, although a reciprocal relationship has been noted in the caliber of this vessel with the ipsilateral PCoA. The cisternal segment passes posteriorly from the lateral to medial aspect of the optic tract in close proximity to the posterior cerebral artery (PCA), extending for about 12 mm, extending to a total length of about 26 mm. The AChA gives off penetrating branches to the optic tract in this segment. As the AChA courses posteriorly it gives off penetrating branches to the globus pallidus and the genu and posterior limb of the internal capsule. Subsequent branches extend laterally to supply the medial temporal lobe cortex, hippocampal and dentate gyri, caudate, and amygdala. Medial branches supply the cerebral peduncle, substantia nigra, red nucleus, subthalamus, and ventral anterior and lateral nuclei of the thalamus. The AChA is the only branch of the ICA that supplies a portion of both the anterior and posterior circulation, although the midbrain and thalamic supply is very variable. More distally, the AChA extends through the choroidal fissure to become the plexal segment. The juncture of the AChA at the choroidal fissure is often referred to as the plexal point. The plexal segment then enters the choroid plexus near the posterior aspect of the temporal horn. Arterial supply of this segment includes the lateral geniculate body, optic radiations, and posterior limb of the internal capsule. The AChA anastomoses with lateral branches of the posterior choroidal artery, PCoA, PCA, and MCA.27,29 Variants include AChA origin from the PCoA or MCA. 8
Middle cerebral artery The MCA provides arterial blood flow to the largest extent of the intracranial circulation. The MCA is typically 75% of the caliber of the parent ICA.30 After diverging from the terminal ICA below the anterior perforated substance, it courses horizontally and slightly anteriorly to reach the sylvian fissure, where branches perfuse the frontal, parietal, and some extent of the temporal and occipital cortices (Fig. 1.5). The proximal or horizontal segment of the MCA averages around 15 mm in length yet may be as long as 30 mm.30 At younger ages, the M1 segment rises obliquely but this segment tends to course more inferiorly or anteriorly with increasing age later in life.31 Between the 7 and 12 mm (7 weeks) embryonic stage, small perforators that are precursors of the MCA may be seen arising from the ICA. The MCA is smaller than the AChA at these early stages and then grows larger. During the second month of fetal life, the sylvian
Fig 1.5 Schematic of the middle cerebral artery, illustrating the proximal segment or M1, lenticulostriate arteries (LSA), and bifurcation into M2, with downstream territories delineated between adjacent anterior carotid artery and posterior cerebral artery regions.
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fissure develops as a groove over the cerebral hemisphere and the MCA grows within this depression. The MCA becomes enveloped in the sulcation of the cerebral cortex, following the growth of each specific brain region. The proximal or M1 division of the MCA provides lenticulostriate arteries that feed the globus pallidus, putamen, internal capsule, corona radiata, and caudate nucleus. This segment is typically around 2.5 mm in internal diameter.30 These end arteries originate from the M1 segment in almost perpendicular fashion to penetrate the brain parenchyma. The lateral lenticulostriates ascend for 2–5 mm posteromedially from the M1 and then course laterally and superiorly for an additional 9–30 mm to penetrate the internal capsule. The medial lenticulostriates generally arise from more proximal segments of the MCA or from distal reaches of the terminal ICA and proximal ACA.32–35 There is considerable variation in the relative distribution and origins of medial versus lateral lenticulostriate perforators. The arterial diameter of lateral lenticulostriates is typically greater than the medial lenticulostriate perforators. Overall, there are typically 5–17 lenticulostriate arteries, although all are barely identifiable at angiography.30 There are three principal patterns that have been described for the anatomy of the lenticulostriates.32–35 Grand et al.33 described a pattern where either one or more of the larger lenticulostriates arise just beyond the MCA bifurcation (49%), all arise proximal to the major bifurcation (39%), and a minority of cases where some of the larger perforators arise from the medial portion of the stem. According to Jain,34 54.1% originate from the MCA trunk, 25.6% from the division point, and 20.3% from one of the branches of the MCA. The lateral lenticulostriates supply the lateral portion of the anterior commissure, the putamen, the lateral segment of the globus pallidus, the superior half of the internal capsule, the adjacent corona radiate, and the body and head of the caudate nucleus. The medial lenticulostriates arise in perpendicular fashion to the parent MCA or ACA, yet bend in mesial fashion. The areas supplied by the medial lenticulostriates, including the prominent recurrent artery of Heubner, and the AChA are adjacent to the territories of the lateral lenticulostriates. The relative territorial extents are reciprocal in size and depend on the development of each of these arterial groups.32–35
The largest branch of the proximal MCA is the anterior temporal artery, extending from the middle of the proximal MCA and winding anteriorly and inferiorly. Although the configuration of the proximal MCA often varies, the vessel most often splits into two or more principal divisions near the sylvian fissure. Although prior studies have suggested symmetry in the morphology of bilateral MCAs, no clear correlations exist. The anterior and posterior divisions of the MCA extend into the sylvian fissure and spread out over the hemisphere. These cortical branches include the temporopolar, frontobasal, operculofrontal, precentral, postcentral, posterior parietal, angular, anterior temporal, middle temporal, and posterior temporal arteries. As the MCA branches loop over the insula in the sylvian fissure, they form the sylvian triangle, a landmark classically used to identify mass lesions on angiography. Terminal branches of the MCA form collateral anastomoses with the ACA and PCA.1 Variation in MCA anatomy is less common than variants in other intracranial arteries. Fenestration of the M1 segment occurs, and duplicated M1 segments may also arise from the ICA.36 Angiographic demonstration of MCA fenestration may be evident in approximately 0.26% of individuals.37 Yamamoto et al.38 described 14 accessory MCAs and seven duplicated MCAs in a series of 455 bilateral carotid angiographies. The M1–M2 junction is characterized by a bifurcation in 64–90% of individuals, trifurcation in 12–29%, and complex branching in isolated individuals.30 Some controversy has surrounded specific landmarks and associated classification of the MCA segments. Whereas many identify the segments of the MCA based on each successive branch point, others use a nomenclature that relates each of these MCA segments with a specific adjacent anatomical structure. For instance, some refer to the M2 origin at the initial bifurcation of the proximal or M1 MCA, whereas others identify the M2 segment as the arterial segment that overlies the insula.
Anterior cerebral artery The ACA develops from residual elements of the primitive olfactory artery at the terminus of the ICA. The paired primitive olfactory arteries from each side form a plexus in the midline that gives rise to the ACoA. During development, the ACA extends superiorly and 9
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Fig 1.6 CT angiography illustration of two different configurations in the anterior carotid artery (ACA) complex and anterior communicating artery (ACoA) anastomosis.
(A) A patent ACoA provides interhemispheric flow between left and right ACAs. (B) ACoA is absent, yet a prominent recurrent artery of Heubner (RAH) is demonstrated.
then posteriorly over the hemispheres in the midline whereas the remainder of the primitive olfactory artery regresses to become a small perforating vessel. The ACA is typically 50% of the caliber of the parent ICA.39 The internal diameter of the A1 is usually 0.9– 4 mm, with hypoplasia defined as a diameter less than 1 mm. The A1 segment measures 7–18 mm, with an average span of 12.7 mm.39 The ACA extends anteromedially between the optic chiasm (70% of individuals) or optic nerve (30% of individuals) and the anterior perforated substance to join the contralateral ACA through an anastomosis via the ACoA. The ACoA forms the anterior aspect of the circle of Willis, a critical route for collateral flow between the cerebral hemispheres. The ACoA is the shortest cerebral artery, measuring only 0.1–3 mm in length.39 The anatomy of the ACA–ACoA is variable (Fig. 1.6) with hypoplasia of different segments, including absence of the ACoA. Accessory routes, fenestrations, and other complex azygous connections between the proximal ACAs are also described. The proximal ACA or A1 segment gives off numerous perforating arteries that supply the adjacent optic nerves and chiasm inferiorly, and the hypothalamus, septum pellucidum, anterior commissure, fornix, and corpus striatum. These mesial lenticulostriate vessels often include a prominent recurrent artery of Heubner
that supplies the caudate head, putamen, and anterior limb of the internal capsule.40 The A2 segment begins at the juncture of the ACA with the ACoA and extends to the genu of the corpus callosum. The recurrent artery of Heubner arises from the A2 segment in 49–78% of individuals.39 The recurrent artery of Heubner may be a single vessel or can be represented by a number of parallel arteries. Beyond the proximal segment of the ACA, azygous connections allow for shunting of flow between the cerebral hemispheres. The ACAs course over the cerebral hemispheres in the interhemispheric fissure as paired vessels, with their distal extent typically determined by the corresponding anatomy of the PCAs. Subsequent divisions including the pericallosal and callosomarginal arteries divide to provide arterial supply to the corpus callosum and anteromesial cortices. Several variations in distal ACA anatomy have been described, including the observation that the left pericallosal artery is located more posteriorly than the corresponding rightsided vessel in 72%.41 Similarly, absence of the callosomarginal artery has been noted in 18–60% of cases studied.41 Cortical branches of the ACA include the orbitofrontal, frontopolar, callosomarginal, and pericallosal arteries. As the terminal portion of the ACA travels along the corpus callosum, its anterior pericallosal
10
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branches form anastomoses with the posterior pericallosal branches of the PCA.41 Variant anatomy of the ACA most commonly includes hypoplasia or absence of the A1 segment (10% of individuals).39 Other variations may include anomalous origin of the ACA from the ICA, agenesis or accessory branches, direct connection of bilateral A1 segments, or other combinations that involve azygous orientation of distal ACA segments.
Vertebral artery The vertebral artery enters the skull at the level of C1 through the foramen magnum. The intracranial or intradural (V4) segment of the vertebral artery ascends anteriorly to the medulla, approaching the midline at the pontomedullary junction, where it meets the contralateral vertebral artery to form the basilar artery. The paired longitudinal arteries that form the arterial supply to the posterior circulation during early fetal development retain their proximal course as the vertebral arteries. The left vertebral artery is larger than the right 42% of the time, whereas the right is larger than the left 32% of the time. In the remainder of individuals, the vertebral arteries are equivalent in caliber. Vertebral artery hypoplasia is fairly common, often involving the right side. The frequency of this finding depends largely on the modality used to image the vessel, the size threshold used to define hypoplasia, and the study population, including healthy subjects or patients with ischemic stroke. Defining hypoplasia as ≤2 mm by ultrasonography, one group reported a frequency of 1.9% in 451 subjects.42 Among healthy subjects with a threshold of <3 mm, another group noted a frequency of 6% in 50 healthy subjects.43 Others have recently noted a frequency as high as 35.2% in 529 patients with ischemic stroke.44 Utilizing a luminal diameter threshold of 2.2 mm, prominent asymmetry in vertebral artery hypoplasia has also been described (7.8% on the right and 3.8% on the left) in 447 subjects.45 Differentiation of hypoplasia from a diseased arterial segment may be difficult to define on the basis of luminal dimensions alone. The configuration or compensatory enlargement of neighboring segments may provide clues to this distinction. Furthermore, definitions may vary considerably depending on the imaging technique employed. The vertebral artery may also terminate in the PICA rather than ex-
tend to the junction with the basilar artery. In such cases, the vertebral artery is generally smaller than the contralateral vertebral artery. The terminal vertebral artery yields several branches that supply the rostral end of the spinal cord and posterior inferior aspect of the cerebellum. Anterior and posterior spinal arteries extend from this segment. Each anterior spinal artery fuses with its counterpart, supplying the ventral medulla and rostral spinal cord. The posterior spinal arteries do not pair in the midline, but descend the spinal cord at the level of the dorsal roots. The posterior inferior cerebellar artery branches from the vertebral artery to supply the inferior aspect of the cerebellum.
Posterior inferior cerebellar artery The largest tributary of the vertebral artery is the PICA, arising 10–20 mm before the vertebrobasilar junction (Fig. 1.7).46 In 20% of individuals, the PICA arises from below the foramen magnum.47 During embryogenesis, the PICA may be evident as a larger branch of numerous arteries that extend posteriorly from the hindbrain in the 20–24 mm embryo stage.
Fig 1.7 Digital subtraction angiography of the posterior inferior cerebellar artery (PICA), showing proximal medullary segments and hemispheric tributaries.
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At later stages, this vessel continues to predominate, growing into the largest arterial offshoot. There are four segments of this vessel, including the anterior, lateral, posterior medullary, and supratonsillar PICA. The anterior medullary segment travels laterally near the inferior aspect of the olive of the medulla oblangata, continuing in a loop that courses between the cerebellum and medulla. Numerous perforating arteries extend from the first three segments of the PICA to supply anterior, lateral, and posterior aspects of the medulla. The PICA then extends posteriorly in the tonsillomedullary fissure adjacent to the glossopharyngeal (IX) and vagus (X) nerves. Beyond this point, the PICA curves over the cerebellar tonsil to become the supratonsillar segment extending further across the cerebellum as the medial and lateral terminal PICA branches. At the juncture of the posterior medullary and supratonsillar segments of the PICA, perforating vessels arise to feed the choroid plexus of the fourth ventricle. This choroidal point is used as a landmark to identify masses within the posterior fossa. Variations in PICA anatomy include hypoplasia or absence of this branch (10–20% of individuals), typically accompanied by a prominent ipsilateral anterior inferior cerebellar artery. Absence of the PICA is also accompanied by numerous medullary perforators that arise directly from the vertebral artery. Duplication of the PICA and double origin with distal arterial convergence of the PICA48 may occur. PICA–AICA connections and other anomalies may be seen, yet the specific frequencies of such anatomic configurations remain unclear. On occasion, both inferior cerebellar territories may be supplied by a bihemispheric PICA originating from one vertebral artery.49
Basilar artery The basilar artery extends from the confluence of the vertebrals near the pontomedullary junction to the terminal bifurcation as the PCAs at the level of the midbrain. During embryologic development, paired vessels on the ventral surface of the hindbrain fuse to form the basilar artery. Distal segments of these paired basilar arteries have connections with the ipsilateral ICA. Over time, the plexus formed by the paired basilar arteries fuses with progressive disappearance of fenestrations. The basilar artery is often tortuous or serpentine, with a straight course noted about 25% of the 12
Fig 1.8 Schematic of posterior circulation, demonstrating cerebellar arteries including superior cerebellar artery (SPA), anterior inferior cerebellar artery (AICA), and posterior inferior cerebellar artery (PICA).
time. Curvature of the basilar as it ascends has been associated with the presence of a wider contralateral vertebral artery, suggesting hemodynamic modeling. The length of the basilar artery is consistently 25–35 mm, irrespective of body size.50 The diameter is about 2.7– 4.3 mm at the proximal portion. The luminal diameter of the basilar artery tends to taper towards the distal end. The largest branches of the basilar artery include the anterior inferior cerebellar artery (AICA) and superior cerebellar artery (SCA) (Fig. 1.8). Numerous smaller perforators embrace the brainstem, coursing from the midline ventral aspect around the surface to the lateral dorsal surface, and diving deep into the substance of the brainstem between fiber tracts. These pontine perforators are grouped into medial and lateral subdivisions, often referred to as paramedian and circumferential arteries. Lateral pontine perforators extend to also supply the ventrolateral surface of the cerebellum, whereas the medial perforators perfuse midline structures of the midbrain. There is a somewhat downward trajectory of brainstem perforating arteries so that the most rostral portion of the basilar artery supplies penetrators to the pontine tegmentum. The internal auditory or labyrinthine artery may arise from the basilar to provide arterial blood flow to the cochlea, labyrinth, and facial (VII) nerve.51 Alternatively, this artery may arise as a branch of the AICA. Owing to the paired structure of posterior circulation arteries,
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asymmetries or relative dominance of one artery such as the PICA, AICA, or SCA may occur. Contralateral cerebellar infarction may therefore result from occlusion or disease of one cerebellar artery. The frequencies of such patterns vary and are difficult to estimate, although the advent of MRI and MRA allows for systematic evaluation of such relatively subtle features. Terminal branches of the PICA, AICA, and SCA form anastomoses that allow for collateral flow to easily shift between their arterial territories.1,52
Anterior inferior cerebellar artery The AICA extends off of the basilar artery approximately one-third to halfway through its course.52 The AICA arises from the caudal third of the basilar 74% of the time.52 This artery is the smallest of the principal cerebellar arteries. During development, the AICA appears as one of the larger perforatoring vessels extending to the posterior aspect of the hindbrain. The AICA extends laterally and inferiorly, in close proximity to the abducens (VI) nerve. Similar to the lateral pontine perforators, it courses around the brainstem and then enters the cerebellopontine angle cistern along with the facial (VII) and vestibulocochlear (VIII) nerves. The AICA crosses the anteroinferior aspect of the cerebellum to supply the middle cerebellar peduncle, flocculus, and adjacent cerebellum. The AICAs supply a rather small variable portion of the anterior inferior cerebellum.53 The supply to the brachium pontis and flocculus is consistent. Numerous pontine perforators may arise from its proximal segment. The lateral branch runs across the cerebellum in the horizontal fissure. The medial branch of the AICA courses inferiorly to supply the biventral lobule. Similar to absence of the PICA, the AICA may be absent or hypoplastic and is typically accompanied by a prominent PICA. Variable infarct patterns may be noted in these regions of the posterior circulation, likely reflecting arterial configurations of the principal cerebellar arteries that may involve hypoplastic segments or anomalous anastomoses.53,54 Combined or multiple territorial infarcts such as the PICA and AICA or AICA and SCA may reflect dominant patterns of arterial supply originating from the vertebral and basilar arteries. Similarly, collateral anastomoses between these territories may provide sufficient arterial inflow to spare distal segments of a particular arterial territory. As individ-
ual anatomy is often studied only after the onset of stroke, the original arterial configuration and mechanistic events may only be surmised. Similarly, the frequency of specific arterial supply patterns may be difficult to ascertain in the healthy population as individuals are most often studied after presentation with potential neurovascular disorders.
Superior cerebellar artery The SCA also extends from the basilar in symmetric fashion, just proximal to the terminal bifurcation of the basilar into the proximal PCAs. SCA morphology is more consistent across individuals than other cerebellar branches.55 The SCA courses laterally below the oculomotor (III) nerve, passing around the cerebral peduncles and below the trochlear (IV) nerve.28 Numerous perforators extend from the proximal or ambient SCA to supply the adjacent pons and midbrain, whereas distal segments split into the lateral marginal and superior vermian branches. These divisions may also arise independently from the basilar artery or even the PCA. Duplication of the SCA is noted in 28% of individuals, with bilateral duplication in 10%.56 The SCA variably divides into medial SCA and lateral SCA branches. The lateral marginal SCA supplies the anterosuperior cerebellum, superior cerebellar peduncle, middle cerebral peduncle, and dentate nuclei. The superior vermian SCA supplies the superior cerebellar peduncle, tentorium, inferior colliculi, cerebellar hemispheres, and dentate nuclei. Anastomoses between this branch and the inferior vermian branch of the PICA allow for robust collateral perfusion across the cerebellar hemispheres.57
Posterior cerebral artery The PCA develops from fusion of several vessels that supply the mesencephalon, diencephalon, and choroid plexus in the fetus.58 These vessels stem from the terminal aspect of the PCoA at the distal end of the carotid circulation. The PCA most often then extends posteriorly to spread over the ipsilateral cortex, whereas the proximal connection with the PCoA regresses. In this common scenario, the primary arterial supply shifts to a source from the terminal basilar artery. In the remainder of individuals, the PCA supply continues 13
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Fig 1.9 Digital subtraction angiography illustrating posterior cerebral artery anastomosis with posterior communicating artery, thalamoperforators, and distal cortical branches.
from what has been termed a fetal PCoA. Variants of PCoA anatomy include a diverse range of caliber in this segment, complete agenesis, and anomalous origins of other vessels from this arterial segment.59 The PCA extends from the terminal portion of the basilar artery in the interpeduncular cistern, passing above the oculomotor (III) nerve to circle the midbrain above the tentorium (Fig. 1.9). As it passes through the peduncular, ambient, and quadrigeminal cisterns, numerous perforators supply adjacent structures.60 This pattern of arterial limbs includes paramedian perforators, short circumferential and long circumferential branches that typify the general structure of the major arterial territories in the posterior circulation. The perforating arteries from these segments range from 200 μm to 800 μm in diameter.60 The artery of Davidoff and Schechter extends from the P1 segment to supply part of the inferior surface of the tentorium. The midbrain receives arterial blood from the peduncular or P1 segment before posterior thalamoperforators arise. In the successive ambient segment, the thalamogeniculate arteries diverge to supply the lateral geniculate and pulvinar nuclei. Medial and lateral 14
branches of the posterior choroidal arteries extend from this portion of the PCA to supply the pineal gland, third ventricle, dorsomedial thalamus, pulvinar, lateral geniculate body, and choroid plexus.61 These distal posterior choroidal arteries form anastomoses with the AChA. These deep arterial territories composed of perforatoring arterioles that encompass the thalamus are often difficult to comprehend because of their complex configuration (Fig. 1.10).62 The P1 or proximal PCA serves as an important arterial segment in this configuration, with variable contributions from the basilar artery, PCoA, and AChA.63 These vessels have perforators that supply these critical structures at the juncture between the anterior and posterior circulations. The anterior thalamoperforating arteries consist of about 7–10 branches that arise from the superior and lateral surfaces of the PCoA.63 A larger branch, the premamillary artery, is often noted.64 This vessel courses from the posterior aspect of the PCoA, penetrates the hypothalamus and subsequently terminates in branches that supply the anterior and ventroanterior nuclei of the thalamus. Further posteriorly, the thalamus is
Fig 1.10 Schematic of the arterial supply to the thalamus, illustrating premamillary arteries (A), interpeduncular perforators (B), thalamogeniculate arteries (C), posterior choroidal arteries (PCoA) (D), and anterior choroidal artery (AChA) (E). PCA, posterior cerebral artery.
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supplied by a combination of vessels arising from the posterior circulation. Interpeduncular branches from the basilar artery and P1 segment ascend superiorly to perfuse mesial aspects of the thalamus. More lateral aspects of the thalamus, including the ventroposteromedial and ventroposterolateral nuclei are supplied by the thalamogeniculate arteries.65 These typically consist of 3–5 small branches that penetrate the inferior aspect of the thalamus and also supply blood to the geniculate bodies.60 The most posterior reaches of the thalamus are supplied via the posterior choroidal arteries, arising from more distal aspects of the subcortical PCA. These posterior choroidal branches supply portions of the medial nuclei, habenula, and rostromedial pulvinar, and choroid plexus.66 The posterior choroidal arteries adjoin and overlap to some extent with distal reaches of the AChA, extending from the ICA to supply lateral and posterior regions of the thalamus. The PCA passes along the free edge of the tentorium to eventually reach the medial aspect of the occipital lobe. Further branching within the hippocampal fissure produces cortical divisions that course over the inferior and mesial aspects of the hemisphere. The cortical territories of the PCA are supplied via the anterior and posterior divisions, fanning out to follow the architecture of the cortical surface in these regions. Cortical branches of the PCA include the hippocampal, anterior temporal, middle temporal, posterior temporal, parieto-occipital, calcarine, and posterior pericallosal or perisplenial arteries.67 Anastomoses of the PCA allow for collateral flow into the MCA via the anterior and posterior temporal arteries and into the ACA via pericallosal divisions that arise from the quadrigeminal PCA.1
Conclusions Anatomy and physiology, or pathophysiology such as intracranial atherosclerosis, are inextricably linked. Knowledge of abnormal or pathological conditions such as intracranial atherosclerosis stems from detailed recognition of the normal or baseline pattern of vascular anatomy. The vascular anatomy of the intracranial arteries, at the level of the vessel wall and as a larger structure or conduit, is a reflection of physiology over time, from in utero stages through adult life. The embryologic development of these structures is
therefore pivotal, for understanding the flux of carotid supply to the hindbrain that ultimately determines PCoA morphology or for deciphering the complex pattern of evolving cortical architecture that shapes distal arterial territories. Variant anatomy may also be understood from this perspective, as persistence of embryologic variants typically reflects ongoing flow requirements. The unique characteristics of arteries at the base of the brain may help our understanding of atherosclerotic lesions that tend to afflict specific arterial segments. Replacement of smooth muscle cells in the arterial media with other cellular components or focal increases in fluid shear stress because of vessel morphology may hasten disease. Similarly, medical and endovascular therapeutic strategies may be refined through consideration of this unique anatomical system. Although much of the knowledge regarding intracranial arteries originates from pathology and angiography series over several centuries, evolving noninvasive techniques have rapidly expanded our perspective on these key arterial segments. As each modality provides a depiction that combines anatomy and flow physiology, it is important to interpret each image with a solid understanding of typical arterial anatomy. Ongoing studies that illustrate the anatomy and pathophysiology of these proximal arterial segments across modalities will help refine our knowledge of the interplay between vascular anatomy and cerebral blood flow. Such descriptions will likely extend far beyond the current standard of characterizing a vascular lesion solely based on the degree of luminal stenosis. Although distal arterial segments have not been emphasized in this chapter, collateral anastomoses at such sites may greatly influence disease management of intracranial atherosclerosis in the proximal intracranial arteries. Collateral flow should theoretically be inconsequential or nonexistent if an atherosclerotic lesion is not hemodynamically significant, determined by a critical threshold around 60–70%. Nevertheless, anecdotal descriptions relate findings of collateral flow with even slight or moderate stenoses. Future studies may help elucidate pivotal arterial factors far beyond the degree of stenosis, examining downstream influences on cerebral perfusion, artery-to-artery thromboembolic potential, amenability to endovascular therapies and stent conformation, or propensity for restenosis due to biophysical factors. 15
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References 1 Liebeskind DS. Collateral circulation. Stroke 2003; 34: 2279–2284. 2 Parmar H, Sitoh YY, Hui F. Normal variants of the intracranial circulation demonstrated by MR angiography at 3T. Eur J Radiol 2005; 56: 220–228. 3 Feldmann E, Wilterdink JL, Kosinski A, et al. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. Neurology 2007; 68: 2099–2106. 4 Stehbens WE. Pathology of the cerebral blood vessels. St Louis, MO: CV Mosby 1972. 5 Walmsley JG, Canham PB. Orientation of nuclei as indicators of smooth muscle cell alignment in the cerebral artery. Blood Vessels 1979; 16: 43–51. 6 Walmsley JG. Vascular smooth muscle orientation in curved branches and bifurcations of human cerebral arteries. J Microsc 1983; 131: 377–389. 7 Walmsley JG. Vascular smooth muscle orientation in straight portions of human cerebral arteries. J Microsc 1983; 131: 361–375. 8 Farrall AJ, Wardlaw JM. Blood–brain barrier: ageing and microvascular disease – systematic review and metaanalysis. Neurobiol Aging (in press). 9 Bang OY, Buck BH, Saver JL, et al. Prediction of hemorrhagic transformation after recanalization therapy using T2∗ -permeability magnetic resonance imaging. Ann Neurol 2007; 62: 170–176. 10 Oldendorf WH, Cornford ME, Brown WJ. The large apparent work capability of the blood–brain barrier: a study of the mitochondrial content of capillary endothelial cells in brain and other tissues of the rat. Ann Neurol 1977; 1: 409–417. 11 McCarron RM, Chen Y, Tomori, T, et al. Endothelialmediated regulation of cerebral microcirculation. J Physiol Pharmacol 2006; 57 (Suppl 11): 133–144. 12 Hassler O. The windows of the internal elastic lamella of the cerebral arteries. Virchows Arch Pathol Anat Physiol Klin Med 1962; 335: 127–132. 13 Takayanagi T, Rennels ML, Nelson E. An electron microscopic study of intimal cushions in intracranial arteries of the cat. Am J Anat 1972; 133: 415–429. 14 Heil M, Eitenmuller I, Schmitz-Rixen T, Schaper W. Arteriogenesis versus angiogenesis: similarities and differences. J Cell Mol Med 2006; 10: 45–55. 15 Schaper W, Scholz D. Factors regulating arteriogenesis. Arterioscler Thromb Vasc Biol 2003; 23: 1143–1151. 16 Zervas NT, Liszczak TM, Mayberg MR, Black PM. Cerebrospinal fluid may nourish cerebral vessels through pathways in the adventitia that may be analogous to systemic vasa vasorum. J Neurosurg 1982; 56: 475–481.
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17 Clower BR, Sullivan DM, Smith RR. Intracranial vessels lack vasa vasorum. J Neurosurg 1984; 61: 44–48. 18 Quisling RG, Rhoton AL, Jr. Intrapetrous carotid artery branches: radioanatomic analysis. Radiology 1979; 131: 133–136. 19 Allen JW, Alastra AJ, Nelson PK. Proximal intracranial internal carotid artery branches: prevalence and importance for balloon occlusion test. J Neurosurg 2005; 102: 45–52. 20 Frugoni P, Nori A, Galligioni F, Giammusso V. Further considerations on the Bernasconi and Cassinari’s artery and other meningeal rami of the internal carotid artery. Neurochirurgia (Stuttg) 1964; 108: 18–23. 21 Gibo H, Lenkey C, Rhoton AL, Jr. Microsurgical anatomy of the supraclinoid portion of the internal carotid artery. 1981; J Neurosurg 55: 560–574. 22 Alpers BJ, Berry RG, Paddison RM. Anatomical studies of the circle of Willis in normal brain. AMA Arch Neurol Psychiatry 1959; 81: 409–418. 23 Schomer DF, Marks MP, Steinberg GK, et al. The anatomy of the posterior communicating artery as a risk factor for ischemic cerebral infarction. N Engl J Med 1994; 330: 1565–1570. 24 Eftekhar B, Dadmehr M, Ansari S, Ghodsi M, Nazparvar B, Ketabchi E. Are the distributions of variations of circle of Willis different in different populations? Results of an anatomical study and review of literature. BMC Neurol 2006; 6: 22. 25 Uchino A, Kato A, Takase Y, Kudo S. Persistent trigeminal artery variants detected by MR angiography. Eur Radiol 2000; 10: 1801–1804. 26 Rhoton AL, Jr, Fujii K, Fradd B. Microsurgical anatomy of the anterior choroidal artery. Surg Neurol 1979; 12: 171–187. 27 Takahashi S, Suga T, Kawata Y, Sakamoto K. Anterior choroidal artery: angiographic analysis of variations and anomalies. AJNR Am J Neuroradiol 1990; 11: 719– 729. 28 Saeki N, Rhoton AL, Jr. Microsurgical anatomy of the upper basilar artery and the posterior circle of Willis. J Neurosurg 1977; 46: 563–578. 29 Morandi X, Brassier G, Darnault P, Mercier P, Scarabin JM, Duval JM. Microsurgical anatomy of the anterior choroidal artery. Surg Radiol Anat 1996; 18: 275– 280. 30 Gibo H, Carver CC, Rhoton AL, Jr, Lenkey C, Mitchell RJ. Microsurgical anatomy of the middle cerebral artery. J Neurosurg 1981; 54: 151–169. 31 Bouissou H, Emery MC, Sorbara R. Age related changes of the middle cerebral artery and a comparison with the radial and coronary artery. Angiology 1975; 26: 257– 268.
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32 Donzelli R, Marinkovic S, Brigante L, et al. Territories of the perforating (lenticulostriate) branches of the middle cerebral artery. Surg Radiol Anat 1998; 20: 393– 398. 33 Grand W. Microsurgical anatomy of the proximal middle cerebral artery and the internal carotid artery bifurcation. Neurosurgery 1980; 7: 215–218. 34 Jain KK. Some observations on the anatomy of the middle cerebral artery. Can J Surg 1964; 7: 134–139. 35 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. 36 Komiyama M, Nakajima H, Nishikawa M, Yasui T. Middle cerebral artery variations: duplicated and accessory arteries. AJNR Am J Neuroradiol 1998; 19: 45–49. 37 Lazar ML, Bland JE, North RR, Bringewald PR. Middle cerebral artery fenestration. Neurosurgery 1980; 6: 297– 300. 38 Yamamoto H, Marubayashi T, Soejima T, Matsuoka S, Matsukado Y, Ushio Y. Accessory middle cerebral artery and duplication of middle cerebral artery – terminology, incidence, vascular etiology, and developmental significance. Neurol Med Chir (Tokyo) 1992; 32: 262–267. 39 Perlmutter D, Rhoton AL, Jr. Microsurgical anatomy of the anterior cerebral-anterior communicating-recurrent artery complex. J Neurosurg 1976; 45: 259–272. 40 Pearce JM. Heubner’s artery. Eur Neurol 2005; 54: 112– 114. 41 Perlmutter D, Rhoton AL, Jr. Microsurgical anatomy of the distal anterior cerebral artery. J Neurosurg 1978; 49: 204–228. 42 Delcker A, Diener HC. [Various ultrasound methods for studying the vertebral artery – comparative evaluation]. Ultraschall Med 1992; 13: 213–220. 43 Touboul PJ, Bousser MG, LaPlane D, Castaigne P. Duplex scanning of normal vertebral arteries. Stroke 1986; 17: 921–923. 44 Park JH, Kim JM, Roh JK. Hypoplastic vertebral artery: frequency and associations with ischaemic stroke territory. J Neurol Neurosurg Psychiatry 2007; 78: 954– 958. 45 Jeng JS, Yip PK. Evaluation of vertebral artery hypoplasia and asymmetry by color-coded duplex ultrasonography. Ultrasound Med Biol 2004; 30: 605–609. 46 Lister JR, Rhoton AL, Jr, Matsushima T, Peace DA. Microsurgical anatomy of the posterior inferior cerebellar artery. Neurosurgery 1982; 10: 170–199. 47 Fine AD, Cardoso A, Rhoton AL, Jr. Microsurgical anatomy of the extracranial-extradural origin of the
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posterior inferior cerebellar artery. J Neurosurg 1999; 91: 645–652. Lesley WS. and Dalsania HJ. Double origin of the posterior inferior cerebellar artery. AJNR Am J Neuroradiol 2004; 25: 425–427. Cullen SP, Ozanne A, Alvarez H, Lasjaunias P. The bihemispheric posterior inferior cerebellar artery. Neuroradiology 2005; 47: 809–812. Brassier G, Morandi X, Riffaud L and Mercier P. Basilar artery anatomy. J Neurosurg 2000; 93: 368–369. Kim JS, Lopez I, DiPatre PL, Liu F, Ishiyama A, Baloh RW. Internal auditory artery infarction: clinicopathologic correlation. Neurology 1999; 52: 40–44. Rhoton AL, Jr. The cerebellar arteries. Neurosurgery 2000; 47: S29–68. 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. Terao S, Miura N, Osano Y, et al. Multiple cerebellar infarcts: clinical and pathophysiologic features. J Stroke Cerebrovasc Dis 2005; 14: 193–198. Hardy DG, Peace DA, Rhoton AL, Jr. Microsurgical anatomy of the superior cerebellar artery. Neurosurgery 1980; 6: 10–28. Icardo JM, Ojeda JL, Garcia-Porrero JA, Hurle JM. The cerebellar arteries: cortical patterns and vascularization of the cerebellar nuclei. Acta Anat (Basle) 1982; 113: 108–116. Brandt T, von Kummer R, Muller-Kuppers M, Hacke W. Thrombolytic therapy of acute basilar artery occlusion. Variables affecting recanalization and outcome. Stroke 1996; 27: 875–881. Zeal AA. and Rhoton AL, Jr. Microsurgical anatomy of the posterior cerebral artery. J Neurosurg 1978; 48: 534– 559. Bisaria KK. Anomalies of the posterior communicating artery and their potential clinical significance. J Neurosurg 1984; 60: 572–576. Milisavljevic MM, Marinkovic SV, Gibo H, Puskas LF. The thalamogeniculate perforators of the posterior cerebral artery: the microsurgical anatomy. Neurosurgery 1991; 28: 523–529; Discussion 9–30. Fujii K, Lenkey C, Rhoton AL, Jr. Microsurgical anatomy of the choroidal arteries: lateral and third ventricles. J Neurosurg 1980; 52: 165–188. Carrera E, Michel P, Bogousslavsky J. Anteromedian, central, and posterolateral infarcts of the thalamus: three variant types. Stroke 2004; 35: 2826–2831. Percheron G. [Arteries of the thalamus in man. Choroidal arteries. III. Absence of the constituted thalamic territory of the anterior choroidal artery. IV. Arteries and thalamic
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territories of the choroidal and postero-median thalamic arterial system. V. Arteries and thalamic territories of the choroidal and postero-lateral thalamic arterial system]. Rev Neurol (Paris) 1977; 133: 547–558. 64 Gibo H, Marinkovic S, Brigante L. The microsurgical anatomy of the premamillary artery. J Clin Neurosci 2001; 8: 256–260. 65 Georgiadis AL, Yamamoto Y, Kwan ES, Pessin MS, Caplan LR. Anatomy of sensory findings in patients with
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posterior cerebral artery territory infarction. Arch Neurol 1999; 56: 835–838. 66 Liebeskind DS, Hurst RW. Infarction of the choroid plexus. AJNR Am J Neuroradiol 2004; 25: 289–290. 67 Brandt T, Steinke W, Thie A, Pessin MS, Caplan LR. Posterior cerebral artery territory infarcts: clinical features, infarct topography, causes and outcome. Multicenter results and a review of the literature. Cerebrovasc Dis 2000; 10: 170–182.
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Pathologic characteristics Xiang-Yan Chen and Mark Fisher
Atherosclerosis is a lifetime illness evolving slowly over many years.1 The course and maturation of atherosclerosis are influenced by cholesterol accumulation in the endothelial cells of the arterial wall.2 Atherosclerosis has traditionally been viewed to simply reflect the deposition of lipids. However, this concept has now been changed. It is currently understood that complex endothelial dysfunction is associated with atheroscerlsosis: elevated or modified low-density lipoproteins (LDLs), free radicals, infectious microorganisms, shear stress, hypertension, toxins derived from cigarette smoking, and associated compensatory inflammatory responses.3 Atherosclerosis involves multiple arteries throughout the body, including the aorta, coronary arteries, arteries of inner organs, or the limbs. Atherosclerosis may affect major intracranial and extracranial arteries. In intracranial vessels, atherosclerosis occurs in the setting of widespread vascular disease. Its onset is much later in life, and the severity of the lesions at various ages is consistently less than that of extracranial arteries in humans,4–9 non-human primates,10 rhesus and cynomolgus monkeys,11 spontaneously hypertensive rats,12,13 cholesterol-fed rabbits,11 and Watanabe heritable hyperlipidemic rabbits.14 However, in the recent years, it has been found that patients with intracranial atherosclerosis are at increased risk of stroke and heart disease. The occurrence of intracranial atherosclerosis seems to occur in two separate patterns: (1) In patients with severe extracranial and systemic atherosclerosis and (2) in some racial and ethnic groups who seem to have isolated intracranial disease with little extracranial, coronary, or systemic disease. Intracra-
nial severe atherosclerotic stenosis is thought to be more often accompanied by brain infarction than comparable extracranial disease.15–17
General features of atherosclerosis Atherosclerotic lesions begin with an inflammatory reaction followed by smooth muscle proliferation and thickening of the arterial wall. Histologically, atherosclerotic plaques have three principal components: (1) cells, including smooth muscle cells, and macrophages and other leukocytes; (2) connective tissue extracellular matrix, including collagen, elastin fibers, and proteoglycans; and (3) intracellular and extracellular lipid deposits. The proportion of these three components differs in different plaques, giving rise to a wide spectrum of lesions.18–20 Its development appears to be progressive, with well-recognized pathologic lesions that develop in a continuum (Fig. 2.1). The first observed pathologic change in the artery is a so-called fatty streak. It is characterized by the adhesion of monocytes to the endothelium and their migration to the subendothelial potions of the arterial wall. In this location, they form a foamy appearance microscopically.21 Fatty streaks can be found in the aorta and the coronary arteries of adolescents and young adults. Hemodynamic factors influence the location of initially developed plaques, and may contribute to their eventual destabilization. The most common locations for the developments of fatty streaks are the areas of vascular bifurcations or with turbulent blood flow. In cerebral arteries, plaques usually develop at the bifurcation of the common carotid
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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A
B
Fig 2.1 Progression of atherosclerosis. (A) Endothelial dysfunction; (B) fatty-streak formation; (C) formation of an advanced, complicated lesion; (D) unstable fibrous plaques (From Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med 1999; 340: 115–126, with permission).
artery where the internal carotid artery originates. Atherosclerosis of the middle cerebral artery (MCA) most commonly affects the first portion (M1 segment), which extends from the origin of the artery to its bifurcation in the sylvian fissure. In the vertebrobasilar system, plaques are most commonly found at the origin of the vertebral arteries and in the basilar artery at its origin. 20
With increasing age, the fatty streak is transformed into a fibrous plaque. A plaque is usually found in middle-aged or older adults. It consists of a core of cellular debris, free extracellular lipid, and cholesterol crystals under a “cap” consisting of foam cells, transformed smooth muscle cells, lymphocytes, and connective tissue.21 The most advanced stage of atherosclerosis is the complicated lesion, which contains
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C
D
Fig 2.1 (Continued)
calcification, hemosiderin deposition, and luminal surface disruption.
Pathological characteristics of atherosclerosis in different arteries The pathological characteristics of atherosclerosis are different depending on arterial regions (coronaries,
carotids, or aorta). The pathology and pathogenesis of atherosclerosis in coronary arteries have been well studied in past years. Rupture-prone plaques in the coronary arteries, the so-called “vulnerable plaques”, tend to have a thin fibrous cap and a large lipid core. Acute coronary syndromes often result from rupture of a modestly stenotic vulnerable plaque.20 21
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The neuropatholgic features of extracranial or intracranial atherosclerosis are encountered in surgical specimens (i.e., derived from carotid endarterectomy) or at the time of necropsy. In contrast to coronary artery vulnerable plaques, high-risk plaques in carotid arteries are usually severely stenotic. Thus, the term “high-risk” has been used rather than the classic term “vulnerable,” which only implies the presence of a lipid-rich core. However, based on a large series in which the carotid endarterectomy specimen was carefully examined, it was found that carotid plaque morphology such as intraplaque hemorrhage or reparative neovascularization importantly influences plaque instability rather than the degree of stenosis.22,23 Fisher et al.24 reported that carotid plaque ulceration and thrombosis are more prevalent in symptomatic patients. Similarly, Barnett et al.25 investigated patients with cerebral embolic ischemia due to carotid artery atherosclerosis, and found that the dynamic state of the intimal surface in corresponding vessels is often associated with thrombus attached to de-endothelialized ulcerative plaque, intraluminal necrotic material, foamy histiocytes, and even foreign-body giant cells being shed on to the lumen. Any of the materials may act as the source of emboli to distal sites leading to subsequent ischemic events. In addition to emboli, hemodynamic conditions are consistently associated with the development of intimal atherosclerosis disease in carotid bifurcation arteries removed in autopsy.26 It is concluded that in the human carotid bifurcation, regions of moderate to high shear stress, where flow remains unidirectional and axially aligned, are relatively spared of intimal thickening. Intimal thickening and atherosclerosis develop largely in regions of relatively low wall shear stress, flow separation, and departure from axially aligned, unidirectional flow. It has been presumed that intracranial atherosclerosis may be similar to that found elsewhere, but this assumption should not be made lightly because of the epidemiologic differences between intra- and extracranial atherosclerotic disease.
Natural course of atherosclerosis Fatty streaks, fibrous plaques, and complicated plaques are the pathologic hallmarks of atheroscle22
rosis. These lesions insidiously progress, and symptoms develop when the plaque luminal surface destabilizes. Its evolution is a slowly progressive complex interaction of cellular events, intercellular messengers, hemodynamic factors, and vascular risk factors.21 The major cellular contributors to plaque development are monocytes/macrophages, endothelial cells, smooth muscle cells, and, to a lesser degree, lymphocytes and platelets. They interact in a complicated fashion. Circulating monocytes are recruited at a very early stage, enter the arterial wall, and become macrophages. Macrophages imbibe lipid, primarily LDL cholesterol, to form foam cells, a hallmark of early plaque formation.26 According to Dr. Russell Ross’s “response to injury” hypothesis, the initiating event for early plaque formation is functional or morphological endothelial injury induced by a variety of mechanical, biochemical, or physical stimuli. Monocytes/macrophages are then recruited, collecting in the arterial wall. Lipids accumulate, growth factors and cytokines are released, and smooth muscle cells and lymphocytes are recruited. As the process continues unimpeded, plaque slowly grows and matures. Platelets may gather at sites of endothelial disruption. As lipid-filled cells die, a central core is formed, leading to plaque remodeling and fibrosis. Macrophages, endothelial cells, smooth muscle cells, platelets, and different factors released by these cells (e.g., cytokines, growth factors, oxygen free radicals) promote the process of plaque development. Hemodynamic factors contribute to atherogenesis at preferential sites within the arterial vasculature, presumably by influencing the cellular mechanisms. Atherosclerotic plaques usually enlarge slowly over decades without any symptomatic presentations. The increase of a plaque over years leads to narrowing of the vessel and reduces blood flow.1 The narrowing may also lead to local turbulence of blood flow or sluggish perfusion. This turbulence and slow flow can activate platelets and clotting factors, which in turn promote thrombosis. Luminal surface disruption is probably the primary event in most cases, and leads to local thrombus formation. These thrombi may then embolize more distally to cause a particular stroke syndrome related to the occluded vascular territory. Alternatively, the compromised vessel may cause hemodynamic failure to produce ischemia in the distal areas.
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Evidence from animal models To evaluate atherosclerosis in intracranial arteries, different animal models have been developed in many species, including swine, chickens, dogs, rabbits, rats, and monkeys.27–34 The models are very useful for studying morphological characteristics, the pathogenesis of cerebral atherosclerosis, and may be applied to the prevention and treatment of the human disease.30–32 Atherosclerosis can be produced in rabbits when they are fed an atherogenic diet.35 In this model, arterial lesions form rapidly, with accumulation of lipids in macrophages and formation of lesions associated with foam cells.36 In contrast, atherosclerosis occurs spontaneously in Watanabe heritable hyperlipidemic (WHHL) rabbits, are well known to develop severe atherosclerotic lesions in extracranial arteries.37 But it is difficult to induce atherosclerosis in the cerebral arteries, especially in intracranial arteries. To produce non-human models of cerebral atherosclerosis, additional application of hypertension is more effective than inducing hyperlipidemia alone.37–43 In a cynomolgus monkey, hypertension appears to accelerate cerebral atherosclerosis.40 In selectively bred homozygous WHHL rabbits that are known to show hypercholesterolemia and severe coronary atherosclerosis, Ito and Shiomi38 also demonstrated spontaneously developed cerebral atherosclerosis beginning at 9 months of age. These intracranial lesions occurred in the absence of hypertension in 24 of 25 animals at various sites, mainly along arteries at the base of the brain. Arterial findings were similar to those in human cerebral atherosclerosis, indicating that the coronary atherosclerosis-prone homozygous WHHL rabbit represents the first animal model for spontaneous cerebral atherosclerosis. In addition, there are other methods to produce cerebral atherosclerosis in animals. Yamori et al.44 successfully developed fat deposition in the posterior communicating arteries in normotensive rats, which were fed high-fat cholesterol (HFC) for 10 weeks after bilateral or unilateral carotid artery ligation or basilar artery ligation. These findings suggest that not only high blood pressure but also hemodynamic derangements are important factors for the development of fat deposition in cerebral arteries. Another model of cerebral arteriosclerosis was induced by intimal injury in rabbits.45 Intimal injury was produced by a silicone
rubber cylinder with nylon thread that was injected from the bifurcation of the right external and internal carotid arteries to embolize either to the intracranial internal carotid or middle cerebral artery. These findings suggest that enhancement of permeability of plasma constituents of the regenerated endothelium plays an important role in the atherogenesis of cerebral arteries. The animal models have demonstrated morphological characteristics of intracranial atherosclerosis and its development from different aspects. In hypertensive WHHL rabbits,37 atherosclerotic lesions developed near the vertebral–basilar arterial confluence and at the circle of Willis by 6 months after hypertensioninducing surgery (right nephrectomy and surgically induced stenoses of the left renal artery). Morphological studies showed that atherosclerotic lesions in cerebral arteries remained less severe than in the aorta and coronary arteries, and exhibited qualitative morphologic differences. Kato et al.41 also studied the development of cerebral atherosclerosis in rabbits. The earliest lesions developed at remarkably localized areas of the basilar artery–posterior cerebral artery Y-bifurcation (area A) and vertebral–basilar artery confluence (area B). By light microscopy, intimal lesions were mainly composed of accumulations of foam cells and smooth muscle cells. Foam cells that accumulated in the intima resembled those of monocyte–macrophage lineage. Early lesions involving only a few endothelial cells with adherent leukocytes occurred at the dividing and confluent portions of the endothelial arrays formed in areas A and B, respectively. Another study39 of experimental rabbits also demonstrated early lesions of intracranial atherosclerosis. By microscopy, widespread thickening and contraction were seen in almost all intracranial small arteries. Hyaline degeneration could be seen in some of the arteries. Most of the cerebral parenchymal capillary endothelia were swollen and some of these cells contained lipid. Imai and Thomas29 investigated cerebral atherosclerosis in swine and found necrosis in progression of diet-induced lesions from the proliferative to the atheromatous stage. Mechanisms of ischemic stroke induced by intracranial atherosclerosis has also been studied in animal models. Jeynes and Warren46 set up an animal model of cerebral atheroembolism by injecting human atheromatous material into the cerebral vasculature of rabbits via the left common carotid artery. 23
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Signs of neurologic deficit with motor dysfunction were seen in some surviving animals; occlusive vascular lesions were predominantly localized in ipsilateral cortical and subcortical vessels within the distribution territory of the middle cerebral artery. The occlusive lesions showed strong evidence of thrombosis. This experimental system may be useful as a model to study blood–atheroembolic vascular reactions, mechanism of cerebral infarction, and to test agents for preventing strokes or stabilizing the atheroma.
Human autopsy studies Investigating pathological characteristics of intracranial atherosclerosis have been particularly difficult because of the limitations of autopsy populations, time-consuming dissections of the arteries, and numerous technical problems associated with specimen preparation, shipment, and storage. Long-term repeated studies and grading systems and validation are also elements adding to the complexity of these studies. Nevertheless, autopsy study is still an important and valuable method to investigate intracranial atherosclerosis. The following is a procedure to obtain complete intracranial and extracranial arteries at autopsy: to facilitate removal of anterior extracranial vessels, bodies are routinely opened by U-shaped cervical incision. The cervical portion of the internal carotid artery is cut as close to the skull as possible and removed with the carotid sinus, the common carotid artery down to its origin in the aortic arch, and the innominate artery. For a patient who dies of ischemic stroke, examination of the complete internal carotid artery is necessary, and the vertebral arteries should be studied throughout their extraspinal length.47 The vessels are fixed in 10% formalin, and cross-sections cut at 5-mm intervals. Blocks are taken from the narrowest parts affected by atherosclerosis. The vessels in the circle of Willis are graded by gross examination using the method of Baker et al. 48 During grading, the vessels are crosssectioned at 5-mm intervals; the narrowest parts in the middle cerebral stem and the anterior cerebral arteries, posterior cerebral arteries, basilar and vertebral arteries are then taken for histological sectioning. The presence of thrombotic or embolic occlusion and ulceration are also recorded. During the process, caution should be taken to ensure perpendicular cutting 24
and embedding. Sections 6 μm thick are prepared and stained for microscopic histology. It is recommended that all basic studies of human atherosclerosis should include both macroscopic and microscopic description of the same arterial segments with the use of adequate terminology.49 According to a study on human coronary and cerebral atherosclerosis, the character of atherosclerotic lesions, the meaning of terms “normal intima”/“fatty streaks”/“fibrous plaques”/“complicated lesions,” the type of the early atherosclerotic lesions, the age of onset of these lesions, their sequence of development, their relationship to advanced lesions, all appear method-dependent. Gross inspection alone may lead us to have a distorted view on the natural history of atherosclerosis, because items such as intimal necrosis, incorporated microthrombi, fibromuscular plaques, mucoid plaques, and foam cell-rich plaques may be overlooked. By gross inspection, early stages of atherosclerotic involvement are frequently undetected as well. Within the same vascular segments, significant differences may occur between the number of atherosclerotic lesions recorded on microscopic and macroscopic examinations.
Risk factors In cerebral atherosclerosis, quantitative differences in severity exist among different age groups, races, and between males and females.50 Comparative neuropathologic features of cerebral atherosclerosis among ethnic groups have revealed that there are significant difference between North American and Asian populations. Autopsy studies in stroke patients have shown that African Americans and Japanese people tend to have intracranial vascular occlusion, whereas Caucasians more often have extracranial lesions.50,51 Atherosclerotic lesions were found primarily in large-caliber vessels of the circle of Willis in a Minnesota population; among Japanese subjects, atherosclerotic lesions were much more likely to occur also in smaller caliber vessels.50 The pathological data from an autopsy study of Hong Kong Chinese people showed that, by comparison with white and Japanese populations, the extent of intracranial atherosclerosis is much more severe; atherosclerotic narrowing of the extracranial carotid artery is less severe in Hong Kong Chinese people than in Caucasians.52
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In addition to race, other risk factors for intracranial atherosclerosis include age, hypertension, cigarette smoking, diabetes mellitus, and lipid disorders.51–56 Atherosclerosis is a progressive disease with age.57–60 Moossy61 investigated development of cerebral atherosclerosis in various age groups and found that the earliest sites of deposition were the internal carotid and vertebral arteries, followed by the basilar artery and middle cerebral artery. Fatty steaks appear in the aorta in the first decade of life and in coronary arteries and extracranial carotid arteries in the second decade. The intracranial and extracranial vertebral arteries mainly have fibrous plaques by the third decade. In a New Orleans study, 1093 extracranial carotid and intracranial arteries were evaluated for black–white and male–female differences during a 10-year period. Raised lesions (fibrous plaques and complicated fibrous plaques) in the carotid arteries increased with age in both races but remained greater in black women. In the intracranial arteries fatty streaks and fibrous plaques start to form at the end of the second decade to the beginning of the third decade. A nationwide study62 of atherosclerosis in infants, children and young adults (from 1 month to 39 years old) in Japan found that atherosclerosis of aortas, coronary arteries, and cerebral arteries increased with age; the most severe lesions were seen in aortas, and then, with decreasing severity, in the coronary and cerebral arteries. Atherosclerosis occurred later and was less extensive in intracranial arteries than in extracranial arteries. Another study suggested that greater activity of antioxidant enzymes in intracranial arteries may contribute to their greater resistance to atherosclerosis and that with increasing age, accelerated atherosclerosis occurs in intracranial arteries secondary to decreased antioxidant protection.63 Hyperlipidemia, an important risk factor of coronary atherosclerosis and myocardial ischemia, is also linked to cerebral arterial atherosclerosis, as verified by a high correlation between increased cholesterol and Baker score.64 Another study65 using morphological methods to assess the severity of cerebral atherosclerosis also demonstrated that in subjects with elevated blood cholesterol levels, some features of advanced atherosclerosis (fibrous plaques, calcifications, stenoses, and occlusions of the vessel lumens) were encountered more frequently than in subjects with normal blood cholesterol level.
On the other hand, another study57 reported that blood pressure was the most important risk factor for cerebral atherosclerosis, even though serum cholesterol was also closely associated with the lesions. A study in Hisayama, Japan,6 investigating the relationship between cerebral atherosclerosis and cholesterol levels, reported that serum cholesterol level correlated better with the severity of aortic than with cerebral atherosclerosis. Studies from Oslo66,67 suggested that total serum cholesterol may be more important than systolic blood pressure in the development of coronary atherosclerosis. Intracranial advanced atherosclerotic lesions were more common in black people of both sexes at all ages.68 Regarding risk factors, black people consistently have higher rates of hypertension than white people, suggesting that hypertension or other unidentified factors may have an impact on the racial difference of intracranial atherosclerosis. A greater degree of blood pressure elevation may enhance intracranial plaque development and plaque destabilization. Cigarette smoking is another well-known risk factor for atherosclerosis in the aorta or coronary arteries.69 Smoking is known to injure endothelial cells and generate thrombi. According to a clinical study56 smoking may be the most significant independent predictor of the presence of atherosclerosis of the intracranial internal carotid artery.
Distribution of intracranial atherosclerosis Common locations for symptomatic cerebrovascular atherosclerosis are the origin of the internal carotid artery, the intracavernous portion of the internal carotid artery, the first segment of the middle cerebral artery, the origin and the distal portion of the vertebral artery, and mid-portion of the basilar artery. The origin of the internal carotid artery is the most frequent site for severe atherosclerosis in persons of European ancestry, whereas intracranial arteries, especially the middle cerebral artery, are most commonly affected among persons of African or Asian heritage.47,51,70–73 Fisher et al.,74 in a detailed autopsy study of the entire vertebrobasilar (including intraspinal) and carotid arterial systems in 178 patients (fourth through the ninth decade) demonstrated that (1) 40% of patients showed some degree of stenosis, whereas almost 10% of individuals had occlusion of a vessel in the neck 25
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and six patients had intracranial vascular occlusion; (2) symptomatic occlusion was more commonly extracranial in the carotid system but intracranial in the vertebral system; (3) stenosis in the carotid and vertebral arteries was asymptomatic; (4) hypertension aggravated cerebral atherosclerosis in general and basilar artery stenosis in particular; (5) the severity of intracranial atherosclerosis was similar in anterior and posterior portions of the circle of Willis. Another autopsy study75 carried out in Chinese subjects demonstrated that patients with cerebral infarction had arterial lesions at different levels, but the principal portions of cerebral artery lesions were the mediumsized intracranial arteries and their main branches. According to a study comparing Japanese people living in Hiroshima, Japan, with Japanese living Honolulu, Hawaii,76 atherosclerosis of the major branches of the circle of Willis was more severe in the Honolulu group whereas arteriosclerosis of penetrating arteries, with histologic features including intimal hyperplasia and subintima foam cells and cholesterol cleft deposition, was more common in men studied in the Hiroshima cohort. The latter group of the two cohorts also showed a higher incidence of cerebral infarcts, which may be attributed to the higher frequency of intraparenchymal arteriosclerosis among these men.76 Another clinical study, carried out among male participants in the Honolulu Heart Program, also showed association of severity of cerebral atherosclerosis with autopsy-verified cerebral infarcts and hemorrhage.77 The study also indicated a strong trend towards decreasing cerebral atherosclerosis in this population
A
Fig 2.2 Transverse paraffin sections of MCAs showing luminal stenosis and intraplaque neovasculature. (A) Stained with Victorial Blue (1.6×), showing 50.7% lumen stenosis. (B) Stained with H&E (10×) demonstrating intraplaque neovasculature (arrows). (From Chen XY,
26
over the years 1965–1983. The association of morphologically verified cerebral atherosclerosis with both cerebral infarcts and hemorrhage, especially in patients with large infarcts, was also confirmed by an autopsy investigation of cerebrovascular disease among 724 patients over the age of 40 who came to autopsy in Hisayama, Japan.78 Atherosclerosis of the middle cerebral artery most commonly affects the first portion (M-1 segment), which extends from the origin of the artery to its bifurcation in the sylvian fissure. The lenticulostriate vessels arise from this section, and the origins of these vessels can be affected by the development of an atherosclerotic plaque. Less commonly, the distal M1 segment or the proximal portions of the first major branches of the middle cerebral artery (M2 segment) can be involved.79 Advanced atherosclerosis of the middle cerebral artery also appears to be relatively common in diabetic patients. The majority of stenoses are less than 7 mm in length.80,81 Hemorrhage, ulceration, and calcification are found much less frequently in intracranial plaques compared with extracranial atherosclerotic plaques.53 Given the paucity of pathology data regarding middle cerebral artery atherosclerosis, an autopsy study was carried out in Hong Kong Chinese and reported that luminal stenosis caused by atherosclerotic plaque, percentage of lipid in lesion, and presence of intraplaque neovasculature in the MCA may play a key role in leading to ischemic stroke.82 The morphological features in middle cerebral artery atherosclerosis are shown in Figs 2.2 and 2.3.
B
Wong KS, Lam WW et al. Middle cerebral artery atherosclerosis: Histological comparison between plaques associated with and not associated with infarct in a postmortem study. Cerebrovasc Dis 2007; 25: 74–80, with permission.)
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A
B
Fig 2.3 Transverse paraffin sections of the MCAs showing the immunostaining results of atherosclerotic plaques (40 × 40). (A) Numerous macrophages are shown when tissues are stained with antibodies for CD 68. (B) T lymphocytes are shown when tissues are stained with
antibodies for CD45RO. (From Chen XY, Wong KS, Lam WW et al. Middle cerebral artery atherosclerosis: Histological comparison between plaques associated with and not associated with infarct in a postmortem study. Cerebrovasc Dis 2007; 25: 74–80, with permission.)
Pathogenesis
flow or hypoperfusion. Severe stenosis or occlusion potentiates the effects of hypoperfusion leading to failure of perfusion to one or more portions of the brain. This turbulence and slow flow can also activate platelets and clotting factors, which in turn promote thrombosis. Although the degree of lumen obstruction is a relevant marker of the risk of stroke,86,87 the recognition of the role of the vulnerable plaque has opened new avenues in the understanding of atherothrombotic stroke. The vulnerability depends in part by plaque morphology, which in turn is influenced by pathophysiologic mechanisms at the cellular and molecular level. All types of atherosclerotic plaques with a high likelihood of thrombotic complications and rapid progression should be considered as vulnerable
Events within atherosclerotic artery walls leading to ischemic stroke may be similar to those that are hypothesized to occur within coronary arteries resulting in myocardial ischemia, which may include thrombosis and occlusion, thromboembolism, haemodynamic compromise, or the combination of these factors.70,83 Acute thrombosis begins with fracturing of the cap of the atherosclerotic plaque, which disrupts the endothelial surface of the artery. Local occlusion and secondary artery-to-artery embolism can result.84,85 Even without thrombosis, plaque gradually increases over years and slowly impinges on the vascular lumen; consequently, the blood flow becomes altered.51 The narrowing leads to local turbulence of blood
Fig 2.4 Biological factors supporting plaque vulnerability. (From Nighoghossian N, Derex L, Douek P. The vulnerable carotid artery plaque: current imaging methods and new perspectives. Stroke 2005; 36: 2764–2772. With permission)
27
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CHAPTER 2
plaque underlying the cause of most clinical events.88 Ischemic stroke and transient ischemic attack are frequently caused by cerebral embolism from an atherothrombotic plaque or thrombosis at the site of plaque rupture.89 Figure 2.4 shows inter-related processes which account for the development of vulnerable atherosclerotic plaques.90,91 Conventional pathologic and imaging markers of plaque vulnerability in carotid artery include carotid artery intima/media thickness (IMT), erosion, ulceration, thrombus, intraplaque hemorrhage, calcification, status of fibrous cap, stratus of lipid core, extent of plaque inflammation, and microembolic signals on transcranial Doppler.91 A detailed histopathologic study92 of segments of thrombosed intracranial arteries performed on eight patients who died within 28 days of brain infarction showed occlusive thrombi in six instances and mural thrombi in two; thrombi had most commonly developed at or immediately distal to the sites of maximal stenosis. Arteries that had undergone thrombosis, showed plaque rupture (three cases), intramural hemorrhage (one) and ulceration (one). Thrombosis without plaque rupture or intramural hemorrhage was also observed in three cases. Two patients showed occlusive emboli distal to the site of thrombosis, indicating the occurrence of intracranial artery-to-artery thromboembolism. Intra-arterial embolism distal to atherosclerotic intracranial artery lesions was once thought to be an unusual occurrence but more recent transcranial Doppler studies have shown that microemboli are commonly found distal to intracranial stenotic lesions in symptomatic patients.83,92–94 A histopathologic study95 demonstrated atheromatous embolism in cerebral arteries with internal diameter of 50–300 μm in a variety of stroke patients. The presence of microembolic signals has been found to be associated with an increased risk of stroke.96 Caplan and Hennerici97 found that hypoperfusion and embolism often coexist and their pathophysiological features are interactive. Arterial luminal narrowing and endothelial abnormalities promote clot formation and subsequent embolization. Reduced perfusion limits clearance of emboli. Consequently, brain borderzones are a favored destination for microemboli that are not cleared. Impaired washout appears to be an important but neglected concept that combines hypoperfusion, embolization, and brain infarction. Until recently, the effect of emboli has 28
been confirmed when the means to detect emboli in cerebral arteries became available.96,98 Clinical studies using transcranial Doppler ultrasound have verified the association between the presence of microembolic signals and an increased risk of stroke.96 The consequences of severe atherosclerotic disease within individual major cerebral arteries have been reviewed.70,99,100 These clinical data highlight the importance of propagation of thrombotic material from the internal carotid artery to both the MCA and ACA. Moreover, the occurrence of lacunar infarcts in patients with large vessel atherosclerosis (e.g., affecting the MCA)70 highlights the probable importance of large vessel disease in the etiology of small areas of ischemia, which previously had been thought to result largely from intraparenchymal cerebral microvascular disease. Note, however, that the association of lacunae with atherosclerosis was commented on frequently by C. Miller Fisher in the 1970s.74,101–103
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10 Wissler RW, Vesselinovitch D. Atherosclerosis in nonhuman primates. Adv Vet Sci Comp Med 1977; 21: 351– 420. 11 Weber G. Delayed experimental atherosclerotic involvement of cerebral arteries in monkeys and rabbits (light, sem and tem observations). Pathol Res Pract 1985; 180: 353–355. 12 Weber G, Alessandrini C, Centi L, et al. Delayed development of intimal lesions in cerebral arteries of spontaneously hypertensive rats subjected to a short-term atherogenic diet (tem observations). Appl Pathol 1986; 4: 233–236. 13 Napoli C, Salomone S, Godfraind T, et al. 1,4dihydropyridine calcium channel blockers inhibit plasma and LDL oxidation and formation of oxidationspecific epitopes in the arterial wall and prolong survival in stroke-prone spontaneously hypertensive rats. Stroke 1999; 30: 1907–1915. 14 Wilson PW, Schaefer EJ, Larson MG, Ordovas JM. Apolipoprotein e alleles and risk of coronary disease. A meta-analysis. Arterioscler Thromb Vasc Biol 1996; 16: 1250–1255. 15 Craig DR, Meguro K, Watridge C, et al. Intracranial internal carotid artery stenosis. Stroke 1982; 13: 825– 828. 16 Marzewski DJ, Furlan AJ, St Louis P, et al. Intracranial internal carotid artery stenosis: Longterm prognosis. Stroke 1982; 13: 821–824. 17 Wechsler LR, Kistler JP, Davis KR, Kaminski MJ. The prognosis of carotid siphon stenosis. Stroke 1986; 17: 714–718. 18 Fuster V, Fayad ZA, Badimon JJ. Acute coronary syndromes: Biology. Lancet 1999; 353 Suppl 2: SII5–9. 19 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657–671. 20 Fuster V, Lewis A. Conner memorial lecture. Mechanisms leading to myocardial infarction: Insights from studies of vascular biology. Circulation 1994; 90: 2126–2146. 21 Navab M, Fogelman AM, Berliner JA, et al. Pathogenesis of atherosclerosis. Am J Cardiol 1995; 76: 18C-23C. 22 Bornstein NM, Norris JW. The unstable carotid plaque. Stroke 1989; 20: 1104–1106. 23 Bornstein NM, Krajewski A, Lewis AJ, Norris JW. Clinical significance of carotid plaque hemorrhage. Arch Neurol 1990; 47: 958–959. 24 Fisher M, Paganini-Hill A, Martin A, Cosgrove M, Toole JF, Barnett HJ, Norris J. Carotid plaque pathology: Thrombosis, ulceration, and stroke pathogenesis. Stroke 2005; 36: 253–257. 25 Barnett HJ, Peerless SJ, Kaufmann JC. “stump” on internal carotid artery–a source for further cerebral embolic ischemia. Stroke 1978; 9: 448–456.
26 Zarins CK, Giddens DP, Bharadvaj BK, et al. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circ Res 1983; 53: 502–514. 27 Kahn SG, Siller WG. Absence of atherosclerosis in the cerebral arteries of chickens fed an atherogenic diet. Nature 1967; 213: 720–721. 28 Ratcliffe HL, Luginbuhl H, Pivnik L. Coronary, aortic and cerebral atherosclerosis in swine of 3 age-groups: Implications. Bull World Health Organ 1970; 42: 225–234. 29 Imai H, Thomas WA. Cerebral atherosclerosis in swine: Role of necrosis in progression of diet-induced lesions from proliferative to atheromatous stage. Exp Mol Pathol 1968; 8: 330–357. 30 Robertson AL, Jr, Butkus A, Ehrhart LA, Lewis LA. Experimental arteriosclerosis in dogs. Evaluation of anatomopathological findings. Atherosclerosis 1972; 15: 307–325. 31 Bhardwaj JR, Kukreja RS, Banerjee AK, et al. A morphological study of experimental cerebral atherosclerosis in rhesus monkeys. Indian J Med Res 1984; 79: 86– 92. 32 Suzuki M. Experimental cerebral atherosclerosis in the dog. I. A morphologic study. Am J Pathol 1972; 67: 387–402. 33 Suzuki M, Fukuuchi Y, Shimazu K, et al. Cerebral atherosclerosis in the dog. Ii. Cerebral circulation. Arch Pathol 1973; 96: 14–17. 34 Kato H. [experimental cerebral atherosclerosis in the rabbit. Scanning electron microscopic observation of initial lesion sites]. Fukuoka Igaku Zasshi 1987; 78: 532–546. 35 Ooboshi H, Rios CD, Chu Y, et al. Augmented adenovirus-mediated gene transfer to atherosclerotic vessels. Arterioscler Thromb Vasc Biol 1997; 17: 1786–1792. 36 Buja LM, Kita T, Goldstein JL, et al. Cellular pathology of progressive atherosclerosis in the WHHL rabbit. An animal model of familial hypercholesterolemia. Arteriosclerosis 1983; 3: 87–101. 37 Kong J, Tamaki N, Asada M. Early lesions of cerebral atherosclerosis from induced hypertension in watanabe heritable hyperlipidemic rabbits. Kobe J Med Sci 2000; 46: 87–101. 38 Ito T, Shiomi M. Cerebral atherosclerosis occurs spontaneously in homozygous WHHL rabbits. Atherosclerosis 2001; 156: 57–66. 39 Zhang T. [an experimental study on cerebral arteriosclerosis]. Zhonghua Shen Jing Jing Shen Ke Za Zhi 1991; 24: 228–230, 253. 40 Hollander W, Prusty S, Kemper T, et al. The effects of hypertension on cerebral atherosclerosis in the
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54 Moossy J. Pathology of cerebral atherosclerosis. Influence of age, race, and gender. Stroke 1993; 24: I22–123; I31–132. 55 Sacco RL, Kargman DE, Zamanillo MC. Race-ethnic differences in stroke risk factors among hospitalized patients with cerebral infarction: The northern Manhattan stroke study. Neurology 1995; 45: 659–663. 56 Ingall TJ, Homer D, Baker HL, Jr, et al. Predictors of intracranial carotid artery atherosclerosis. Duration of cigarette smoking and hypertension are more powerful than serum lipid levels. Arch Neurol 1991; 48: 687– 691. 57 Iwamoto M. [atherosclerosis. 1. Atherosclerotic changes with advancing age in the aorta, coronary artery and the arteries of the base of the brain]. Nippon Ronen Igakkai Zasshi 1972; 9: 133–143. 58 Bouissou H, Emery MC, Sorbara R. Age related changes of the middle cerebral artery and a comparison with the radial and coronary artery. Angiology 1975; 26: 257–268. 59 Flora G, Dahl E, Nelson E. Electron microscopic observations on human intracranial arteries. Changes seen with aging and atherosclerosis. Arch Neurol 1967; 17: 162–173. 60 Grunnet M. Changes in cerebral arteries with aging. Arch Pathol 1969; 88: 314–318. 61 Moossy J. Development of cerebral atherosclerosis in various age groups. Neurology 1959; 9: 569–574. 62 Tanaka K, Masuda J, Imamura T, et al. A nationwide study of atherosclerosis in infants, children and young adults in japan. Atherosclerosis 1988; 72: 143– 156. 63 D’Armiento FP, Bianchi A, de Nigris F, et al. Agerelated effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis. Stroke 2001; 32: 2472–2479. 64 Nakamura M, Imaizumi K, Kikuchi Y, Kanaide H. Cerebral atherosclerosis in Japanese. Part 4: Relationship between lipid content and macroscopic severity of atherosclerosis. Stroke 1976; 7: 591–594. 65 Vavilova TI. [Atherosclerosis of the major arteries of the head and vessels of the base of the brain in persons with different serum cholesterol levels (biometric study)]. Zh Nevropatol Psikhiatr Im S S Korsakova 1979; 79: 1336–1340. 66 Holme I, Enger SC, Helgeland A, et al. Risk factors and raised atherosclerotic lesions in coronary and cerebral arteries. Statistical analysis from the Oslo study. Arteriosclerosis 1981; 1: 250–256. 67 Holme I, Helgeland A, Hjermann I, et al. Physical activity at work and at leisure in relation to coronary risk
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factors and social class. A 4-year mortality follow-up. The Oslo study. Acta Med Scand 1981; 209: 277–283. Inzitari D, Hachinski VC, Taylor DW, Barnett HJ. Racial differences in the anterior circulation in cerebrovascular disease. How much can be explained by risk factors? Arch Neurol 1990; 47: 1080–1084. McGill HC, Jr. Cerebral artery atherosclerosis and diet. Stroke 1988; 19: 801. Bogousslavsky J, Barnett HJ, Fox AJ, et al. Atherosclerotic disease of the middle cerebral artery. Stroke 1986; 17: 1112–1120. Wityk RJ, Lehman D, Klag M, et al. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996; 27: 1974–1980. Wong KS, Li H, Chan YL, et al. Use of transcranial Doppler ultrasound to predict outcome in patients with intracranial large-artery occlusive disease. Stroke 2000; 31: 2641–2647. Huang YN, Gao S, Li SW, et al. Vascular lesions in Chinese patients with transient ischemic attacks. Neurology 1997; 48: 524–525. Fisher CM GI, Okabe N, White PD. Atherosclerosis of the carotid and vertebral arteries-extracranial and intracranial. J Neuropathol Exp Neurol 1965; 24: 455–476. Liu F, Zhang W, Zhou Y. [pathological changes of intracranial arteries in cerebral infarction]. Zhonghua Yi Xue Za Zhi 1999; 79: 607–609. Mitsuyama Y, Thompson LR, Hayashi T, et al. Autopsy study of cerebrovascular disease in Japanese men who lived in Hiroshima, Japan, and Honolulu, Hawaii. Stroke 1979; 10: 389–395. Reed DM, Resch JA, Hayashi T, et al. A prospective study of cerebral artery atherosclerosis. Stroke 1988; 19: 820–825. Masuda J, Tanaka K, Omae T, et al. Cerebrovascular diseases and their underlying vascular lesions in hisayama, japan–a pathological study of autopsy cases. Stroke 1983; 14: 934–940. Ueda S, Fujitsu K, Inomori S, Kuwabara T. Thrombotic occlusion of the middle cerebral artery. Stroke 1992; 23: 1761–1766. Hinton RC, Mohr JP, Ackerman RH, et al. Symptomatic middle cerebral artery stenosis. Ann Neurol 1979; 5: 152–157. Corston RN, Kendall BE, Marshall J. Prognosis in middle cerebral artery stenosis. Stroke 1984; 15: 237–241. Chen XY, Wong KS, Lam WW, et al. Middle cerebral artery atherosclerosis: Histological comparison between plaques associated with and not associated with infarct in a postmortem study. Cerebrovasc Dis 2007; 25: 74–80.
83 Wong KS, Gao S, Chan YL, et al. Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: A diffusion-weighted imaging and microemboli monitoring study. Ann Neurol 2002; 52: 74–81. 84 Lafont A, Libby P. The smooth muscle cell: Sinner or saint in restenosis and the acute coronary syndromes? J Am Coll Cardiol 1998; 32: 283–285. 85 Sitzer M, Muller W, Siebler M, et al. Plaque ulceration and lumen thrombus are the main sources of cerebral microemboli in high-grade internal carotid artery stenosis. Stroke 1995; 26: 1231–1233. 86 Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American symptomatic carotid endarterectomy trial collaborators. N Engl J Med 1998; 339: 1415–1425. 87 Randomised trial of endarterectomy for recently symptomatic carotid stenosis: Final results of the MRC European carotid surgery trial (ECST). Lancet 1998; 351: 1379–1387. 88 Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: A call for new definitions and risk assessment strategies: Part i. Circulation 2003; 108: 1664–1672. 89 Bamford J, Sandercock P, Dennis M, et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991; 337: 1521–1526. 90 Faxon DP, Fuster V, Libby P, et al. Atherosclerotic vascular disease conference: Writing group iii: Pathophysiology. Circulation 2004; 109: 2617–2625. 91 Nighoghossian N, Derex L, Douek P. The vulnerable carotid artery plaque: Current imaging methods and new perspectives. Stroke 2005; 36: 2764–2772. 92 Ogata J, Masuda J, Yutani C, Yamaguchi T. Mechanisms of cerebral artery thrombosis: A histopathological analysis on eight necropsy cases. J Neurol Neurosurg Psychiatry 1994; 57: 17–21. 93 Gao S, Wong KS, Hansberg T, et al. Microembolic signal predicts recurrent cerebral ischemic events in acute stroke patients with middle cerebral artery stenosis. Stroke 2004; 35: 2832–2836. 94 Droste DW, Junker K, Hansberg T, et al. Circulating microemboli in 33 patients with intracranial arterial stenosis. Cerebrovasc Dis 2002; 13: 26–30. 95 Masuda J, Yutani C, Ogata J, et al. Atheromatous embolism in the brain: A clinicopathologic analysis of 15 autopsy cases. Neurology 1994; 44: 1231–1237. 96 Van Zuilen EV, Van Gijn J, Ackerstaff RG. The clinical relevance of cerebral microemboli detection by transcranial Doppler ultrasound. J Neuroimaging 1998; 8: 32–37.
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97 Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55: 1475–1482. 98 Markus H. Monitoring embolism in real time. Circulation 2000; 102: 826–828. 99 Gacs G, Fox AJ, Barnett HJ, Vinuela F. Occurrence and mechanisms of occlusion of the anterior cerebral artery. Stroke 1983; 14: 952–959.
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100 Lhermitte F, Gautier JC, Derouesne C. Nature of occlusions of the middle cerebral artery. Neurology 1970; 20: 82–88. 101 Mohr JP. Lacunes. Stroke 1982; 13: 3–11. 102 Miller VT. Lacunar stroke. A reassessment. Arch Neurol 1983; 40: 129–134. 103 Fisher CM. Capsular infarcts: The underlying vascular lesions. Arch Neurol 1979; 36: 65–73.
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Epidemiology Philip Gorelick, Jinghao Han, Yining Huang and KS Lawrence Wong
Intracranial atherosclerosis (ICAS) is an important cause of stroke worldwide.1–5 Population groups that are at high risk for ICAS include black people in the USA, Asians, and Hispanics. In the USA, it has been estimated that of the 900 000 estimated stroke or transient ischemic attacks (TIAs) annually, up to 10% are caused by ICAS, and recurrence rates in these patients are 15% per year.6 The frequency of stroke attributable to ICAS in the USA is dwarfed by corresponding statistics from Asian countries. In Chinese populations, ICAS is estimated to account for 33–50% of stroke and >50% of TIAs, in Thailand 47% of stroke, in Korea about 28–60% of stroke, and in Singapore about 48% of stroke.7–10 The frequency of ICAS is also high in Japan, although there is increasing frequency of symptomatic extracranial carotid artery stenosis. In the USA, the relative rate of stroke associated with ICAS is about 5.0 for Hispanics (mostly from Puerto Rico and the Dominican Republic) and 5.85 for black people compared with white people. As the majority of the world’s population is Asian, African, or Hispanic, it seems that ICAS is the most common cerebral vascular lesion worldwide, whereas Caucasians may be a group predominantly predisposed to develop extracranial occlusive disease.7 Prior hypotheses to explain racial differences in the distribution of occlusive cerebrovascular disease lesions include, for example, low lipid levels and high blood pressure predisposing to intracerebral vascular disease; high lipids and high blood pressure predisposing to extracranial occlusive vascular lesions; and diabetes mellitus and metabolic syndrome for ICAS.1,2,8,11–13 However, the reason for racial
differences in the incidence of ICAS still remains unclear. Attempts to prevent recurrence of stroke events in ICAS have focused mainly on anticoagulant therapy, antiplatelet therapy, revascularization procedures, and other medical therapies.6,14,15 In this chapter, we review the epidemiology of ICAS in China, Japan, Korea, and the remainder of Asian countries in which ICAS is prevalent. Ethnic differences observed in the studies from North America and related regions will also be discussed.
China, Japan, Korea, and other Asian regions (Table 3.1) Autopsy studies For decades, it has been reported that patients of Asian, African, and Hispanic ancestry are at high risk of ICAS.1 Sufficient evidence from autopsy studies has shown that African Americans and Japanese have more ICAS, whereas Caucasians have more extracranial diseases.16–18 Masuda’s autopsy series of 724 patients aged 40 years or older, in the community of Hisayama, Japan, showed that ischemic stroke patients had more severe atherosclerosis of the major cerebral arteries than those without stroke or cerebral hemorrhage. In addition, a decline in frequency of cerebral hemorrhage was noted during the study period of 1961–81, with no definite change in the severity of cerebral atherosclerosis.19 However, a more recent study reported a marked decrease in ICAS in the recent 28 years, in contrast with unchanged incidence of coronary artery stenosis in Japanese elderly subjects.20 The authors pointed out that blood pressure lowering,
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
33
34 Study design Cross-sectional n = 2202 Cross-sectional n = 966 Community-based n = 590 Community-based n = 1068 Cross-sectional n = 3057 Prospective n = 156 Prospective n = 151 Retrospective n = 246 Retrospective n = 24 Prospective n = 21 Prospective n = 108
Prospective n = 96 Prospective n = 100
Study
Thomas et al., 200312
Thomas et al., 200413
Wong et al., 200724
Huang et al., 200725
Wong et al., 200729
Uehara et al., 199830
Uehara et al., 200131
Bae et al., 200611
Feldmann et al., 199036
Thajeb et al., 199337
Liu et al., 199645
Huang et al., 199746
Wong et al., 199847
Chinese
Chinese
Chinese
Chinese
Chinese Caucasian
Korean
Japanese
Japanese
Chinese
Chinese
Symptomatic ischemic stroke with adequate temporal windows (n = 66)
Symptomatic TIA
Symptomatic stroke
Symptomatic stroke
Symptomatic stroke
Asymptomatic in CABG patients
Asymptomatic in CABG patients
Asymptomatic
Asymptomatic in patients with vascular risk factors
Asymptomatic
Asymptomatic
Asymptomatic in DM patients
Asymptomatic in DM patients
Condition
TCD
TCD carotid duplex
MRA
DSA
DSA
TCD MRA
MRA
MRA
TCD
TCD
TCD
TCD
TCD
Assessment
Albuminuria may be related with ICAS in DM patients HT, glycosuria, IHD, family history of stroke Male, age, HT, and DM Age, HT, DM, and hyperlipidemia Age, HT No risk factor identified Age, male, HT, DM, and history of stroke/TIA
n = 137 (14.2) n = 41 (6.9) n = 63 (5.9) n = 385 (12.6)
n = 23 (14.7) n = 32 (21.1) n = 71 (28.9)
22 (33)
50 (51)
28 (26)
18 (85.7)
Intracranial occlusive disease is the most commonly found vascular lesion in our acute stroke patients
Most common in terminal internal carotid artery or proximal middle cerebral artery
No difference in vascular risk factors between patients with intracranial and extracranial lesions
HT, hyperfibrinogenemia, polycythemia, and low HDL cholesterol
Chinese had more intracranial lesions while white people had more extracranial lesions
HT, albuminuria
n = 217 (9.9)
White 2 (8) Chinese 6 (26)
Risk factors/results
Number (%)
August 9, 2008
Chinese
Chinese
Chinese
Racial
Table 3.1 Summary of clinical studies in asymptomatic and symptomatic ICAS in Asia regions.
BLBK041-Kim 18:10
Prospective n = 300
Retrospective n = 296
Retrospective n = 64
retrospective n = 279 Retrospective n = 268 Prospective n = 512
Retrospective n = 922 Prospective n = 392 Retrospective n = 100 Prospective n = 205
Zhou et al., 200444
Brust et al., 197534
Nishimaru et al., 198433
Takahashi et al., 199938
Suh et al., 200310
Bang et al., 20058
Nam et al., 2006 9
Kaul et al., 200240
Suwanwela et al., 200343
De Silva et al., 200741 South Asian
Thailand
Indian
Korean
Korean
Korean
Japanese
Japanese Caucasian
Japanese and other population groups in Hawaii
Chinese
Chinese
Symptomatic stroke
Symptomatic stroke or TIA
Symptomatic stroke
Symptomatic
Symptomatic stroke
Symptomatic stroke
Symptomatic stroke (n = 152) and others
Symptomatic carotid system TIA patients
Symptomatic stroke
Symptomatic stroke
Symptomatic stroke
TCCD MRA
TCD carotid duplex
TCD
DSA
DSA
DSA
MRA
DSA
DSA
MRA, DSA
TCD
93 (50)
51 (51)
11 (79) with TACI, 14 (47) PACI, 17 (65) POCI and 51 (44) LACI
DM and IHD
HT, DM, and smoking
Age, HT, smoking, IHD, history of stroke, and simple aortic plaques
n = 245 (48) 161 (41) LAD
Metabolic syndrome was independently associated with intracranial atherosclerosis
Korean patients with severe atherosclerotic stenosis tend to have more intracranial stenosis
HT and HbAlc
10 of 12 severe lesions in Japanese were located intracranially, 17 of 20 severe lesions present in the American group occurred in the extracranial portion of the internal or common carotid arteries
Significant difference between frequency of involvement of >50% stenosis in extracranial and intracranial vessels in Caucasian and that in the Hawaiian-born and Japan-born Japanese populations
The incidence of LAD in Chinese patients is higher than that of the other four subtypes of stroke due to TOAST criteria
The risk of vascular events or death increased rapidly with rising numbers of occlusive arteries
EC-LAA 77 (15.0) IC-LAA 143 (27.9) Non-atherosclerotic 292 (57.0)
Single lesion 37 (66) Multiple lesions 166 (50)
36 (12.9)
Mild lesion n = 25 (78.1) in Japanese n = 29 (90.6) in Caucasians
White 5 (5.4) Hawaii Japanese 8 (9.4) Japan Japanese 8 (34.8)
120 (40) LAD
258 (37)
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CABG, coronary artery bypass grafting; DSA digital subtraction angiography; EC-LAA, extracranial portion of large artery atherosclerosis; DM, diabetes mellitus; HT, hypertension; IC-LAA, intracranial portion of large artery atherosclerosis; IHD, ischemic heart disease; LAD, large artery atherosclerosis; MRA, magnetic resonance angiography; TCD, transcranial Doppler; TCCD, transcranial color-coded doppler; TIA, transient ischemic attack; TOAST, Trial of ORG 10 172 in Acute Stroke Treatment. TACI, total anterior circulation infarction; PACI, partial anterior circulation infarction; POCI, posterior circulation infarction; LACI, lacunar infarction.
Prospective n = 705
Wong et al., 200048
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elevation of total cholesterol, and increased incidence of diabetes mellitus may be responsible for this trend. Compared with studies in Japanese populations, data in Chinese populations are relatively limited. In the early 1990s, among 114 consecutive Hong Kong Chinese patients who underwent autopsy, ICAS was found to be more severe than that of extracranial atherosclerosis.21 Both the proximal and distal branches of the intracranial arteries were involved. Hypertension and diabetes mellitus were identified as factors associated only with ICAS, whereas ischemic heart disease was associated with atherosclerosis in both the intracranial and extracranial vessels.21 In another autopsy study from mainland China, Liu et al.22 showed that atherosclerotic narrowing of medium-sized intracranial arteries and their primary branches was more severe than that found in the extracranial carotid arteries in stroke patients. A recent autopsy study in Hong Kong compared the detailed morphological characteristics of middle cerebral artery (MCA) atherosclerosis in patients with and without cerebral infarcts.23 Luminal stenosis caused by atherosclerotic plaques, the percentage of lipid area, and the presence of intraplaque neovasculature were independent risk factors of MCA territory infarcts.23 Prevalence of asymptomatic ICAS in community-based populations With the availability of transcranial Doppler ultrasound (TCD), intracranial stenosis can now be diagnosed easily and non-invasively. Wong et al.24 published the first door-to-door study of ICAS in middle-aged, asymptomatic subjects in rural China. Five hundred and ninety villagers aged 40 years or above were screened by TCD and 41 subjects (prevalence 6.9%) were found to have ICAS. In a multivariate analysis, the significant risk factors for ICAS were hypertension [odds ratio (OR) 2.53; 95% confidence interval (CI 1.12–5.72), glycosuria (OR 3; CI 1.19– 7.97), heart disease (OR 4; CI 1.39–11.6), and family history of stroke (OR 5.2; CI 1.38–20). In another community-based study using TCD in Southern China involving 1068 asymptomatic subjects over 50 years of age, MCA stenosis was evident in 63 subjects (prevalence 5.9%). Male sex, advanced age, hypertension, and diabetes mellitus were independent risk factors for MCA stenosis.25 In a substudy aiming to 36
determine the relationship between hyperhomocysteinemia and MCA stenosis, it was found that hyperhomocysteinemia was an independent risk factor for MCA stenosis.26 The prevalence of asymptomatic carotid stenosis in the white population has been estimated at about 2–8% in the middle-aged and elderly population.27 Therefore, the prevalence of ICAS in the Chinese population appears to be of a similar order of magnitude as the prevalence of asymptomatic carotid stenosis in the white population. Although the ICAS detected in these studies were asymptomatic ones, the presence of ICAS is of clinical significance because it is an independent predictor for survival and recurrent ischemic events.28 These study results provide an estimate of the burden of ICAS in the Chinese population and may be used as a basis for establishing future strategies for the prevention or the management of stroke in this population. Population-based studies have been rare in other Asian countries. However, some results from subjects undergoing health screening are available. Uehara et al.31 studied 156 Japanese subjects (37–83 years, mean age 63 years) with no evidence of stroke who had undergone magnetic resonance angiography (MRA) for other reasons such as non-specific dizziness, tension headache, or forgetfulness. They found that 14.7% had intracranial artery stenosis whereas 11.5% had cervical carotid artery stenosis.29 Multiple logistic regression analysis showed that age and hyperlipidemia were independent predictors for extracranial atherosclerosis, and that age and hypertension were predictors for ICAS. Park et al.30 studied 835 Korean subjects (29–85 years, mean age 53 years) who had visited a hospital for the purpose of routine health screening. MRA showed that 3% had ICAS and 0.48% had extracranial atherosclerosis. Old age and hypertension were independent risk factors for ICAS. The higher incidence of cerebral atherosclerosis in Japanese than in Korean subjects may be due to differences in age (higher mean age in Japanese than in Korean subjects), the criteria for MRA abnormality (>25% in the Japanese study and ≥50% in the Korean study), and subjects’ characteristics (subjects studied by Uehara et al.31 may have been the more risky group). Nevertheless, both results show that ICAS is more prevalent than extracranial atherosclerosis, perhaps more markedly in Korea than in Japan.
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Prevalence of asymptomatic ICAS in high-risk patients Population-based screening is the best scientific approach for epidemiological studies, but the yield among patients without vascular risk factors is low. Therefore, Wong et al.29 carried out a prevalence study of MCA stenosis among high-risk individuals who had vascular risk factors without history of stroke or TIA. Among 3057 subjects who had at least one vascular risk factor (hypertension, diabetes, hyperlipidemia), 385 (12.6%) had MCA stenosis. Old age, hypertension, diabetes, and hyperlipidemia were associated risk factors. The prevalence escalated quadratically with increasing number of associated factors: from 7.2% for one to 29.6% for four associated factors.29 Two studies from Hong Kong on type II diabetic patients12,13 also reported that blood pressure indices and albuminuria were closely associated with asymptomatic MCA stenosis. Patients scheduled for coronary artery bypass graft surgery (CABG) may have a high risk of cerebrovascular disease. In a study from Japan, 151 consecutive patients who were scheduled for CABG were evaluated with MRA. The results showed that cervical carotid artery narrowing of ≥50% was detected in 16.6%, and intracranial artery stenoses of ≥50% was detected in 21.2% of the subjects.32 This finding is not surprising as previous studies found ICAS was associated with aortic plaques and the metabolic syndrome, which in turn are closely related to coronary artery disease.9,33 However, it seems that extracranial atherosclerosis is more closely related to coronary heart disease than is ICAS, even in Asian countries; a Korean study in 246 consecutive CABG patients showed that the correlation of coronary atherosclerosis with extracranial carotid atherosclerosis was stronger than that of coronary artery atherosclerosis with ICAS, and that this difference was not explained by classic vascular risk factors.11
Symptomatic ICAS in stroke patients Conventional cerebral angiography-based studies There are a number of cerebral angiographic studies in Japan, Korea, and China showing the distribution and severity of ICAS in patients with ischemic stroke. In a case–control study of patients with symptomatic anterior circulation ischemia, 83% of severely stenotic le-
sions involved the intracranial arteries of 32 Japanese patients, whereas 85% of severe lesions involved the extracranial internal carotid artery in 32 American white subjects. For minor lesions, the frequency was similar in the two ethnic groups.34 Another angiogram study in 296 stroke patients living in Hawaii showed a more frequent involvement of the extracranial arteries in white people, and noticeably more frequent involvement of the intracranial arteries in the Hawaiianborn Japanese population.35 Based on the study by Suh et al.,10 Korean patients with severe atherosclerotic stenoses tend to have more intracranial than extracranial stenosis (52% versus 48%), and 59% of intracranial lesions were located in the anterior circulation. Nam et al.9 reported that among 922 Korean stroke patients intracranial or extracranial atherosclerosis was found in 511 patients (55%). Interestingly, simple aortic plaque assessed by transesophageal echocardiography was an independent predictor of ICAS. In an earlier angiographic study in Taiwan, Chinese patients with carotid territory TIAs reported that intracranial stenosis was present in 15% of 47 patients.36 In a case–control study comparing Chinese people living in the USA with American white people, Chinese patients had significantly higher rates of intracranial carotid artery and MCA stenosis.37 Of 24 Chinese patients with cerebral ischemia, 43% had symptomatic MCA stenosis, whereas the same lesion was present in only 14% of 24 age- and sex-matched white patients. In contrast, 50% of white patients had severe stenosis of the extracranial ICA, whereas only 9% of the Chinese patients had a similar lesion. A recent angiographic study of Chinese patients with acute capsular infarcts and prior ipsilateral TIA showed that intracranial stenosis was found in 67% of 21 patients.38 MR angiography and TCD studies Although cerebral angiography remains the gold standard for diagnosing large artery occlusive disease, recent advances in non-invasive diagnostic technologies such as MRA and TCD enable us to study a large number of patients. Studies from Korea, Japan, and China, and various regions of South Asia have shown that these racial groups are at high risk of developing ICAS. Kim et al.39 analyzed 1167 Korean stroke patients who had undergone MRI and MRA. A total of 491 patients (42%) showed large artery atherosclerosis that 37
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was responsible for the stroke. Excluding the patients with tandem vascular lesions, they found that symptomatic atherosclerotic lesions were most often located in the MCA (38%), followed by ICA (28%), vertebral artery (15%), posterior cerebral artery (9%) basilar artery (8%), and the anterior cerebral artery (2%). Among patients with symptomatic ICA disease proximal ICA slightly outnumbered distal ICA diseases. Thus, symptomatic ICAS seems to be more common than symptomatic extracranial atherosclerosis with an approximate ratio of 7:3. The ratio is greater than what was shown in the previous Korean study using conventional angiography,10 which may be explained by the presence of selection bias in conventional angiogram studies; patients with mild intracranial stenosis are likely to be under-represented in those studies. Features may be similar in Japan and other Asian countries. Takahashi et al.40 showed that 12.9% of Japanese stroke patients had MCA stenosis on MRA, and that hypertension and high serum HbAlc levels contributed to the development of MCA lesions. An MRA study from India showed that ICAS as a cause of strokes is probably more common in India than in Japan.41 Hospital-based stroke registry data from South India showed that among all ischemic stroke patients, 41%, 18%, 10%, 4%, and 27% were classified as large-artery atherosclerosis, lacunae, cardioembolism, other determined etiology, and undetermined etiology, respectively.42 The most notable difference between this and Western registries was the predominance of the intracranial rather than the extracranial location of large artery atherosclerosis in the southern Asia region. Similarly, a study from Singapore showed that significant ICAS was common among all Oxfordshire Community Stroke Project subtypes: 79% with total anterior circulation infarct, 47% partial anterior circulation infarct, 65% posterior circulation infarct, and 44% lacunar infarct.43 The finding is consistent with the ethnic Chinese data.44 A retrospective study in Thailand on patients with ischemic stroke or TIA found 98% of patients with extracranial stenosis had associated intracranial disease, whereas none of those with intracranial stenosis had more than 50% extracranial carotid stenosis.45 A study from mainland China suggested that largeartery atherosclerosis (40%) is the main cause of ischemic stroke according to the Trial of ORG 10172 in Acute Stroke Therapy (TOAST) criteria.46 The racial 38
difference between Chinese and white patients in the location of atherosclerotic lesions was also confirmed by an MRA study among 108 symptomatic Taiwan Chinese patients. In this study, approximately 24% of patients had only extracranial carotid disease, about 26% had only intracranial carotid tributary disease, and 17.6% had significant lesions in both extracranial and intracranial carotid artery tributaries.47 Ultrasonographical studies of Chinese subjects showed that ICAS occurred in 30–67% of stroke or TIA patients. One of these studies found ICAS in 51% of 96 TIA patients, whereas extracranial carotid disease occurred in 19% of all patients.48 Another TCD series showed that ICAS was the most common vascular lesion, which accounted for 33% of 66 ischemic stroke patients, whereas an extracranial carotid lesion was found only in 6%.49 Another study from Hong Kong on 705 Chinese stroke patients reported that ICAS only accounted for 37% of patients, and both intracranial and extracranial diseases accounted for 10% of patients, whereas 16 patients (2%) had extracranial carotid artery abnormality only. Overall, ICAS (47%) was nearly fourfold higher in frequency than extracranial carotid occlusive disease (12%).50 Recent data from the same research group was consistent with previous findings. Among the 345 patients who had TCD evidence of intracranial or carotid artery abnormalities, 75% had intracranial involvement only, 5% extracranial involvement only, and 20% had both intracranial and extracranial involvement.51
Symptomatic ICAS in Europe Most European studies have focused on extracranial carotid artery lesions, for this is the most common cause of ischemic stroke in Caucasians. However, there were still some studies investigating ICAS in acute stroke patients. The Group d’Etude ˆ des St´enoses Intra-Craniennes Ath´eromateuses symptomatiques (GESICA) study based in France included 102 stroke patients with ICAS; they found that ICAS involved the vertebral artery in 22.5%, the basilar artery in 25.5%, the MCA in 26.5%, and the internal carotid artery in 25.5%. This prospective study further suggested both a high 2-year recurrence rate of ischemic events in the stenotic cerebral artery territory (38.2%: stroke 13.7%, TIA 24.5%) and cardiovascular events (18.6%) with an 8.8% vascular death rate.52 Olsen et al.53 reported that 40% of
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patients with stroke in the carotid territory had MCA occlusion. MCA occlusion was responsible for 62% of the large or medium-sized infarcts on CT scan, whereas only 11% of the patients with small infarcts had significant MCA lesions. A Spanish study of 132 stroke patients found 50% had symptomatic intracranial stenosis, and only 26.5% had significant carotid atheromas. For the location of intracranial lesions, the vertebral artery accounted for 28%; MCA 27%; carotid siphon 21%; basilar artery 10%; anterior cerebral artery 5% and posterior cerebral artery 4%.54
North America and related regions Early autopsy studies The early history of ICAS in North America and related areas is replete with studies that have emphasized the importance of extracranial occlusive disease.55 In the early 1950s, for example, Fisher’s56 autopsy series of 200 patients with cerebrovascular disease did not include a single patient who had occlusion of the MCA. Yet, prior to this, patients with anterior circulation occlusive disease were routinely diagnosed as having MCA occlusion. In another autopsy study, Hutchinson and Yates57 emphasized that atherosclerosis of the vertebral artery was most prevalent in the proximal portion of this vessel, was contiguous with occlusive changes of the subclavian artery, and the severity of proximal vertebral artery occlusive disease often paralleled such disease in the proximal ICA. Baker and Iannone,58 in the late 1950s, described cerebral atherosclerosis at autopsy that not only involved the origin of the ICA but also included such areas as the distal, proximal, and mid-portions of the basilar artery and the MCA. Others such as Whisnant and colleagues in the USA confirmed the importance of proximal ICA occlusive disease, and Swartz and Mitchell in the UK and Torvik and Jorgenson in Norway corroborated the importance of occlusive ICA disease at the origin and in the intracranial portion at autopsy.1 Others such as Lhermitte and colleagues and Blackwood et al. suggested that intracranial MCA occlusion was predominantly embolic in origin.1 The studies cited above, however, included predominantly Caucasian patients. Later, Fisher59 elucidated the pathological lesions underlying lacunar infarcts within intracranial penetrating artery distributions. He described microscopic pathology in small blood vessels measuring less than
200 μm in diameter in some cases and that included fibrinoid degeneration of vessel walls and hyaline change within the vascular media (so-called lipohyalinosis). Racial differences in ICAS: autopsy studies In an autopsy study from the Charity Hospital in New Orleans in 1959, Moossy60 showed that cerebral atherosclerosis typically involved the ICA and vertebral arteries followed by the basilar artery and MCA. The youngest patient in that series was a black woman in her 20s. In a more extensive study of 2650 brain dissections, Moossy61 reported the importance of intracranial arterial thrombosis in those with recent ischemic stroke. In the International Atherosclerosis Project (IAP), black people in New Orleans had a higher extent of raised lesions than white people in New Orleans, and Jamaican black people had more raised lesions in the vertebral and other intracranial arteries. Later, McGarry et al.16 reported that in randomly selected autopsy subjects, black people in New Orleans had more advanced ICAS. A comparison among autopsy subjects from New Orleans, Oslo, and Kingston showed that black people had more atherosclerosis intracranially and as much or more cervical atherosclerosis, but white people had more occlusive disease in the aorta and coronary arteries.62 Sex differences in ICAS: autopsy study Whereas men have a higher risk of stroke overall, more women than men in the USA die of stroke. This has been attributed to the fact that women live longer than men and stroke risk is substantially linked to age. It has been suggested that women may have more intrinsic occlusive intracranial vascular disease.1 Flora et al.62 reported that the frequency of cerebral atherosclerosis increased more rapidly in women after the sixth decade; by the ninth decade it was more common than in men; and diabetic women were particularly at risk of cerebral atherosclerosis. Caplan1 has suggested that persons with medium-sized ICAS and major branch disease may be disproportionately more often women, black, or Asian, or hypertensive subjects. Conventional cerebral angiography-based studies of racial differences in ICAS There is a substantial history of cerebral angiographic studies showing racial differences in the distribution 39
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and severity of occlusive intracranial and extracranial arterial lesions. Caplan et al.1 and Gorelick2 have previously reviewed this literature. Overall, based on studies by Bauer et al., Fields et al., Russo, Heyden et al., and Heyman et al., there seems to be more surgically accessible extracranial lesions in white people than in black people and a higher frequency of intrinsic intracranial occlusive lesions among black people.63–67 We now review the findings from a series of angiographic studies among a hospital-based, racially mixed population of black and white people with symptomatic and asymptomatic occlusive cerebral vascular disease in Chicago, IL, which was carried out in the 1980s. We focus on the distribution, severity, and predictors of ICAS in this population. Chicago experience Symptomatic occlusive disease Gorelick et al. studied 26 white and 45 black subjects with symptomatic occlusive cerebrovascular disease of the anterior circulation.3 The patients had been entered into the Michael Reese Hospital Stroke Registry. Overall, white patients had more severe disease of the extracranial carotid artery at the origin, and a clinical history of more TIAs and carotid bruits, whereas black patients had more severe disease of the MCA stem and supraclinoid ICA. This study did not include multivariable analysis. However, in a companion conventional cerebral angiographic study that included 27 white and 24 black subjects predominantly from the Chicago area, white subjects had significantly more angina pectoris, more lesions of the origin of the left vertebral artery, and more severe lesions of the extracranial vertebral arteries, whereas black patients had significantly higher mean diastolic blood pressure, more diabetes mellitus, more lesions of the distal basilar artery, more severe lesions of intracranial branch vessels, and more symptomatic intracranial branch disease.4 Furthermore, logistic regression analysis showed that race was an independent predictor of the site of occlusive disease in the posterior circulation. Although the statistical power may have been low based on the small sample size in the study, there were significantly more intracranial lesions and symptomatic intracranial lesions among non-diabetic black people than among non-diabetic white people. Asymptomatic occlusive disease In a second companion conventional cerebral angiographic study, 40
Gorelick et al. compared clinical and arteriographic characteristics in 106 subjects who had symptomatic unilateral carotid territory occlusive disease to elucidate the frequency and distribution of occlusive arterial lesions in asymptomatic arterial vessels.5 Among the black patients, who were predominantly from Chicago, younger, and more often female than the white patients, there were fewer TIAs and myocardial infarctions and less claudication by medical history, but more asymptomatic lesions of the supraclinoid carotid artery, anterior cerebral artery stem, and MCA stem. Whereas the white patients, predominantly from New England, elderly, and men, had more frequent and severe occlusive asymptomatic disease of the extracranial carotid artery and vertebral artery sites. By stepwise logistic regression analysis, predictors of asymptomatic arterial sites included white race (extracranial carotid artery), black race (major intracranial artery sites), black race (major MCA sties), and black race and diabetes (anterior cerebral artery sites). Contemporary studies and perspectives The above autopsy and conventional cerebral angiographic studies from North America and related regions suggest that black people may have a propensity for ICAS, whereas white people may be more predisposed to extracranial occlusive disease. Circle of Willis ICAS has been linked to hypertension in an autopsy study.68 Interestingly, black populations, for example, in West Africa have been shown to have little atherosclerosis of the circle of Willis when the prevalence of hypertension is low. However, in urban West African populations, the prevalence of ICAS is believed to increase in conjunction with raised blood pressure. Furthermore, based on conventional cerebral angiographic studies outside of North America, black Zambian patients had been shown to have extracranial atherosclerosis rarely, and black South African patients with stroke had extracranial lesions infrequently.69 Caplan has set forth the following hypothesis to explain racial differences in the distribution and severity of intracranial and extracranial occlusive disease.69 He suggests that hypertension differs in black people and white people. For example, black people and Asians retain more sodium, and their hypertension responds to diuretics. Therefore, hypertension in these groups can be related to high volume states. In addition, diabetes is a disorder often accompanied by high blood
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volume, as are certain conditions in women, e.g., menstruation, pregnancy, and sex hormone use. These conditions associated with high blood volume, female sex, diabetes, and hypertension in black people and Asians, also are associated with intracranial occlusive disease. In contrast, hypertension in white people, for example, is associated with extracranial carotid artery and vertebral artery disease. It is possible that the medium of the blood vessel, which is more important in intracranial arteries, is more susceptible to high volume states that cause more stress on these vessels, whereas highresistance hypertension more commonly adversely affects the extracranial arteries. Several key studies based in North America have determined risk profiles for occlusive cerebrovascular disease. For example, in the international Extracranial/Intracranial Bypass Study entry characteristics were analyzed to determine whether there were differences in the site of the lesion on the basis of racial group.70 In this trial, black people more often had hypertension, diabetes, or smoked cigarettes, whereas white people had higher systolic blood pressure and hemoglobin levels. Asian subjects had the lowest prevalence of vascular risk factors. Keeping in mind the study limitations related to possible patient selection biases, multivariate analysis showed that race (black, Asian) was an independent predictor of the location of cerebrovascular lesions. In the Northern Manhattan Stroke Study (NoMASS), a greater prevalence of diabetes and hypercholesterolemia was noted among black and Hispanic people, accounting for a substantial proportion of the increased frequency of ICAS.71 In addition, in NoMASS the maximum internal carotid artery plaque thickness (MICPT) was measured among 526 racially mixed, stroke-free community residents.72 The mean MICPT was greater in white and black subjects than in Hispanic subjects. Independent predictors of MICPT included smoking, glucose, low-density lipoprotein (LDL) cholesterol, and hypertension. When covariates were controlled in statistical analyses, Hispanic race– ethnicity remained an independent predictor of less carotid plaque. In addition, there was a significant interaction between race–ethnicity and LDL cholesterol, with a greater effect with increasing LDL cholesterol in Hispanic sublects. Finally, in the Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial, the metabolic syndrome was found in about 50% of subjects and was associated with higher risk of major vas-
cular events.33 In WASID, among persons with ICAS, the risk of subsequent stroke was predicted by stenosis ≥70%, the presence of recent symptoms (≤17 days), and being women.73 Burke and Howard74 provide a perspective regarding racial differences in the distribution and severity of asymptomatic extracranial atherosclerosis. Whereas clinical studies suggest a greater degree of atherosclerosis in white than in black patients, population studies [e.g., Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Insulin Resistance Atherosclerosis Study,75 the Northern Manhatlan Stroke Study (NoMASS) suggest a similar extent of atherosclerosis amongst white and black people. They explain the disparity between clinical and population studies in the following manner: (1) black people have a large excess of stroke mortality at relatively young ages (e.g., 45–50 years) in which atherosclerosis is unlikely to play a major role in stroke etiology as the underlying causes are more likely to be hemorrhage, ICAS, embolism, etc.); and (2) because of a higher burden of stroke risk factors, black people have a higher risk of stroke at relatively lower levels of extracranial carotid artery stenosis, yet atherosclerosis remains an important factor.
Implication of racial distribution of cerebrovascular atherosclerosis ICAS is a common cause of stroke in Asian, black, and Hispanic patients but not in white patients. The cause of this disparity remains uncertain. Risk factors such as hypertension, diabetes, and hyperlipidemia are also prevalent in white subjects, so that vascular risk factors alone cannot explain this difference. Whether other environmental factors such as diet, lifestyle, or genetics play a role deserves further investigation. Other studies have suggested that genetic susceptibility may play a key role. black, Hispanic, and Asian people might be susceptible to ICAS.5,37 Laboratory work has shown that genes are highly associated with phenotypic variation in carotid artery occlusive disease76–78 as well as ICAS.79–82 There has been suggestion that the metabolic syndrome and related abnormalities may explain the high prevalence of ICAS in Asians. This aspect will be more thoroughly discussed in Chapter 4. Elucidating the factors responsible for the racial differences in the distribution of 41
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cerebrovascular atherosclerosis may provide important insights of the pathogenesis and may help to develop a better prevention and treatment strategy.
15
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29 Wong KS, Ng PW, Tang A, et al. Prevalence of asymptomatic intracranial atherosclerosis in high-risk patients. Neurology 2007; 68: 2035–2038. 30 Park KY, Chung CS, Lee KH, et al. Prevalence and risk factors of intracranial atherosclerosis in an asymptomatic Korean population. J Clin Neurol 2006; 2: 29–33. 31 Uehara T, Tabuchi M, Mori E. Frequency and clinical correlates of occlusive lesions of cerebral arteries in Japanese patients without stroke. Evaluation by MR angiography. Cerebrovasc Dis 1998; 8: 267–272. 32 Uehara T, Tabuchi M, Kozawa S, Mori E. MR angiographic evaluation of carotid and intracranial arteries in Japanese patients scheduled for coronary artery bypass grafting. Cerebrovasc Dis 2001; 11: 341–345. 33 Ovbiagele B, Saver JL, Lynn MJ, Chimowitz M. Impact of metabolic syndrome on prognosis of symptomatic intracranial atherostenosis. Neurology 2006; 66: 1344– 1349. 34 Nishimaru K, McHenry LC, Jr, Toole JF. Cerebral angiographic and clinical differences in carotid system transient ischemic attacks between American Caucasian and Japanese patients. Stroke 1984; 15: 56–59. 35 Brust RW, Jr. Patterns of cerebrovascular disease in Japanese and other population groups in Hawaii: an angiographical study. Stroke 1975; 6: 539–542. 36 Ryu SJ. Angiographic features in Chinese patients with occlusive cerebrovascular disease. Stroke 1987; 18: 686. 37 Feldmann E, Daneault N, Kwan E, et al. Chinese-white differences in the distribution of occlusive cerebrovascular disease. Neurology 1990; 40: 1541–1545. 38 Thajeb P. Large vessel disease in Chinese patients with capsular infarcts and prior ipsilateral transient ischaemia. Neuroradiology 1993; 35: 190–195. 39 Kim JT, Yoo SH, Kwon J-H, Kwon SU, Kim JS. Subtyping of ischemic stroke based on vascular imaging: analysis of 1,167 acute, consecutive patients. J Clin Neurol 2006; 2: 225–230. 40 Takahashi K, Kitani M, Fukuda H, Kobayashi S. Vascular risk factors for atherosclerotic lesions of the middle cerebral artery detected by magnetic resonance angiography (MRA). Acta Neurol Scand 1999; 100: 395–399. 41 Padma MV, Gaikwad S, Jain S, et al. Distribution of vascular lesions in ischaemic stroke: a magnetic resonance angiographic study. Natl Med J India 1997; 10: 217– 220. 42 Kaul S, Sunitha P, Suvarna A, et al. Subtypes of Ischemic Stroke in a Metropolitan City of South India (One year data from a hospital based stroke registry). Neurol India 2002; 50 (Suppl): S8–S14. 43 De Silva DA, Woon FP, Pin LM, et al. Intracranial large artery disease among OCSP subtypes in ethnic South Asian ischemic stroke patients. J Neurol Sci 2007; 260: 147–149.
44 Li H, Wong KS. Racial distribution of intracranial and extracranial atherosclerosis. J Clin Neurosci 2003; 10: 30–34. 45 Suwanwela NC, Chutinetr A. Risk factors for atherosclerosis of cervicocerebral arteries: intracranial versus extracranial. Neuroepidemiology 2003; 22: 37–40. 46 Zhou H, Wang YJ, Wang SX, Zhao XQ. [TOAST subtyping of acute ischemic stroke]. Zhonghua Nei Ke Za Zhi 2004; 43: 495–498. 47 Liu HM, Tu YK, Yip PK, Su CT. Evaluation of intracranial and extracranial carotid steno-occlusive diseases in Taiwan Chinese patients with MR angiography: preliminary experience. Stroke 1996; 27: 650–653. 48 Huang YN, Gao S, Li SW, et al. Vascular lesions in Chinese patients with transient ischemic attacks. Neurology 1997; 48: 524–525. 49 Wong KS, Huang YN, Gao S, et al. Intracranial stenosis in Chinese patients with acute stroke. Neurology 1998; 50: 812–813. 50 Wong KS, Li H, Chan YL, et al. Use of transcranial Doppler ultrasound to predict outcome in patients with intracranial large-artery occlusive disease. Stroke 2000; 31: 2641–2647. 51 Li H, Wong KS, Kay R. Relationship between the Oxfordshire Community Stroke Project classification and vascular abnormalities in patients with predominantly intracranial atherosclerosis. J Neurol Sci 2003; 207: 65–69. 52 Mazighi M, Tanasescu R, Ducrocq X, et al. Prospective study of symptomatic atherothrombotic intracranial stenoses: the GESICA study. Neurology 2006; 66: 1187– 1191. 53 Olsen TS, Skriver EB, Herning M. Cause of cerebral infarction in the carotid territory. Its relation to the size and the location of the infarct and to the underlying vascular lesion. Stroke 1985; 16: 459–466. 54 Sanchez-Sanchez C, Egido JA, Gonzalez-Gutierrez JL, et al. [Stroke and intracranial stenosis: clinical profile in a series of 134 patients in Spain]. Rev Neurol 2004; 39: 305–311. 55 Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55: 1475–1482. 56 Fisher M. Occlusion of the internal carotid artery. AMA Arch Neurol Psychiatry 1951; 65: 346–377. 57 Hutchinson EC, Yates PO. Carotico-vertebral stenosis. Lancet 1957; 272: 2–8. 58 Baker AB, Iannone A. Cerebrovascular disease. I. The large arteries of the circle of Willis. Neurology 1959; 9: 321–332. 59 Fisher CM. Lacunar strokes and infarcts: a review. Neurology 1982; 32: 871–876.
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60 Moossy J. Development of cerebral atherosclerosis in various age groups. Neurology 1959; 9: 569–574. 61 Moossy J. Cerebral infarction and intracranial arterial thrombosis. Necropsy studies and clinical implications. Arch Neurol 1966; 14: 119–123. 62 Flora GC, Baker AB, Loewenson RB, Klassen AC. A comparative study of cerebral atherosclerosis in males and females. Circulation 1968; 38: 859–869. 63 Fields WS, North RR, Hass WK, et al. Joint study of extracranial arterial occlusion as a cause of stroke. I. Organization of study and survey of patient population. JAMA 1968; 203: 955–960. 64 Heyden S, Heyman A, Goree JA. Nonembolic occlusion of the middle cerebral and carotid arteries – a comparison of predisposing factors. Stroke 1970; 1: 363– 369. 65 Heyman A, Karp HR, Heyden S, et al. Cerebrovascular disease in the biracial population of Evans County, Georgia. Arch Intern Med 1971; 128: 949–955. 66 Russo LS, Jr. Carotid system transient ischemic attacks: clinical, racial, and angiographic correlations. Stroke 1981; 12: 470–473. 67 Bauer RB, Sheehan S, Wechsler N, Meyer JS. Arteriographic study of sites, incidence, and treatment of arteriosclerotic cerebrovascular lesions. Neurology 1962; 12: 698–711. 68 Kuller LH. Introduction and overview commentary. In: Gillum R, Gorelick PB, Cooper ES (eds): Stroke in blacks. A guide to management and prevention. Basel: S. Karger AG, 1999, pp. 1–6. 69 Caplan LR. Cerebral ischemia and infarction in blacks. Clinical, autopsy and angiographic studies. In: Gillum R, Gorelick PB, Cooper ES (eds): Stroke in blacks. A guide to management and prevention. Basel: S. Karger AG, 1999, pp. 7–18. 70 Inzitari D, Hachinski VC, Taylor DW, Barnett HJ. Racial differences in the anterior circulation in cerebrovascular disease. How much can be explained by risk factors? Arch Neurol 1990; 47: 1080–1084. 71 Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Raceethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke 1995; 26: 14–20.
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72 Sacco RL, Roberts JK, Boden-Albala B, et al. Raceethnicity and determinants of carotid atherosclerosis in a multiethnic population. The Northern Manhattan Stroke Study. Stroke 1997; 28: 929–935. 73 Kasner SE, Chimowitz MI, Lynn MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113: 555–563. 74 Burke GL, Howard G. Ethnic differences in cerebral atherosclerosis. In: Gillum R, Gorelick PB, Cooper ES (eds): Stroke in blacks. A guide to management and prevention. Basel: S. Karger AG 1999, pp. 94–105. 75 Oda K, Tanaka N, Arai T, et al. Polymorphisms in proand anti-inflammatory cytokine genes and susceptibility to atherosclerosis: a pathological study of 1503 consecutive autopsy cases. Hum Mol Genet 2007; 16: 592–599. 76 Robinet P, Vedie B, Chironi G, et al. Characterization of polymorphic structure of SREBP-2 gene: role in atherosclerosis. Atherosclerosis 2003; 168: 381–387. 77 Markus HS, Labrum R, Bevan S, et al. Genetic and acquired inflammatory conditions are synergistically associated with early carotid atherosclerosis. Stroke 2006; 37: 2253–2259. 78 Fiotti N, Altamura N, Fisicaro M, et al. MMP-9 microsatellite polymorphism and susceptibility to carotid arteries atherosclerosis. Arterioscler Thromb Vasc Biol 2006; 26: 1330–1336. 79 Wang L, Gu Y, Wu G, et al. [A case control study on the distribution of apolipoprotein AI gene polymorphisms in the survivors of atherosclerosis cerebral infarction]. Zhonghua Liu Xing Bing Xue Za Zhi 2000; 21: 22–25. 80 Sertic J, Hebrang D, Janus D, et al. Association between deletion polymorphism of the angiotensin-converting enzyme gene and cerebral atherosclerosis. Eur J Clin Chem Clin Biochem 1996; 34: 301–304. 81 Liu ZZ, Lv H, Gao F, et al. Polymorphism in the human C-reactive protein (CRP) gene, serum concentrations of CRP, and the difference between intracranial and extracranial atherosclerosis. Clin Chim Acta 2008; 389: 40– 44. 82 Abboud S, Karhunen PJ, Lutjohann D, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) gene is a risk factor of large-vessel atherosclerosis stroke. PLoS ONE 2007; 2: e1043.
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Risk factors Kazuo Minematsu, Oh Young Bang and Toshiyuki Uehara
Studies investigating risk factors for intracranial atherosclerosis (ICAS) have been rare compared with those for extracranial carotid atherosclerosis. This may be attributable to the limited availability of vascular imaging techniques assessing intracranial cerebral arteries. During the last decades, a variety of imaging technologies have become available to directly and non-invasively evaluate the status of the intracranial vascular system, including transcranial Doppler ultrasonography (TCD), magnetic resonance angiography (MRA), and computed tomography angiography (CTA). With these new techniques, we can assess the intracranial vascular system not only in stroke patients but also in asymptomatic individuals. These improvements in vascular imaging technologies have yielded a growing number of studies on risk factors for ICAS. It is well known that the distribution of atherosclerotic lesions in the cervicocephalic vascular systems varies among different race–ethnic groups.1–6 In Caucasians, atherosclerosis develops frequently in the extracranial carotid arteries, whereas ICAS is the common cause of stroke in Asians, Africans, and Hispanics. Several studies have demonstrated that hypercholesterolemia and ischemic heart disease (IHD) are more frequent, whereas hypertension and diabetes mellitus are less prevalent in Caucasians than in African Americans.4,5 It still remains elusive, however, whether the race–ethnicity is an independent risk factor of ICAS or is confounded by differences in stroke risk factors among different ethnic groups. Recently, it has been suggested that the metabolic syndrome, which refers to a constellation of metabolic risk factors linked to insulin resistance, is associated
with increased risks of coronary heart disease and stroke. The number of people with the metabolic syndrome has rapidly increased over the past two decades, in association with the global epidemics of obesity and diabetes.7 The Adult Treatment Panel III (ATP-III) defined this syndrome as the presence of three or more of the following: (1) abdominal obesity; (2) elevated triglyceride levels (≥150 mg/dL); (3) low high-density lipoprotein cholesterol levels (<40 mg/dL for men and <50 mg/dL for women); (4) hypertension (systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg); and (5) impaired fasting glucose levels (≥110 mg/dL).8 The ATP-III recognized the metabolic syndrome as a secondary target for risk reduction therapy,8 and it was recently reported that the metabolic syndrome is associated with risks that are not accounted for entirely by conventional riskscoring paradigms.9 Numerous studies have addressed the independent association of the metabolic syndrome with heart disease-related mortality, with the relative hazard ratio reported to be 1.5 to 5.0.10 Stroke was considered as a combined co-morbidity in most studies. Several studies, however, reported that the metabolic syndrome or insulin resistance is associated with ischemic stroke across the study populations,11–16 especially with the atherosclerotic subtype of stroke.17–20 Since metabolic syndrome is almost three times as prevalent as diabetes mellitus, the population-attributable risk of stroke may be greater for the metabolic syndrome than for diabetes mellitus.21 In this chapter, various risk factors for ICAS, including the metabolic syndrome, are reviewed and discussed.
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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Differences in risk factors between extra- and intracranial atherosclerosis Several studies have revealed that risk factors are different between extracranial carotid atherosclerosis and ICAS. Kuller et al.2 reported that the role of blood pressure may be greater than that of hyperlipidemia in major ICAS. In contrast, extracranial carotid and coronary atherosclerosis was more closely related to serum lipid levels than to blood pressure. Similarly, Caplan et al.1 reported that the extracranial internal carotid artery (ICA) lesions were closely related to hyperlipidemia and IHD, whereas middle cerebral artery (MCA) diseases were related to hypertension rather than hypercholesterolemia. Heyden et al.22 analyzed a group of patients with angiographically documented non-embolic MCA occlusion and noted that they had IHD and hypercholesterolemia less frequently than those with extracranial ICA lesions. A study evaluating stroke-free Japanese subjects using MRA found that risk factors for extracranial ICA disease were age and hyperlipidemia, whereas those for ICAS were age and hypertension.23 Thus, it seems that there are certain differences in risk factors between extracranial arterial diseases and ICAS. However, the results have not always been consistent. For instance, Inzitari et al.5 studied patients recruited in the EC/IC Bypass Study and found that Asians and black people more often had ICAS than did Caucasians. They then noticed that race was the only independent factor determining the location of atherosclerosis. Similarly, Wityk et al.24 found that the distribution of cerebral atherosclerosis was influenced by race and sex, but not other vascular risk factors. More recently, Kim and Choi-Kwon25 investigated risk factors and lifestyle factors in patients with cerebrovascular diseases. They meticulously evaluated atherosclerotic lesions at different levels of cerebral arteries using MRA and found that there were no risk factors that differentiate ICAS from extracranial arterial diseases. Therefore, there still remain controversies regarding whether there are risk factors preferentially affecting a specific level of cerebral vessels. Recently, several studies have reported that the metabolic syndrome, a constellation of a group of risk factors, may be more closely associated with ICAS than extracranial atherosclerosis.26–28 This issue
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will be discussed in detail in the last sections of this chapter.
Intracranial atherosclerosis and coronary diseases Patients with IHD are more likely to have stroke than those without,29 and IHD is a frequent cause of death among stroke survivors.30 IHD shares risk factors with ischemic stroke. In Caucasians, the degree of extracranial carotid atherosclerosis has been shown to correlate with the extent of coronary atherosclerosis.31–34 On the other hand, although earlier autopsy-based studies reported a correlation between ICAS and coronary atherosclerosis,35,36 the relationship seems to be less clear. Uehara et al.37 evaluated atherosclerotic lesions in the extracranial and intracranial cerebral arteries using MRA in 67 Japanese patients who underwent selective coronary angiography to estimate the extent of IHD. Stenotic lesions >25% in diameter were found in 15 patients (22.4%) in the extracranial carotid artery and in 11 patients (16.4%) in the intracranial cerebral arteries. They compared the patients with IHD with age- and sex-matched control subjects without a history of IHD. The prevalence of carotid artery lesions was significantly higher in the IHD group than in the control group. Although the prevalence of ICAS was also higher in the IHD group than in the control group, the difference was not statistically significant. When the patients with IHD were divided into four groups as zero-, single-, two-, and three-vessel disease groups according to the number of affected major coronary branches, extracranial carotid artery lesions were significantly more common in the three-vessel group than in the zero- and single-vessel groups. A similar trend was also observed for ICAS, but the difference was not statistically significant. However, the failure to find an association between the severity of ICAS and that of coronary artery disease might be attributable to the small number of patients with ICAS who had two- or three-vessels disease. Recently, a study with a larger number of subjects found that the prevalence of ICAS as well as that of extracranial atherosclerosis increased significantly as coronary atherosclerosis became more severe, from zero- to three-vessel disease.38 The prevalence of ICAS
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Table 4.1 Studies on risk factors for intracranial atherosclerosis
Author (year)
Country
Sym/Asym
Evaluation method
Evaluation sites
Significant risk factors
Yasaka et al. (1993)43
Japan
Sym
CA
MCA, BA
MCA: advanced HT BA: DM, HL, IHD
Uehara et al. (1998)23 Kim et al. (1999)25 Takahashi et al. (1999)44 Arenillas et al. (2004)45
Japan Korea Japan Spain
Asym Sym Sym+Asym Sym
Korea Japan
Sym Asym
ICA, MCA, BA MCA, ACA, BA, PCA MCA ICA, MCA, ACA VA, BA, PCA MCA, VA, BA ICA, MCA, VA, BA
Age, HT HT, DM HT, HbA1c DM, Lp(a)
Bang et al. (2005)26 Uehara et al. (2005)46
MRA CA, MRA MRA MRA, CTA, TCD CA, MRA MRA
Bae et al. (2007)47
Korea
Asym
TCD
Park et al. (2007)27 Wong et al. (2007)48
Korea Hong Kong
Sym Asym
MRA TCD
Wong et al. (2007)49 Huang et al. (2007)50
Hong Kong Hong Kong
Asym Asym
TCD TCD
ICA, MCA, ACA VA, BA, PCA MCA, ACA, BA, PCA ICA, MCA, ACA VA, BA, PCA MCA MCA
MetS ICA: Age, HT, DM, IHD MCA: Age, HT BA: HT, DM VA: HL, IHD Age, HT, DM MetS HT, glycosuria, heart disease Family history of stroke Age, HT, DM, HL Age, male, HT, DM
Sym, symptomatic; Asym, asymptomatic. ACA, anterior cerebral artery; BA, basilar artery; CA, conventional angiography; CTA, CT angiography; DM, diabetes mellitus; IHD, ischemic heart disease; HL, hyperlipidemia; HT, hypertension; ICA, internal carotid artery; Lp(a), lipoprotein (a); MCA, middle cerebral artery; MetS, metabolic syndrome; MRA, MR angiography; PCA, posterior cerebral artery TCD, transcranial Doppler; VA, vertebral artery.
was high in patients who had severe coronary artery lesions or those scheduled for coronary artery bypass graft (CABG) surgery, although the relationship was less strong than in patients with extracranial carotid disease.39,40 Similarly, a more recent study41 analyzing 246 consecutive patients undergoing CABG surgery showed that the correlation of coronary atherosclerosis was stronger with extracranial carotid atherosclerosis than with ICAS. Finally, Arenillas et al.42 reported that the existence of symptomatic vertebral, basilar artery (BA), and intracranial ICA stenosis was an independent marker of myocardial perfusion abnormalities in single-photon emission computed tomography studies. These results, taken together, suggest that ICAS is closely associated with coronary atherosclerosis, but the association is weaker than in extracranial carotid atherosclerosis.
Conventional stroke risk factors in intracranial atherosclerosis A number of clinical studies have assessed conventional risk factors for ICAS mainly in Asian populations. Table 4.1 summarizes the results.23,25–28,43–50 Age It is well known that advanced age is a significant risk factor for ICAS. Solberg et al.51 suggested that atherosclerotic lesions develop in the intracranial cerebral arteries about one decade later in life than in the extracranial ICA. Gender The relationship of ICAS and gender remains controversial. Several studies have shown a female
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predominance in ICAS1 whereas others have reported that men are more likely to have ICAS than women.24 A clinical study in Chinese subjects50 and autopsy studies51,52 mainly on asymptomatic subjects also reported a male predominance in ICAS. Progression of atherosclerosis with age may also be different between men and women.53 In one study, ICAS developed earlier in men than in women with increasing age; however, it progressed faster in women than in men.1 It was speculated that hormonal changes secondary to the menopause may influence the progression rate of ICAS54 as in extracranial carotid atherosclerosis. Hypertension Early autopsy studies reported that hypertension may exert a strong influence on atherosclerosis in the intracranial cerebral arteries.51,55 Many clinical studies23,43,44,46–50 have also found a close correlation between hypertension and ICAS. Diabetes mellitus An autopsy-based study from Hong Kong demonstrated that the risk of ICAS was increased by the presence of diabetes mellitus.56 In clinical studies, diabetes mellitus has also been found to be a significant risk factor for ICAS. Bae et al.47 indicated that diabetes mellitus was a significant predictor of asymptomatic ICAS and might even be a more potent predictor than hypertension. This result was also supported by a few studies on symptomatic individuals.3,45,57 Diabetes mellitus was also found to be a significant risk factor in patients with combined extracranial and intracranial arterial diseases.58,59 Hyperlipidemia Hyperlipidemia is an established risk factor for carotid atherosclerosis. However, its role in ICAS remains unclear, because previous studies have shown controversial results. In the Northern Manhattan Stroke Study, the higher prevalence of diabetes mellitus and hypercholesterolemia among African Americans and Hispanics accounted for the much higher frequency of stroke related to ICAS when compared with white individuals.3 However, most of previous studies have shown that hyperlipidemia is a less important risk factor for ICAS than extracranial ICA diseases. Only a 48
few studies reported a positive correlation between serum cholesterol levels and ICAS.43,49 Cigarette smoking Cigarette smoking is an established risk factor for ischemic stroke.60 However, studies on smoking and ICAS have failed to prove a clear association between them.23,46
Risk factors in different vascular territories Several studies were carried out to examine and compare risk factors for occlusive lesions among different intracranial arteries, especially MCA, ICA, and BA. For example, in a study investigating risk factors for occlusive intracranial arterial lesions in stroke-free Japanese individuals, significant and independent predictors were age and hypertension for MCA lesions; age, hypertension, diabetes mellitus, and IHD for ICA lesions; and hypertension and diabetes mellitus for BA lesions.46 This observation suggests that the impact of risk factors may not be uniform throughout the intracranial arteries. Middle cerebral artery Caplan et al.1 reported that the high prevalence of hypertension and the relatively low prevalence of hypercholesterolemia could explain the high prevalence of MCA lesions in Japan. Yasaka et al.43 demonstrated that advanced hypertension was related to MCA atherosclerosis, whereas Takahashi and his colleagues44 reported that hypertension and high serum levels of glycosylated hemoglobin A1c were significant predictors of MCA disease. In a study on subjects who had vascular risk factors but without history of stroke or transient ischemic attack (TIA), advanced age, hyperlipidemia, hypertension, and diabetes mellitus were risk factors for MCA stenosis.49 In Chinese subjects, male sex, advanced age, hypertension, and diabetes mellitus were found to be risk factors for MCA stenosis.50 Intracranial internal carotid artery Little is known about the risk factors for intracranial ICA occlusive lesions. Ingall et al.61 demonstrated
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that age, hypertension, diabetes mellitus, and duration of cigarette smoking were significant and independent predictors. Intracranial ICA stenosis may be a marker for extensive cerebrovascular and systemic atherosclerotic diseases, especially coronary artery disease, and thus predicts poor prognosis.62
Basilar artery Previous studies yielded controversial results about risk factors for BA lesions. As mentioned above, a study on stroke-free subjects demonstrated that atherosclerosis of BA was associated with hypertension and diabetes mellitus.46 On the other hand, Caplan et al.1 and Yasaka et al.43 found that hyperlipidemia and IHD were closely related to extracranial ICA and BA atherosclerosis. This discrepancy might be attributable to the different study designs or relatively small numbers of subjects with BA stenosis in those studies.
Metabolic syndrome as a novel risk factor for intracranial atherosclerosis As discussed above, whether risk factors differentially affect different vascular system remains uncertain. Recently, two distinct studies suggested that metabolic syndrome, a constellation of risk factors, was independently associated with strokes with ICAS, whereas individual conventional risk factors were not.26,27 Patients with one or two, three, and four or five components of metabolic syndrome were about 2.5–3.8, 4.4, and 5.9–6.4 times, respectively, more likely to have ICAS than those who had no components.26 By contrast, such associations were not observed in patients with extracranial carotid atherosclerosis.26,27 A subgroup analysis of the Warfarin–Aspirin for Symptomatic Intracranial Disease (WASID) trial showed a high prevalence of metabolic syndrome in patients with ICAS; the metabolic syndrome was present in about half of individuals with symptomatic ICAS and was associated with a substantially higher risk of major vascular events.63 Supporting the role of metabolic syndrome on the development of ICAS, a dose–response relationship was observed: the frequency of multiple, tandem ICAS lesions increased as the number of syndrome components increased.26,27
Thus, treatment of the metabolic syndrome including lifestyle modifications, the use of insulinsensitizing drugs, and the management of associated risk factors could potentially be beneficial in preventing intracranial atherogenic progression and subsequent development of stroke. The Insulin Resistance Intervention After Stroke (IRIS) Trial is currently ongoing to determine whether reduction of insulin resistance by Pioglitazone (thiazolidinedione, an insulin sensitizer) prevents subsequent strokes or myocardial infarctions in patients with non-embolic ischemic strokes and insulin resistance.
Possible pathophysiologic interactions between metabolic syndrome and intracranial atherosclerosis There are several possible links explaining the high frequency of the metabolic syndrome in patients with ICAS. First, adiponectin may be one of the mediators connecting metabolic syndrome with ICAS. Adiponectin is one of abundant adipose tissue-specific cytokines that is closely linked to obesity.64 The level of adiponectin has been reported to be reduced in various conditions, including obesity, type 2 diabetes, insulin resistance, metabolic syndrome, dyslipidemia, oxidative stress, and cardiovascular disease.65 Adiponectin may have a protective effect against atherosclerosis through various mechanisms: suppression of neointimal formation, inhibiting the expression of inflammatory cytokines and adhesion molecules.65,66 Hypoadiponectinemia was also reported to be associated with endothelial dysfunction.67 The adiponectin level was found to be decreased in adults with early68 and advanced69,70 stages of atherosclerosis. It was recently reported that symptomatic ICAS was associated with the lower serum adiponectin level when compared with other ischemic stroke subtypes, regardless of the patients’ metabolic condition.28 Second, the metabolic syndrome is associated with several potentially harmful effects to the cerebrovascular system, which include endothelial dysfunction, increased oxidative stress, systemic inflammation, and sleep apnea. Oxidative stress, which is associated with this syndrome, has been suggested to play a role in endothelial dysfunction and subsequent atherosclerosis71,72 ; adults with metabolic 49
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syndrome had suboptimal concentrations of several antioxidants.73 An autopsy study revealed that intracranial arteries responded with accelerated atherogenesis to a greater degree than extracranial arteries when antioxidant protection was decreased.74 The authors suggested that the progression of atherosclerosis within intracranial arteries might be partly attributable to the failure of the intracellular defense system against free radical-mediated processes. Therefore, it is conceivable that intracranial arteries may become susceptible to oxidative stress, resulting in atherosclerotic changes, under the conditions of increased oxidative stress such as the metabolic syndrome. It was also suggested that inflammation within the vasculature might be an important pathogenic link between cardiovascular disease and the metabolic syndrome.75 Lastly, sleep apnea syndrome is another possible link between the metabolic syndrome and ICAS. The relationship between obstructive sleep apnea and the metabolic syndrome76–80 and chronic inflammation81 has been demonstrated. Vgontzas and colleagues82 summarized accumulating evidence that sleep apnea may be a manifestation of the metabolic syndrome: (a) there is a high prevalence of symptomatic sleep apnea in patients with insulin resistance78 and in women with polycystic ovarian syndrome (a disorder in which insulin resistance is the primary pathogenetic mechanism),83 (b) metabolic syndrome and insulin resistance are stronger determinants of sleepiness than the apnea/hypopnea index, (c) similar age distribution between symptomatic sleep apnea and the metabolic syndrome,84 and (d) the beneficial effect of exercise on both sleep apnea and insulin resistance.85 A growing line of evidence has shown that obstructive sleep apnea is a risk factor for ischemic heart disease and stroke in middle-aged or elderly populations.86,87 Thus, sleep apnea may be involved in the relationship between the metabolic syndrome and atherosclerotic stroke. The impact of the metabolic syndrome on the development of atherosclerotic stroke may differ according to the presence of obstructive sleep apnea. However, further studies are needed to elucidate the precise relationship between metabolic syndrome, sleep apnea and ICAS.
50
Metabolic syndrome and ethnic differences in the pattern of atherosclerosis As mentioned above, the distribution of atherosclerosis is different among different ethnicities. The metabolic syndrome and related conditions may at least in part explain the difference. First, adiponectin was reported to be a predictor of insulin sensitivity independent of visceral adipose tissue, leptin, and race.88 However, racial differences in insulin sensitivity and adipose secretion may exist. Despite the similar age, body mass index, and total adiposity, young African Americans have a lower adiponectin level and insulin sensitivity than young non-Hispanic white people, and the lower adiponectin level in the former may in part explain the lower insulin sensitivity.88 It was also reported that Indo-Asians have a lower adiponectin level than non-Hispanic white people.89 Such differences in adiponectin levels may be related with the ethnic differences in the distribution of atherosclerosis.27 In addition, race–ethnic difference in the levels of visceral adiposity, insulin resistance, and C-reactive protein may in part account for the difference in the patterns of disease presentation.90 Further studies on ethnic differences in adiponectin levels and adiponectin polymorphisms91 in both healthy individuals and patients with atherosclerotic stroke are warranted. Second, the estimated prevalence of insulin resistance syndrome, obesity, and obesity-related comorbidities may be different among race–ethnic groups. There was a higher prevalence of the obesityrelated hypertension in African-Americans, the obesity-related diabetes in Hispanics, and the predisposition to glucose intolerance in healthy lean young Asians, than in non-Hispanic white people.92 Certain genetic predisposition is likely to be involved in these observations.92 Third, race- and gender-based differences in the mechanisms of metabolic syndrome-induced atherosclerotic progression were reported.93,94 The race-specific impact of the metabolic syndrome on the distribution of atherosclerosis may be related to racespecific differences in the host response to the specific metabolic components (i.e., obesity and plasma lipid level) as well as by the differences in the prevalence of metabolic components. A study involving
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comprehensive work-ups in stroke patients with diverse race–ethnic backgrounds is currently underway to understand the possible race–ethnic differences in the impact of the metabolic syndrome on the different distribution of cerebral atherosclerosis. Lastly, obstructive sleep apnea syndrome was reported to be more prevalent or severe in certain ethnic groups. For instance, sleep apnea was found to be associated with a lesser degree of obesity in Asians than in white people.95 This different prevalence or severity of sleep apnea syndrome among different ethnic groups might play a role in ethnic differences in the manifestation of cerebral atherosclerosis. Further multicenter, multi-ethnic studies are needed to elucidate the relationship between ICAS and metabolic syndrome and related conditions. In addition, prospective trials focusing on the efficacy of modifying risk factors of metabolic syndrome in stroke patients with ICAS are warranted.
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detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel iii). JAMA 2001; 285: 2486–2497. Girman CJ, Rhodes T, Mercuri M, et al. The metabolic syndrome and risk of major coronary events in the Scandinavian Simvastatin Survival Study (4s) and the air Force/TEXAS coronary atherosclerosis prevention study (AFCAPS/TEXCAPS). Am J Cardiol 2004; 93: 136–141. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365: 1415–28. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001; 24: 683–689. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002; 288: 2709– 2716. Pyorala M, Miettinen H, Halonen P, et al. Insulin resistance syndrome predicts the risk of coronary heart disease and stroke in healthy middle-aged men: The 22-year follow-up results of the Helsinki policemen study. Arterioscler Thromb Vasc Biol 2000; 20: 538–544. Kawamoto R, Tomita H, Oka Y, Kodama A. Metabolic syndrome as a predictor of ischemic stroke in elderly persons. Intern Med 2005; 44: 922–927. Kurl S, Laukkanen JA, Niskanen L, et al. Metabolic syndrome and the risk of stroke in middle-aged men. Stroke 2006; 37: 806–811. Kernan WN, Inzucchi SE, Viscoli CM, et al. Insulin resistance and risk for stroke. Neurology 2002; 59: 809–815. Milionis HJ, Rizos E, Goudevenos J, et al. Components of the metabolic syndrome and risk for first-ever acute ischemic nonembolic stroke in elderly subjects. Stroke 2005; 36: 1372–1376. Ninomiya JK, L’Italien G, Criqui MH, et al. Association of the metabolic syndrome with history of myocardial infarction and stroke in the third national health and nutrition examination survey. Circulation 2004; 109: 42–46. Ohira T, Shahar E, Chambless LE, et al. Risk factors for ischemic stroke subtypes: the atherosclerosis risk in communities study. Stroke 2006; 37: 2493–2498. Chen HJ, Bai CH, Yeh WT, et al. Influence of metabolic syndrome and general obesity on the risk of ischemic stroke. Stroke 2006; 37: 1060–1064. Najarian RM, Sullivan LM, Kannel WB, et al. Metabolic syndrome compared with type 2 diabetes mellitus as a risk factor for stroke: The Framingham offspring study. Arch Intern Med 2006; 166: 106–111. Heyden S, Heyman A, Goree JA. Nonembolic occlusion of the middle cerebral and carotid arteries: a comparison of predisposing factors. Stroke 1970; 1: 363–369.
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23 Uehara T, Tabuchi M, Mori E. Frequency and clinical correlates of occlusive lesions of cerebral arteries in Japanese patients without stroke: Evaluation by MR angiography. Cerebrovasc Dis 1998; 8: 267–272. 24 Wityk RJ, Lehman D, Klag M, et al. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996; 27: 1974–1980. 25 Kim JS, Choi-Kwon S. Risk factors for stroke in different levels of cerebral arterial disease. Eur Neurol 1999; 42: 150–156. 26 Bang OY, Kim JW, Lee JH, et al. Association of the metabolic syndrome with intracranial atherosclerotic stroke. Neurology 2005; 65: 296–298. 27 Park JH, Kwon HM, Roh JK. Metabolic syndrome is more associated with intracranial atherosclerosis than extracranial atherosclerosis. Eur J Neurol 2007; 14: 379– 386. 28 Bang OY, Saver JL, Ovbiagele B, et al. Adiponectin levels in patients with intracranial atherosclerosis. Neurology 2007; 68: 1931–1937. 29 Kannel WB, Wolf PA, Verter J. Manifestations of coronary disease predisposing to stroke. The Framingham study. JAMA 1983; 250: 2942–2946. 30 Hartmann A, Rundek T, Mast H, et al. Mortality and causes of death after first ischemic stroke. The Northern Manhattan Stroke Study. Neurology 2001; 57: 2000– 2005. 31 Crouse JR, Toole JF, McKinney WM, et al. Risk factors for extracranial carotid artery atherosclerosis. Stroke 1987; 18: 990–996. 32 Howard G, Ryu JE, Evans GW, et al. Extracranial carotid atherosclerosis in patients with and without transient ischemic attacks and coronary artery disease. Arteriosclerosis 1990; 10: 714–719. 33 Crouse JR, Harpold GH, Kahl FR, et al. Evaluation of a scoring system for extracranial carotid atherosclerosis extent with B-mode ultrasound. Stroke 1986; 17: 270– 275. 34 Craven TE, Ryu JE, Espeland MA, et al. Evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis. a case-control study. Circulation 1990; 82: 1230–1242. 35 Mathur KS, Kashyap SK, Kumar V. Correlation of the extent and severity of atherosclerosis in the coronary and cerebral arteries. Circulation 1963; 27: 929– 934. 36 Holme I, Enger SC, Helgeland A, et al. Risk factors and raised atherosclerotic lesions in coronary and cerebral arteries: Statistical analysis from the Oslo study. Atherosclerosis 1981; 1: 250–256. 37 Uehara T, Tabuchi M, Hayashi T, et al. Asymptomatic occlusive lesions of carotid and intracranial arteries in Japanese patients with ischemic heart disease: Evaluation
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by brain magnetic resonance angiography. Stroke 1996; 27: 393–397. Uekita K, Hasebe N, Funayama N, et al. Cervical and intracranial atherosclerosis and silent brain infarction in Japanese patients with coronary artery disease. Cerebrovasc Dis 2003; 16: 61–68. Uehara T, Tabuchi M, Kozawa S, Mori E. MR angiographic evaluation of carotid and intracranial arteries in Japanese patients scheduled for coronary artery bypass grafting. Cerebrovasc Dis 2001; 11: 341–345. Yoon BW, Bae HJ, Kang DW, et al. Intracranial cerebral artery disease as a risk factor for central nervous system complications of coronary artery bypass graft surgery. Stroke 2001; 32: 94–99. Bae HJ, Yoon BW, Kang DW, et al. Correlation of coronary and cerebral atherosclerosis: difference between extracranial and intracranial arteries. Cerebrovasc Dis 2006; 21: 112–119. Arenillas JF, Candell-Riera J, Romero-Farina G, et al. Silent myocardial ischemia in patients with symptomatic intracranial atherosclerosis: associated factors. Stroke 2005; 36: 1201–1206. Yasaka M, Yamaguchi T, Shichiri M. Distribution of atherosclerosis and risk factors in atherothrombotic occlusion. Stroke 1993; 24: 206–211. Takahashi K, Kitani M, Fukuda H, Kobayashi S. Vascular risk factors for atherosclerotic lesions of the middle cerebral artery detected by magnetic resonance angiography (MRA). Acta Neurol Scand 1999; 100: 395–399. Arenillas JF, Molina CA, Chacon P, et al. High Lipoprotein (a), diabetes, and the extent of symptomatic intracranial atherosclerosis. Neurology 2004; 63: 27–32. Uehara T, Tabuchi M, Mori E. Risk factors for occlusive lesions of intracranial arteries in stroke-free Japanese. Er J Neurol 2005; 12: 218–222. Bae HJ, Lee J, Park JM, et al. Risk factors of intracranial cerebral atherosclerosis among asymptomatics. Cerebrovasc Dis 2007; 24: 355–360. Wong KS, Huang YN, Yang HB, et al. A door-to-door survey of intracranial atherosclerosis in Liangbei County, China. Neurology 2007; 68: 2031–2034. Wong KS, Ng PW, Tang A, et al. Prevalence of asymptomatic intracranial atherosclerosis in high-risk patients. Neurology 2007; 68: 2035–2038. Huang HW, Guo MH, Lin RJ, et al. Prevalence and risk factors of middle cerebral artery stenosis in asymptomatic residents in Rongqi County, Guangdong. Cerevrovasc Dis 2007; 24: 111–115. Solberg LA, McGarry PA. Cerebral atherosclerosis in Negroes and Caucasians. Atherosclerosis 1972; 16: 141– 154. Williams AO, Resch JA, Loewenson RB. Cerebral atherosclerosis: a comparative autopsy study between
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Nigerian Negroes and American Negroes and Caucasians. Neurology 1969; 19: 205–210. Resch JA, Baker AB. Etiologic mechanisms in cerebral atherosclerosis. Arch Neurol 1964; 10: 617–628. Joakimsen O, Bonaa KH, Stensland-Bugge E, Jacobsen BK. Population-based study of age at menopause and ultrasound assessed carotid atherosclerosis: the Tromso Study. J Clin Epdemiol 2000; 53: 525–530. Fisher CM, Gore I, Okabe N, White PD. Atherosclerosis of the carotid and vertebral arteries – extracranial and intracranial. J Neuropathol Exp Neurol 1965: 24: 455– 476. Leung SY, Ng THK, Yuen ST, et al. Pattern of cerebral atherosclerosis in Hong Kong Chinese: severity in intracranial and extracranial vessels. Stroke 1993; 24: 779– 786. Gorelick PB, Caplan LR, Langenberg P, et al. Clinical and angiographic comparison of asymptomatic occlusive cerebrovascular disease. Neurology 1988; 38: 852–858. Lee SJ, Cho SJ, Moon HS, et al. Combined extracranial and intracranial atherosclerosis in Korean patients. Arch Neurol 2003; 60: 1561–1564. Suwanwela NC, Chutinetr A. Risk factors for atherosclerosis of cervicocerebral arteries: intracranial versus extracranial. Neuroepidemiology 2003; 22: 37–40. Wolf A, D’Agostino RB, Kannel WB, et al. Cigarette smoking as a risk factor for stroke: The Framingham Study. JAMA 1988; 259: 1025–1029. Ingall TJ, Homer D, Baker, HL, Jr, et al. Predictors of intracranial carotid artery atherosclerosis. Duration of cigarette smoking and hypertension are more powerful than serum lipid levels. Arch Neurol 1991; 48: 687–691. Marzewski DJ, Furlan AJ, St. Louis P, et al. Intracranial internal carotid artery stenosis: Long-term prognosis. Stroke 1982; 13: 821–824. Ovbiagele B, Saver JL, Lynn MJ, Chimowitz M. Impact of metabolic syndrome on prognosis of symptomatic intracranial atherostenosis. Neurology 2006; 66: 1344– 1349. Arita Y, Kihara S, Ouchi N, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79–83. Kadowaki T, Yamauchi T, Kubota N, et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116: 1784–1792. Matsuda M, Shimomura I, Sata M, et al. Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis. J Biol Chem 2002; 277: 37487–37491. Shimabukuro M, Higa N, Asahi T, et al. Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 2003; 88: 3236–3240.
68 Pilz S, Horejsi R, Moller R, Almer G, et al. Early atherosclerosis in obese juveniles is associated with low serum levels of adiponectin. J Clin Endocrinol Metab 2005; 90: 4792–4796. 69 Kumada M, Kihara S, Sumitsuji S, et al. Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 2003; 23: 85–89. 70 Pischon T, Girman CJ, Hotamisligil GS, et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 2004; 291: 1730–1737. 71 Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress. Circ Res 2000; 87: 840–844. 72 Lee KU. Oxidative stress markers in Korean subjects with insulin resistance syndrome. Diabetes Res Clin Pract 2001; 54 (Suppl 2): S29–33. 73 Ford ES, Mokdad AH, Giles WH, Brown DW. The metabolic syndrome and antioxidant concentrations: Findings from the third national health and nutrition examination survey. Diabetes 2003; 52: 2346–2352. 74 D’Armiento FP, Bianchi A, de Nigris F, et al. Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis. Stroke 2001; 32: 2472– 2479. 75 Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: An 8-year follow-up of 14 719 initially healthy American women. Circulation 2003; 107: 391– 397. 76 Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328: 1230–1235. 77 Grunstein RR, Stenlof K, Hedner J, Sjostrom L. Impact of obstructive sleep apnea and sleepiness on metabolic and cardiovascular risk factors in the Swedish Obese Subjects (SOS) study. Int J Obes Relat Metab Disord 1995; 19: 410–418. 78 Ip MS, Lam B, Ng Mm, et al. Obstructive sleep apnea is independently associated with insulin resistance. Am J Respir Crit Care Med 2002; 165: 670–676. 79 Gruber A, Horwood F, Sithole J, et al. Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state. Cardiovasc Diabetol 2006; 5: 22. 80 Coughlin SR, Mawdsley L, Mugarza JA, et al. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 2004; 25: 735–741. 81 Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000; 85: 1151– 1158.
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82 Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 2005; 9: 211–224. 83 Vgontzas AN, Legro RS, Bixler EO, et al. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: Role of insulin resistance. J Clin Endocrinol Metab 2001; 86: 517– 520. 84 Park YW, Zhu S, Palaniappan L, et al. The metabolic syndrome: Prevalence and associated risk factor findings in the US population from the third national health and nutrition examination survey, 1988–1994. Arch Intern Med 2003; 163: 427–436. 85 Peppard PE, Young T. Exercise and sleep-disordered breathing: An association independent of body habitus. Sleep 2004; 27: 480–484. 86 Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005; 353: 2034–2041. 87 Munoz R, Duran-Cantolla J, Martinez-Vila E, et al. Severe sleep apnea and risk of ischemic stroke in the elderly. Stroke 2006; 37: 2317–2321. 88 Lee S, Bacha F, Gungor N, Arslanian SA. Racial differences in adiponectin in youth: Relationship to visceral fat and insulin sensitivity. Diabetes Care 2006; 29: 51–56.
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89 Valsamakis G, Chetty R, McTernan PG, et al. Fasting serum adiponectin concentration is reduced in Indo-Asian subjects and is related to HDL cholesterol. Diabetes Obes Metab 2003; 5: 131–135. 90 Forouhi NG, Sattar N. CVD risk factors and ethnicity– a homogeneous relationship? Atheroscler Suppl 2006; 7: 11–19. 91 Ukkola O, Santaniemi M, Rankinen T, et al. Adiponectin polymorphisms, adiposity and insulin metabolism: heritage family study and Oulu diabetic study. Ann Med 2005; 37: 141–150. 92 Cossrow N, Falkner B. Race/ethnic issues in obesity and obesity-related comorbidities. J Clin Endocrinol Metab 2004; 89: 2590–2594. 93 Fan AZ. Metabolic syndrome and progression of atherosclerosis among middle-aged US adults. J Atheroscler Thromb 2006; 13: 46–54. 94 Li S, Chen W, Srinivasan SR, Tang R, Bond MG, Berenson GS. Race (black–white) and gender divergences in the relationship of childhood cardiovascular risk factors to carotid artery intima-media thickness in adulthood: the Bogalusa Heart Study. Atherosclerosis 2007; 194: 421– 425. 95 Villaneuva AT, Buchanan PR, Yee BJ, Grunstein RR. Ethnicity and obstructive sleep apnoea. Sleep Med Rev 2005; 9: 419–436.
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PART TWO
Stroke mechanism and clinical consequence
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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Stroke mechanisms KS Lawrence Wong, Louis R Caplan and Jong S Kim
Atherosclerotic disease of the intracranial large arteries, especially the middle cerebral artery (MCA), is the commonest cause of stroke and transient ischemic attack (TIA) in most parts of the world, apart from Europe and North America. The pathology of intracranial atherosclerosis (ICAS) is not much different from atherosclerosis in other parts of the circulation such as the aorta and the coronary and carotid arteries. Lipidladen plaques with various thickness of capsule are commonly found in ICAS. The details of the pathological features are covered in Chapter 2. Yet, the stroke mechanisms may vary in different patients. Artery-to-artery embolism, hemodynamic insufficiency, branch occlusive diseases or the combination of these mechanisms leads to brain ischemia. Coexisting causes such as small vessel disease and cardioembolism are also found in the same patient. Recently, advances in neuroimaging technologies such as microembolic signal (MES) detection, diffusion weighted imaging (DWI), and various blood flow measurements have provided insights into various aspects of stroke mechanism in patients with ICAS. It is important to delineate the stroke mechanism since treatment and prevention strategies should be based on the correct understanding of pathophysiological mechanism in an individual patient.
Neuroimaging investigations to study stroke mechanisms Advances in neuroimaging have provided new insights into the stroke mechanisms of ICAS. Newer generation
CT angiography and MR angiography easily depict the location and severity of intracranial stenosis. DWI is the most sensitive tool to detect tiny, symptomatic, or asymptomatic cerebral ischemic lesions and can differentiate recent infarcts from old ones.1–3 Using DWI, the characteristic topographic patterns of cerebral infarcts may be individually assessed. On the other hand, fluid-attenuated inversion recovery (FLAIR) sequences offer advantages in detection of infarcts affecting the cortical ribbon, because cortical infarcts may be hard to detect given the similarly high signal of cortical gray matter and adjacent cerebrospinal fluid, and the complex convolutional geometry of the surface of the brain.4 In addition, transcranial Doppler ultrasound (TCD) can non-invasively identify narrowing and collateralization of major intracranial large arteries in patients with good temporal windows. MES detected by TCD is likely to represent an embolus passing through the insonated artery,5–8 and helps us to identify the mechanism of stroke or TIA in patients with ICAS. The application of these advanced imaging technologies is described in detail in other chapters (Chapters 10–12).
Stroke mechanisms in intracranial atherosclerosis Possible mechanisms for brain infarction or TIA arising from ICAS include thrombosis leading to complete occlusion, artery-to-artery embolism, hemodynamic compromise (hypoperfusion), local branch occlusion of the orifice of a deep perforator, or the combination of these mechanisms9,10 (Table 5.1).
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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Table 5.1 Mechanisms of brain infarction and TIA in patients with intracranial atherosclerosis Stroke mechanism
Frequency
Pattern of infarcts
Number of infarcts
In situ thrombotic occlusion
Uncommon
Large subcortical Sometimes with borderzone Rarely, whole territory
Single Sometimes enlarging
Artery-to-artery embolism∗
Common
Small cortical and subcortical
Multiple
Impaired clearance of emboli∗
Common
Small, scattered, alongside the borderzone region
Multiple
Branch occlusive disease
Common
Small subcortical, lacune-like
Single
Hemodynamic
Uncommon
Borderzone May be without lesion
Multiple None
∗ These
mechanisms frequently coexist.
In situ thrombotic occlusion Acute thrombosis begins with fissuring of the fibrous cap of the atherosclerotic plaque, which disrupts the endothelial surface of the artery. Release of tissue factors promotes the development of a clot adjacent to the plaque.11 Local occlusion and secondary artery-to-artery embolism can then result.12,13 Lammie et al.14 reported that coronary-type rupture of an unstable atherosclerotic plaque is the usual cause of fatal occlusion of the carotid sinus, but other causes usually underlie intracranial carotid occlusion. Plaque instability can be related to factors such as inflammation, autoimmunity, or genetic predisposition, and these conditions may play a role in acceleration of atherosclerosis in addition to traditional risk factors.15 In patients with ICAS, in situ thrombotic occlusion usually produces infarcts that are larger than those caused by other mechanisms. However, unlike patients with cardiogenic embolism, the in situ thrombotic occlusion rarely produces whole territory infarction because of the relatively well-developed collateral circulation in patients with chronic atherosclerotic disease. In patients with MCA steno-occlusion, the initial lesions are usually restricted to the striatocapsular area, borderzone area or the combination of both. Occasionally, an initial infarct evolves to a larger lesion along with progressive neurological worsening (Fig. 5.1). Thus, the ultimate size of the infarct may vary according to the development of collateral 58
circulation, the speed of arterial occlusion and hemodynamic stability after the occurrence of stroke. With sufficient collaterals, total thrombotic intracranial occlusion may remain asymptomatic, or produce only minor brain infarcts or TIAs.
Artery-to-artery embolism Apart from occlusion at the site of thrombosis, forceful blood flow can break up a portion of the thrombus and carry it to distal branches. Besides, ulceration of the surface of the plaque can be the source of atherosclerotic debris (cholesterol embolism) that migrates to distal vessels. Blockage of the distal branches by embolism causes cerebral infarction. MES monitoring is now an established method to detect symptomatic or asymptomatic embolism in patients with MCA disease.5,16 For MCA occlusion, particularly cardiac diseases, atrial fibrillation is the most frequent cause. The resultant stroke is usually quite large and disabling.17,18 Internal carotid artery (ICA) atherosclerotic disease is another important source of embolism, leading to MCA occlusion and brain infarcts.19 Cerebral angiography within the first 6 hours after the onset of ischemic symptoms shows intracranial occlusion in about 80% of the cases that are usually caused by emboli.20,21 Cardioembolic stroke is commonly associated with a bigger infarct than an embolic stroke of arterial origin partly because the clots are larger and
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Fig 5.1 A 64-year-old hypertensive man developed mild right hemiparesis and sensory aphasia. Diffusion weighted magnetic resonance imaging (A–D) at the time of admission showed acute infarcts in the left lenticulocapsular and borderzone area between middle cerebral artery (MCA) and
posterior cerebral artery. MR angiography showed thrombotic occlusion of the left MCA (E). The patient’s neurologic symptoms gradually worsened to have severe right hemiparesis and global aphasia. Follow-up MRI 4 days later showed enlarged size of the lesion (F–J).
partly because of the insufficient development of collateral circulation. In patients with ICAS, artery-to-artery embolism (i.e., proximal MCA to distal MCA) is also an important mechanism of stroke. DWI is particularly useful in assessing the embolic mechanism of stroke because it can reliably detect small, scattered, cortical embolic infarcts (see Chapter 11 for details). According to previous studies, artery-to-artery embolism is usually associated with a more severe degree of intracranial stenosis than found in patients having branch occlusion.22 Moreover, the artery-to-artery embolism is often associated with perfusion deficits in the territory of the stenosed vessel. Perhaps, underlying perfusion deficits may contribute to the development of embolic infarction through impaired clearance of emboli (Fig. 5.2).
media of small vessels. Lipohyalinosis causes segmental disorganization of penetrating arteries along the course of the vessel, whereas atheromatous branch disease affects the vessel orifice. Pathological features of this type of branch occlusion have previously been described by Lhermitte et al.24 and Fisher.25–27 The pathology includes microdissection, plague hemorrhage, and platelet and platelet–fibrin materials. The concept of atheromatous branch occlusive disease has broadened our understanding on the pathogenesis of deep, subcortical (lacunar) infarcts. Traditionally accepted pathological hallmarks of lacunar infarction are 15–20 mm, irregular cavities deep in the cerebral hemisphere, brain stem, and cerebellum. 25,28–34 However, true lacunar infarcts are usually smaller than 0.5–1 cm when they are detected by brain imaging studies. If the lesion is larger than 1 cm, the diagnosis of small artery occlusive disease may have to be questioned. Although lipohyalinosis or fibrinoid necrosis of a small artery is still an important cause of these small, deep subcortical infarcts,35 Caplan23 argued that (1) deep infarcts may also be caused by large cerebral artery diseases or even embolization from proximal artery or the heart;36,37 (2) the clinical diagnosis of lacune is difficult to make
Branch occlusive disease Atherosclerotic plaque in the intracranial artery can protrude into the orifice of the perforators and occlude the lumen, causing a subcortical infarct.23 This so-called atheromatous branch occlusion is different from lipohyalinosis, a hypertensive change in the
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Fig 5.2 A 55 year-old-man with hypertension and diabetes mellitus developed recurrent, brief episodes of speech disturbances. Diffusion-weighted magnetic resonance imaging (MRI) showed several tiny, scattered, embolic infarcts in the left middle cerebral artery (MCA) territory
(left, thin arrows). Perfusion weighted MRI showed decreased perfusion in the whole left MCA territory (middle). MR angiography showed severe atherosclerotic narrowing of the left MCA (right, short arrow).
and not easily be differentiated from symptoms caused by large artery occlusive disease; and (3) many patients with lacunar infarction do not have hypertension nor have a history of high blood pressure. Thus, lacunar infarcts are actually caused by intracranial branch atheromatous disease in many patients.23 Nevertheless, atheromatous branch disease has been uncommonly documented because of the rarity of careful neuropathologic studies of intracranial arteries. Branch pathology can be accurately assessed only by meticulous analysis of serial sections of intracranial vascular specimens at necropsy. Although branch disease is a pathologic entity that can only be diagnosed with certainty at postmortem, the following clinical or imaging features may support the diagnosis of atheromatous branch disease: (1) the infarcts are small, deep, and confined to the territory of one or a few penetrating branches; (2) gradual or stepwise progression or fluctuation of symptoms and signs suggesting intrinsic “thrombotic” disease rather than embolism; (3) vascular studies and cardiac evaluation show no significant extracranial large artery occlusive disease or emboligenic heart disease; and (4) there is no past or present hypertension and no evidence of end organ damage from hypertension such as retinopathy or left ventricular cardiac hypertrophy.23 With the advances of imaging technologies such as magnetic resonance (MR) angiogram or computerized tomography (CT) angiogram, ICAS producing branch
occlusion is nowadays more easily recognized. Recent literatures from Asian countries that used such imaging tools have shown that perforating branch occlusion is an important stroke mechanism of intracranial atherosclerosis and that many of the socalled lacunar infarcts are actually caused by intracranial large artery disease rather than lipohyalinosis38–41 (Fig. 5.3). The infarction resulting from occlusion of the orifice of the branch tends to extend to the basal surface whereas a lacune caused by lipohyalinosis usually produces an island of ischemic tissue within the parenchyma. The subcortical infarcts caused by branch atheromatous disease are expected to be larger in size and associated with a more unstable clinical course than those caused by lipohyalinosis.38,39 However, other studies argued that the size and clinical presentations are not different between these two groups of subcortical infarction.41 One of the problems in investigating this issue is the sensitivity and specificity of existing imaging techniques in detecting mild atherosclerosis. As discussed above, the arterial stenosis producing branch occlusion is usually less severe than that producing arteryto-artery embolism or hemodynamic stroke22 (see Figs 5.2 and 5.3). In patients with very mild intracranial stenosis, the stenotic lesion cannot be detected by TCD, and often remains questionable even when MR angiography is used. Moreover, because the imaging
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Fig 5.3 A 75-year-old hypertensive woman developed left hemiparesis and dysarthria. Diffusion-weighed MRI showed a small subcortical infarct in the right lenticulocapsular area. MR angiography showed a moderate, focal stenosis that probably occluded the orifice of the perforating artery (arrow).
diagnosis of atherosclerosis is based on findings of luminal narrowing of an artery, atherosclerotic thickening of the vessel walls without causing intraluminal narrowing cannot be identified with current technologies. In this sense, it seems likely that atheromatous branch disease is still underestimated even in this era of MRI and MR angiography. Application of technologies that can image the abnormal vessel wall will further improve our understanding of branch atheromatous disease in the future.42 Hypoperfusion Before the onset of acute thromboembolism formation, atherosclerotic plaque gradually increases over years. The vessel can remodel to expand outward initially43 but later the plaque grows slowly and impinges on the vascular lumen; consequently, blood flow becomes disturbed.44 The narrowing leads to turbulence of blood flow and finally hypoperfusion distal to the stenosis. Severe stenosis or occlusion leads to failure of perfusion to one or more regions of the brain. In addition, turbulence and fast flow velocity increase the shear stress on the endothelium and encourage fissuring of the plaque, which in turn activates platelets and clotting factors. Recent observations45,46 have shown a close correlation between the recurrence of ischemic stroke and the severity of occlusive disease producing hypoperfusion. In clinical practice, hypoperfusion caused by a process occurring at a distance from the brain (for example, the heart or neck arteries) rarely produces major
brain infarction.47 In contrast, decreased blood flow caused by a lesion directly at the site of vulnerable brain tissue is not so benign. Occlusion of penetrating arteries by a lipohyalinotic process or by atheromatous branch disease23,25,39,41 often causes an infarct directly in the center of perfusion of the obstructed artery. Similarly, severe intracranial arterial occlusive disease seems more likely to cause brain infarction than extracranial occlusive disease.48–50 Although the circle of Willis serves as a collateral supply in patients with extracranial diseases, it may take more time to develop cortical collaterals in those with intracranial arterial diseases. Although hypoperfusion to a specific region of the brain is clearly an important factor for the development of infarct, the status of the collateral circulation can influence the size of the lesion. Insufficient collaterals and blood flow may be a factor predicting future strokes as well. According to Han et al.,51 who measured the extracranial arterial blood flow volume by color velocity imaging quantification ultrasound (CVIQ) in a cohort of 210 acute stroke patients, total cerebral blood flow was an independent predictor for future ischemic events; the mean extracranial blood flow volume was significantly lower for patients who had a recurrent stroke than for those without. In patients with insufficient collaterals, so-called hemodyamic strokes or TIAs may occur. Typically, TIA symptoms such as hemiparesis, dysarthria, aphasia (in anterior circulation disease) or dizziness, diplopia, visual disturbances (in posterior circulation disease) occur briefly and stereotypically when the patients are 61
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Fig 5.4 A 74-year-old woman with hypertension and diabetes mellitus developed brief and stereotypical episodes of right hemiparesis that developed when she stood up suddenly or when she was exhausted and dehydrated. Diffusion-weighted magnetic resonance imaging (MRI) showed no lesions (A) while perfusion weighted MRI showed decreased perfusion in the left middle cerebral artery (MCA) territory (B). MR angiography showed severe stenosis of the left MCA (C, white arrow). Angiography showed severe MCA stenosis and downward shift of MCA–ACA (anterior cerebral artery) borderzone area (D, dark arrow). After angioplasty and stenting, the stenosis improved and the borderzone area ascended (E, dark arrow). The patient no longer developed neurological symptoms afterwards.
dehydrated or exhausted or at the time when they suddenly stand up. When stroke occurs, the symptoms may fluctuate widely according to the degree of hydration and head position. Adequate hydration and cerebral blood flow maintenance is important in the management of these patients. Occasionally, interventional revascularization therapies such as bypass surgery or angiography/stenting relieve the patients’ symptoms dramatically (Fig. 5.4). Traditionally, hypoperfusion and embolism are considered independent mechanisms of stroke in patients with arterial occlusive diseases. However, very often they coexist in patients with severe occlusive lesions. This is explained in part by the fact that both mechanisms are related to shared pathologic features: a complicated atherosclerotic plaque easily protrudes into the lumen leading to a hypoperfused status in the distal area and also tends to produce plaque fissuring resulting in embolism to distal arteries. In addition, recent imaging studies have shown that hypoperfusion and embolism interacts complementarily. For instance, Sedlaczek et al.52 described patients with arterial occlusive diseases who had subcortical em62
bolization within the borderzone areas. Caplan and Hennerici53 analyzed the pattern of small infarcts detected by DWI in patients with large artery occlusive disease, and realized that many of these tiny infarcts were located in the borderzone regions. They proposed that in the region with poor perfusion (borderzone area), emboli cannot be washed out and therefore ultimately result in small infarcts. Thus, embolism and hypoperfusion synergistically contribute to development of stroke in patients with severe large artery occlusive disease,17 including ICAS disease (Fig. 5.2). Finally, there is a phenomenon called Bernoulli’s principle, which may contribute to low flow to the perforating artery even without actual branch occlusion. This principle states that for any flow, an increase in the velocity occurs simultaneously with a decrease in pressure. Progressive narrowing in arterial stenosis invariably increases the flow velocity in the MCA, which is the hallmark for diagnosis of stenosis by Doppler. Sometimes the flow velocity in the MCA exceeds 300 m/sec. According to the Bernoulli’s principle, the higher the flow velocity in the MCA, the
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A
B
C
Fig 5.5 Lesion pattern shown in middle cerebral artery (MCA) atherosclerosis. MR angiogram shows moderately severe left MCA stenosis (A). Diffusion-weighted imaging
shows the typical pattern of multiple small infarcts along the borderzone regions (B) and also multiple small infarcts in the cortical region (C).
lower the pressure in the perforating arteries, which often arise from the MCA perpendicularly. The potential importance of this mechanical cause of low perfusion remains unknown clinical.
with moderate to severe MCA stenosis, Wong et al.10 found that common stroke mechanisms in these patients are the occlusion of a single penetrating artery to produce a small subcortical infarction and arteryto-artery embolism with impaired clearance of emboli producing multiple, small cerebral infarcts especially along the borderzone region. Thus, small scattered infarcts along the border zone are common with severe MCA stenosis (Fig. 5.5). Other studies using DWI and MR angiography, also showed that perforating artery infarcts, whether single or occurring in addition to pial or borderzone infarcts, are the most common lesion pattern in patients with MCA stenosis22,58 (Fig. 5.6). Another report54 indicated that concomitant small cortical or subcortical lesions are commonly associated findings in diverse patterns of MCA territory infarction, which could mostly be explained by probable embolic mechanism. The severity of MCA stenosis is an independent predictor of future stroke, suggesting the importance of hypoperfusion in the pathogenesis of infarction.59 Droste et al.60 also reported that more severe MCA stenosis, as evidenced by very high flow velocity (>210 cm/s) in TCD, was associated with detection of MES and clinical symptoms. The presence and the frequency of MES predicts further risk of stroke and TIAs.61 In addition, Wong et al.62 reported that involvement of multiple vessels is more likely to cause further strokes both in the short term and the long term.63
Stroke mechanisms in different vascular territories Anterior circulation disorders MCA atherosclerosis Although embolic occlusion of MCA either from the heart or the atherosclerotic ICA has been considered the main cause of MCA territory infarction, intrinsic atherosclerosis is an important cause of stroke at least in Asian population (see Chapter 6). Relatively little was known about the frequency and stroke mechanisms of intrinsic MCA stenosis before the advances in neuroimaging. MCA atherosclerosis produces diverse topographic patterns of infarction depending on the variability in blood supply, degree of primary and secondary collateralization, and pathogenesis of infarcts.54 Secondary ischemic lesions visualized by brain imaging include small deep infarcts, large striatocapsular lesions, branch cortical strokes, or a combination of these lesions.10,22,54–56 Histopathologically observed fibrin–platelet microembolism has been found in patients with MCA stenosis presenting with TIA.57 Using MES detection by TCD together with DWI to explore the pathophysiology of cerebral infarct in acute stoke patients
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A
B
C
Fig 5.6 MR angiogram shows moderate stenosis of left middle cerebral artery (A). Diffusion-weighted imagining reveals a solitary infarct in the corona radiate region (B) and in the cortical region as well (C).
On the other hand, in subjects with chronic, asymptomatic MCA stenosis (lasting more than 12 months), MESs are rarely detectable regardless of the patients’ medication.60,64,65 Therefore, chronic, asymptomatic MCA stenosis does not seem to representa significant embolic source. Follow-up studies of patients with asymptomatic stenosis also confirmed the low risk of stroke in these patients.49 However, as discussed earlier, severe MCA occlusive disease with insufficient collateralization may produce recurrent hemodynamc TIAs. In addition, the patients with severe MCA occlusive disease may have disabling cognitive impairment, especially when they have bilateral MCA diseases (see Chapter 8 for further detail). Finally, sudden thrombotic MCA occlusion may produce relatively large infarction in the MCA territory. However, compared with cardiogenic infarction the so-called malignant MCA territory infarction involving the whole MCA territory is definitely uncommon in patients with intrinsic MCA atherosclerotic disease, probably due to relatively well-developed collateral circulation in these patients. Thus, even in patients with acute thrombotic occlusion, the infarct may be limited to the part of the MCA territory, usually at the striatocapsular region or borderzone areas. In some of these patients, however, a relatively small initial lesion may progressively enlarge along with neurological deterioration (Fig. 5.1). Revascularization procedures such as stenting and angioplasty, if performed early enough, may be of help in these patients.
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Anterior cerebral artery atherosclerosis Compared with MCA territory infarction, anterior cerebral artery (ACA) territory infarction is rare, occurring in less than 3% of all strokes.66–70 As in patients with MCA territory infarction, embolism either from the heart or the proximal ICA atherosclerotic disease has been considered the most important cause of ACA territory infarction.66,67 However, intrinsic atherosclerotic disease seems to be the more important cause of ACA territory infarction in Asian populations.68,70 According to Kang and Kim,70 intrinsic ACA atherosclerosis is the cause of ACA territory infarction in 61 of 100 Korean patients with ACA territory infarction. As in intrinsic MCA disease, ACA atherosclerosis produces infarction by way of in situ thrombotic occlusion, local branch occlusion, arteryto-artery embolization, and the combination of these mechanisms. Collateral circulation and hemodynamic factors also play a role in determining the location and size of the final infarct (for details, see Chapter 6). Unlike MCA territory infarction, however, embolism from the diseased heart or ICA disease does not necessarily produce massive ACA territory infarction, probably due to the presence of abundant collaterals connecting both ACA systems. Posterior circulation disorders Vertebral artery atherosclerosis The most common location for atherosclerosis of the vertebral artery (VA) is the extracranial first
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segment. Less commonly, atherosclerotic disease can cause stenosis of the second and third segments of the VA or the distal intracranial segment adjacent to the origin of the posterior inferior cerebellar artery.71,72 Atherosclerosis in the intracranial portion of the VA can produce occlusion of the branches supplying the medulla, which is the most important pathogenic mechanism for medullary (either lateral or medial) infarction.73,74 In patients with relatively severe atherosclerosis, either at the extracranial or extracranial VA, mural thrombosis can lead to artery-to-artery emboli that cause occlusion of distal branches such as the posterior cerebral artery, the superior cerebellar artery, the posterior inferior cerebellar artery, the basilar artery, or a combination of some of these.75–78 In patients with bilateral, severe atherosclerosis or in those with unilateral VA disease with contralateral hypoplasic VA, hemodynamic disturbances may contribute to ischemic symptoms. However, the lesion pattern of hemodynamic stroke is less well established in posterior circulation diseases than in anterior circulation diseases. It seems that both distal embolization and hemodynamic insufficiency play a role in development of ischemic stroke in many patients. Although rare, patients have repeated episodes of hemodynamic TIAs, which may be improved by revascularization such as angioplasty and stenting (see Fig. 7.5). In patients with severe and long-standing hemodynamic compromise, MRI may reveal atrophic changes in the posterior fossa. Basilar artery atherosclerosis The middle portion of the basilar artery (BA) is a relatively common site for advanced atherosclerosis. Patients with high-grade BA stenosis are at risk of a local thrombosis. Acute BA thrombotic occlusion may occlude multiple perforators producing bilateral pontine infarcts, resulting in coma, quadriparesis, and ocular motor disturbances. In many cases, the patients’ neurological deficits progress from unilateral to bilateral as the steno-occlusive process continues. The resultant stroke and consequent neuralgic deficits (lockedin syndrome) are one of the most devastating sequelae of stroke (see Fig 7.3). However, chronic occlusion in the presence of sufficient collaterals, especially from the posterior communicating arteries, may not produce any significant neurologic deficits (see Fig. 7.4).
More commonly, a milder degree of BA stenosis and resultant local thrombus produces occlusion of one or a few perforating branches producing more benign unilateral pontine infarction. In these cases, patients usually present with lacunar syndromes. Occlusion of the anterior inferior cerebellar artery also results from BA atherothrombosis. In addition, embolization arising from the clot formed in the BA can migrate to the distal BA, the posterior cerebral artery, the superior cerebellar arteries, or some of these vessels, resulting in relevant clinical syndromes. Combined branch artery occlusion and artery-to-artery embolization is also commonly observed. Acute, multiple brain infarcts due to distal embolization are more clearly observed when DWI is used, which helps us understand the embolic nature of strokes.79 Finally, basilar artery dolichoectesia is a vascular anomaly related to atherosclerosis, which may cause brainstem ischemia by multiple mechanisms, including thrombosis, embolism, and occlusion of deep penetrating arteries.80 Posterior cerebral artery atherosclerosis The frequency and stroke mechanism of intrinsic posterior cerebral artery (PCA) atherosclerosis has been rarely studied. Literatures have shown that the leading etiology of PCA territory infarcts is the embolism from the heart or proximal vertebrobasilar atherosclerotic disease, whereas intrinsic atherosclerosis of the PCA has been considered an uncommon occurrence.81–84 As in anterior circulation disease, however, the importance of intrinsic PCA atherosclerotic disease as a cause of PCA territory infarction seems to greater in Asians than in Caucasians. In a recent study from Korea using DWI and MR angiography (Lee E. et al., unpublished data), out of 205 patients with PCA territory infarction, large artery atherosclerosis was the cause of stroke in 87 patients, of whom 38 patients had intrinsic PCA atherosclerotic disease. In these patients, the most frequent stroke mechanism was atheromatous branch occlusion (19 patients) followed by in situ thromboocclusion (11 patients), and artery-to-artery embolism (eight patients). Although embolic PCA occlusion most frequently damages the occipital lobe, intrinsic PCA atherothrombosis produces subcortical lesions (i.e., ventrolateral thalamus) more frequently. Branch occlusion due to atheromatous PCA disease is an
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important mechanism of stroke occurring in the midbrain and thalamus.85 Although uncommon, patients with PCA stenosis may have recurrent TIAs as happens in patients with MCA stenosis.86
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75 Wityk RJ, Chang HM, Rosengart A, et al. Proximal extracranial vertebral artery disease in the New England Medical Center Posterior Circulation Registry. Arch Neurol 1998; 55: 470–478. 76 Pessin MS, Daneault N, Kwan ES, et al. Local embolism from vertebral artery occlusion. Stroke 1988; 19: 112– 115. 77 Caplan LR, Amarenco P, Rosengart A, et al. Embolism from vertebral artery origin occlusive disease. Neurology 1992; 42: 1505–1512. 78 Levine SR, Quint DJ, Pessin MS, et al. Intraluminal clot in the vertebrobasilar circulation: clinical and radiologic features. Neurology 1989; 39: 515–522. 79 Koch S, Amir M, Rabinstein AA, et al. Diffusionweighted magnetic resonance imaging in symptomatic vertebrobasilar atherosclerosis and dissection. Arch Neurol 2005; 62: 1228–1231. 80 Kumral E, Kisabay A, Atac C, et al. The mechanism of ischemic stroke in patients with dolichoectatic basilar artery. Eur J Neurol 2005; 12: 437–444. 81 Steinke W, Mangold J, Schwartz A, Hennerici M. Mechanisms of infarction in the superficial posterior cerebral artery territory. J Neurol 1997; 244: 571–578. 82 Yamamoto Y, Georgiadis AL, Chang HM, Caplan LR. Posterior cerebral artery territory infarcts in the New England Medical Center Posterior Circulation Registry. Arch Neurol 1999; 56: 824–832. 83 Brandt T, Steinke W, Thie A, Pessin MS, Caplan LR. Posterior cerebral artery territory infarcts: Clinical features, infarct topography, causes and outcome. Multicenter results and a review of the literature. Cerebrovasc Dis 2000; 10: 170–182. 84 Kumral E, Bayulkem G, Atac C, Alper Y. Spectrum of superficial posterior cerebral artery territory infarcts. Eur J Neurol 2004; 11: 237–246. 85 Kim JS, Kim JY. Pure midbrain infarction: clinical, radiological and pathophyiological findings. Neurology 2005; 64: 1227–1232. 86 Kim JS. Pure or predominantly sensory transient ischemic attacks associated with posterior cerebral artery stenosis. Cerebrovasc Dis 2002; 14: 136–138.
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Anterior circulation disorders Jong S Kim
Intracranial atherosclerosis is an important cause of stroke occurring in the anterior circulation. The stroke mechanisms of intracranial atherosclerosis in general are amply described in the previous chapter (Chapter 5). Based on diverse stroke mechanisms, stroke patterns and clinical syndromes manifest diversely also. In this chapter, strokes caused by atherosclerosis in the middle cerebral artery (MCA), anterior cerebral artery (ACA), and intracranial internal carotid artery (ICA) are reviewed.
resonance angiography (MRA), and computerized angiography (CTA), MCA atherosclerosis is now being increasingly recognized as a cause of MCA territory infarction. The role of MCA atherosclerosis as a cause of MCA territory infarction is especially important in Asians, black people, and Hispanics. Recent studies performed in these populations have suggested that the resultant lesion patterns, clinical syndromes, and prognosis are different between infarction due to intrinsic atherosclerosis and infarction due to embolism.
Middle cerebral artery infarction
MCA territory infarction due to intrinsic MCA atherosclerosis
General features MCA territory infarction is the most commonly encountered stroke subtype in our clinical practice. Occlusion of the main MCA trunk produces contralateral hemiparesis, hemisensory deficit, deviation of eyes towards the side of the infarct, and hemianopia. Global aphasia occurs when the dominant hemisphere is severely damaged, whereas hemineglect occurs when the infarct develops in the right hemisphere. Divisional or branch occlusion induces partial or minor neurological deficits. Occlusion of perforating arteries produces subcortical infarction sparing the cortex and typically yields lacunar syndromes such as pure motor, sensorimotor, ataxic-hemiparesis, or dysarthria clumsy syndromes. Occlusion of the MCA because of embolism arising from the atherosclerotic ICA or the diseased heart has been regarded as the most important cause of MCA territory infarction. However, with the advent of techniques such as transcranial Doppler (TCD), magnetic
MCA atherosclerosis has been considered a rare cause of MCA territory infarction. About 40 years ago, Lhermitte et al.1 studied 122 patients with MCA territory infarction, 94 assessed by cardiac and angiographic examination and 28 patients by post-mortem examination. MCA occlusion was identified in 40 cases (41.7%). However, atherosclerotic MCA occlusive disease accounted for only 11 cases (27.5% of MCA occlusion). Moreover, in six of them, there remained the possibility of embolic occlusion from an atherosclerotic proximal ICA. Thus, there were only five cases in which firm evidence of atherosclerotic MCA occlusion was documented. When two patients with MCA stenosis were added, atherosclerosis of MCA disease with sufficient evidence was found in only seven (16.6%) patients with MCA territory infarction. In a subsequent study,2 they reported postmortem findings in 47 infarcts in the MCA territory from 41 patients. Again, intrinsic MCA atherosclerosis was rare; only two patients were considered
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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to have atherosclerotic thrombotic occlusion, in the proximal MCA in one and in the inferior branch of the MCA in the other. The findings from autopsy3 and angiogram studies4–8 by subsequent authors have also revealed that MCA atherosclerosis is a much less common cause of MCA territory infarction than embolism. However, it is likely that the findings of post-mortem or angiogram studies are from patients who had severe symptoms. Therefore, the results may not be generalizable to all MCA territory infarction. With the advances of techniques such as TCD, MRA, and CTA, we can now more easily detect stenosis of intracranial vessels that produces milder clinical symptoms. More importantly, subsequent studies have clearly illustrated that there is an ethnic difference in the etiology of MCA territory infarction: MCA atherosclerosis as a cause of MCA territory infarction is more important in Asians, black people’ and Hispanics than in Caucasians.9–13 Recent series of studies from Asian countries using advanced imaging technologies have confirmed this and suggested that the characteristics of lesion patterns and clinical outcomes are different from those produced by embolism. Min et al.14 studied 42 Korean patients with MCA territory infarction who underwent MRI and angiographic studies (either conventional angiogram or MRA). Patients with potential cardiogenic embolism were excluded. They found that intrinsic MCA atherosclerosis was the cause of infarction in as many as 30 patients (71%). In another study,15 107 stroke patients with isolated MCA disease (stenosis of >50% or occlusion) were studied, all of whom underwent diffusion-weighted MRI (DWI) and angiogram (conventional or MRA). Patients with significant ICA disease were excluded. There were 76 patients with intrinsic MCA atherosclerosis, whereas only 31 patients had a potential source of cardiac embolism. This result suggests that MCA atherosclerosis may be the more important cause of MCA territory infarction than cardiac embolism in Asians. However, embolic infarcts with recanalized vessels were not included in this study, and therefore cardiogenic embolism might have been underestimated. More recently, Lee et al.16 studied 185 Korean patients with MCA territory infarction diagnosed by DWI and MRA. Vascular disease was considered significant when there was stenosis of ≥50% or occlusion. There were 63 patients with MCA atheroscle70
rotic disease (34%), 38 with ICA disease (21%), and 84 with cardiac embolism (45%). Thus, this result suggests that even in Asian countries, cardiac embolism may still be the most important etiology of MCA territory infarction. In this study, however, MCA atherosclerosis might have been underestimated, since mild (<50%) stenosis was not included. There are other limitations in the above studies: echocardiogram was not performed in every case, and MCA stenosis shown by angiography might potentially represent a partial recanalization of an embolus from an unknown source rather than intrinsic atherosclerosis. More importantly, these are hospitalbased studies with a relatively small number of patients. Therefore, the results should be interpreted with caution. Nevertheless, based on the above series of reports, it seems clear that MCA atherosclerosis is one of the main causes of MCA territory infarction in Asian populations. Lesion pattern and clinical syndrome in patients with MCA atherosclerosis Studies have shown that demography, lesion pattern, and consequent stroke syndrome of MCA territory infarction are different according to different etiologies. The difference was elegantly suggested by Caplan et al.17 more than 20 years ago. They compared 20 patients with angiographically proven MCA atherosclerotic disease with 25 patients with MCA territory infarction caused by embolism from proximal ICA disease. They reported that patients with MCA atherosclerosis were more often black, female, and younger, more often had hypertension, and had fewer transient ischemic attacks (TIAs) and a lower incidence of subsequent cardiac death. In the following year, Bogousslavsky et al.18 analyzed 352 patients with intrinsic MCA disease recruited from the patient pool of the EC/IC Bypass Study, and suggested that there may be characteristic lesion patterns in these patients: approximately 30% of the strokes were deep infarcts in the lenticulostriate artery territory. A more detailed lesion pattern analysis was performed by Lyrer et al.,19 who studied 22 stroke patients with intrinsic MCA stenosis. CT scan showed small deep infarcts in 10 (46%), large striatocapsular infarcts in 2 (9%), pial MCA branch infarction in 3 (14%), and striatocapsular plus pial in 4 patients (18%). Only one patient (5%) had large territorial infarction. Clinical features included
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lacunar syndrome in 10 (46%), whereas 12 (54.4%) had non-lacunar syndrome such as aphasia, neglect, or visual field defect. Subsequently, Yoo et al.12 analyzed 89 patients with MCA territory infarction from the New England Stroke Registry. There were 28 patients with intrinsic MCA diseases, 17 with embolism (either cardiogenic or unknown), and 44 patients with significant ICA diseases. Infarcts in patients with intrinsic MCA disease mostly involved the striatocapuslar area (61%), whereas those due to embolism from the heart or ICA disease most often involved the parietal lobe (75% and 43%, respectively). With the advent of MRI, the lesion pattern of MCA territory infarction could be analyzed more precisely. Excluding the patients with cardiogenic embolism, Min et al.14 analyzed lesion patterns in 42 patients with MCA territory infarction. They found that the topographic patterns seen on MRI could be divided into following four groups: (1) cortical borderzone infarcts (n = 6); among them, four had concomitant small cortical or subcortical multiple lesions. Angiography showed intrinsic MCA disease in four. patients. (2) Pial territory infarcts without insular infarct (n = 3); two also had small, multiple centrum ovale lesions. All had intrinsic MCA disease. (3) Pial territory infarcts with insular infarct (n = 14); five had additional multiple cortical or subcortical lesions. Ten patients had intrinsic MCA disease. (4) Large subcortical infarcts (n = 19); 10 had concomitant small cortical or subcortical lesions, and six patients had intrinsic MCA disease. Although the results are complex, what they underscored was that similar MCA lesions may produce diverse topographic lesion patterns, which appears to be related to individual variations of vascular territory, degree of collateralization, and etio-pathogenesis of infarcts. One of the disadvantages in using CT or conventional MRI in stroke research is that we cannot assess the age of infarcts precisely enough. Recently developed DWI has an advantage in that it can identify small, early infarcts more reliably.20–22 Studies using DWI have provided further insights into the stroke patterns in patients with MCA territory infarction. The aforementioned study by Lee et al.15 used DWI in all the patients and compared the stroke patterns between 76 lesions due to intrinsic MCA atherosclerosis and 31 due to cardiac embolism. The lesion patterns produced by MCA atherosclerosis were subcortical in 53 (83%) patients, cortical (involving one
M2 branch territory) in eight (13%), and territorial (involving more than one M2 territories) in three (5%) patients. On the other hand, locations of MCA infarcts associated with cardiac embolism were subcortical in six (19%), cortical in 10 (32%), and territorial in 15 (48%) patients. In addition, borderzone infarction was more common in the atherosclerosis group than in the embolism group (24 vs 1). Clinical features were also different between the two groups. In patients with MCA atherosclerosis, there were lacunar syndromes in 31 (48%), partial MCA syndromes in 25 (39%), and total MCA syndromes in eight (13%), whereas those with cardiac embolism included lacunar syndromes in six (20%), partial syndromes in three (10%), and total syndromes in 21 (70%). In addition, the patients with embolism showed more abrupt onset of disease, higher initial National Institutes of Health Stroke Score (NIHSS) (9.7 vs 4.6), and shorter onsetto-admission time than those with MCA atherosclerosis. Although this study has elegantly demonstrated different lesion patterns according to different etiologies, it was unfortunate that patients with ICA disease were excluded in this study. A subsequent study from another center16 including patients with ICA disease presented more comprehensive results. The study involved 185 patients with MCA territory infarction assessed by DWI and MRA who showed corresponding MCA disease (stenosis of ≥50% or occlusion), ICA disease (stenosis of ≥50% or occlusion), or cardiac embolism. There were 63 (34%) patients with MCA disease, 38 (21%) with ICA disease, and 84 (45%) cardiac embolism. Among the 63 patients with MCA atherosclerosis, single perforator infarction occurred in 17 patients, perforator + pial in 14, and perforator + pial + borderzone in nine patients. On the other hand, among 84 patients with cardiac embolism, pial territory infarction occurred in 27 patients, and large territorial infarction in 23. The most frequent lesion pattern of ICA disease (n = 38) was the pial territory + borderzone (n = 13) pattern. The DWI lesion patterns due to MCA atherosclerosis are shown in other chapters (Figs 5.1, 5.2, and 5.3; Fig. 11.2). Thus, in line with the previous studies with CT scan,19 subcortical infarcts are significantly more common in MCA atherosclerosis than in the embolism group, whereas cortical or territorial infarcts are more common in patients with embolism. The frequent sparing of the cortex in patients with MCA atherosclerosis 71
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Table 6.1 Differences in MCA territory infarction according to difference etiologies Intrinsic MCA disease
Cardiac embolism
ICA disease
Ethnicities Onset Precedence by TIAs Important risk factors
Asian, Black, Hispanics Gradual ++ Advanced hypertension Metabolic syndrome
Variable Abrupt + Emboligenic heart disease
Caucasian Variable +++ Hyperlipidemia
Degree of arterial stenosis Coronary heart disease Peripheral artery disease Lesion pattern
Either severe or mild ++ ++ Subcortical Combined cortical and subcortical +++ + +++ +
none ++ + Cortical Territorial
Usually severe +++ +++ Cortical Internal borderzone
+ +++ + +++
+ ++ ++ ++
Lacunar syndrome Cortical symptoms Neurological progression Acute herniation
ICA, internal carotid artery; MCA, middle cerebral artery; TIA, transient ischemic attack; +, less frequent; ++, moderately frequent; + + +, frequent.
is probably related to pre-existing, well-developed collateral circulation. The less frequent cortical damage in patients with MCA atherosclerosis explains less frequent cortical symptoms such as aphasia, neglect, eyeball deviation, and post-stroke seizures (2% according to Bogousslavsky et al.18 ). Owing to the sparing of the cortex, malignant, whole territory MCA infarction is rare in MCA atherosclerosis. Indeed, embolism was a presumed cause of stroke in all the 55 patients with malignant MCA infarction.23 Accordingly, we rarely observe fatal herniation in patients with intrinsic MCA disease, although progressive worsening of motor symptoms are not infrequent (see Fig. 5.1). Table 6.1 summarizes the differences in MCA territory infarction according to difference etiologies.
Subcortical infarction associated with MCA atherosclerosis Importance of MCA atherosclerosis as a cause of subcortical infarction Because subcortical infarction sparing the cortex is one of the important stroke patterns caused by MCA atherosclerosis, this topic deserves a separate description. Subcortical infarction in the territory of 72
perforating arteries has long been described as lacunar infarction caused by small vessel occlusion due to lipohyalinosis.24,25 However, other etiologies such as embolism from the heart or ICA disease have also been found to be associated with strictly subcortical infarction.26 In addition, strictly subcortical infarction due to MCA atherosclerosis has been identified; Lhermtte et al.2 and Fisher27 described autopsy findings of patients with lacunar infarction caused by perforator occlusion due to atherosclerotic plaque of the MCA trunk. Such patients have also been identified in a study using angiography.28 However, subcortical infarcts due to intrinsic MCA disease appear to be uncommon in Caucasians. Rather, there have been arguments regarding the role of ICA disease or cardiac disease as a cause of subcortical infarction. In a prospective study using CT scan and conventional angiography, 14 of 45 patients with lacunar infarction were found to have ipsilateral ICA stenosis.29 However, the authors thought that the ICA diseases were likely to be a general marker for atherosclerosis rather than a specific cause of lacunar infarction, since the stenosis was severe only in six patients and a half of them had concurrent stenosis on the contralateral ICA. Although Waterston et al.30 agreed to this, they raised the possibility that hemodynamic
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failure caused by ICA disease might have contributed to at least some of the small subcortical infarction. However, Mead et al.31 recently found that the prevalence of severe ICA disease was not different between the symptomatic (5%) and asymptomatic (4%) side in 259 patients with lacunar infarction, and stated that ICA disease seems to be a mere coincidental finding. There also have been arguments regarding the role of cardiogenic embolism in the subcortical infarction. Horowitiz et al.26 studied 108 patients with CT-based subcortical infarction who presented clinically with lacunar syndrome, and identified a potential source of cardiogenic embolism in 18%. Donnan et al.32 prospectively studied 50 patients with striatocapsular infarction identified by CT scan with the longest diameter greater than 1.5 cm. Among them, 43 patients could be divided into four subgroups: cardiac emboli to the origin of the MCA (n = 17), severe ICA disease with artery-to-artery embolism with or without associated hemodynamic factors (n = 12), subjects with normal angiogram (n = 11), and intrinsic MCA disease (n = 3). Thus, they underscored the importance of potential cardiogenic embolism in patients with relatively large subcortical infarction. These results suggest that embolism either from the heart or ICA disease may produce subcortical infarction, especially when the size of the lesion is large.33 In these series studying Caucasian patients, MCA atherosclerosis as a cause of subcortical infarction has largely been neglected. However, results from studies in Asian countries have been quite different. Studies from Japan,34,35 Korea,36,37 or Hong Kong38 have illustrated that MCA atherosclerotic disease is an important cause of infarction occurring in the subcortical area. It seems clear that the importance of MCA atherosclerosis as a cause of subcortical infarction in these countries is significantly greater than the importance of ICA disease as a cause of subcortical infarction in Caucasians (see Fig. 5.3). Bang et al.36 studied 102 Korean patients with lacunar syndromes and relevant small (<1.5 cm), MRIidentified subcortical infarction. Angiograms (conventional or MRA) were performed in all the patients. They detected MCA atherosclerotic disease responsible for the infarction in as many as 37 (36%) patients. Embolic sources from the ICA, aorta, or heart were found in 25 patients (25%), whereas small vessel occlusion was considered to be the cause of infarcts in the rest of the patients. Thus, MCA disease may
be an important cause of lacune-like small, subcortical infarction in this population. A study from Hong Kong, China also confirmed that MCA disease is an important cause of small, subcortical infarction.38 The authors studied 257 patients with ischemic stroke, in whom DWI was performed in 226 patients. Among them, 71 patients (27.6%) had small (0.2–2.0 cm in diameter) subcortical infarction, which was related to relevant intracranial large artery disease in 12 (16.9%) and ipsilateral ICA disease in three patients (4.2%). None had cardiac embolism. Thus, although 1.5 cm or 2.0 cm in diameter has been traditionally considered a criteria for lacunar infarction due to small perforating artery occlusion,39 studies described above have shown that these small lesions can still be caused by etiologies other than small artery occlusion. Thus, a question has been raised whether the size criteria is still valuable; in other words, whether there indeed is a difference in the size of the lesions or clinical symptoms between patients with subcortical infarction due to small vessel occlusion and those due to other causes. To address this issue, Cho et al.37 studied 118 Korean patients with acute, strictly subcortical infarction assessed by DWI and angiogram (mostly MRA). The mechanisms of stroke were arbitrarily categorized regardless of the lesion size: (1) middle cerebral artery disease (MCAD) when there was a corresponding MCA lesion that probably occluded the orifice of a perforator, (2) internal carotid artery disease (ICAD) when there was a significant (>50%) ipsilateral ICAD, (3) cardiogenic infarction (CE) when there was emboligenic heart disease without MCAD or ICAD, and (4) small vessel occlusive disease (SVD) when there was neither CE nor MCAD. SVD was further divided into definite SVD (dSVD, longest diameter <15 mm) or probable SVD (pSVD, diameter ≥15 mm). They compared the clinical symptoms and lesion diameters among different subgroups. Seventy-three patients (62%) had SVD: 38 (32%) had pSVD, and 35 (30%) had dSVD. Thirty-three patients (28%) had MCAD, five (4%) had CE, and seven (6%) had ICAD. Thus, in patients with strictly subcortical infarction assessed with DWI, embolism either from the heart or ICA was a rare cause of stroke in Korea, even if the size criteria were not applied. As expected, the lesion size due to embolism either from the heart or ICA disease tended to be large compared with the patients with SVD. However, the size of the infarct caused by 73
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MCAD was not significantly larger than that of SVD. Moreover, there was no difference in clinical features or risk factors between MCAD and SVD, or between pSVD and dSVD. Therefore, the authors concluded that the lesion smaller than 1.5 cm in diameter does not necessarily indicate that it is caused by small artery occlusion, and that there seems to be no rationale in using the size criteria for lacunar infarction. When they used lesion volume rather than diameter, or 2.0 cm rather than 1.5 cm size criteria, the results were similar; there was no difference between MCAD and SVD. Clinical significance of MCA atherosclerosis in patients with subcortical infarction The majority of the patients with strictly subcortical infarction present with lacunar syndrome, and the clinical outcome is clearly better than those with whole MCA territory infarction. However, acute or subacute neurologic progression, occurring in 25–35% of the patients with ischemic stroke,40 does occur in patients subcortical infarction.41 Several studies have identified factors associated with the neurologic progression as old age, diabetes mellitus, increased C-reactive protein (CRP), and the lesion size.42–45 Since the subcortical infarction can either be caused by small artery occlusion or MCA disease, a question has been raised whether the presence of MCA disease exerts any impact on the neurologic progression, or ultimately, on clinical outcomes in patients with subcortical infarction. As mentioned before, Cho et al.37 reported that the lesion size and the clinical features are not different between the subcortical infarcts due to MCA disease or those caused by small artery occlusion. Although Bang et al.36 reported similar results, they also noted that an unstable clinical course (fluctuating or worsening) was more common in patients with MCA lesions (38%) than in those without (12%). They further showed that patients with lacunar syndrome caused by MCA atherosclerosis more often experienced recurrent strokes than those without MCA disease.46 Adachi et al.34 also stated that a progressive clinical course may be more common in patients with MCA disease than in those with small artery occlusion. However, these results were not consistent with a more recent study by Cho et al.,47 who reported that neurologic progression in subcortical infarction was closely related to subacute lesion volume increase measured by serial DWI images but not to the presence of 74
MCA disease. The difference in results may be caused by different definitions of neurologic progression or lesion size criteria used in each study. Thus, the relationship among neurologic progression, unstable clinical course, and MCA atherosclerosis in patients with subcortical infarction still remains elusive. Appropriate treatment strategy for neurologic progression based on those factors should also await further studies. Studies from Hong Kong38,48 have stressed that multiple infarcts are more common, and the severity of stroke and cognitive impairment are also more severe in patients with subcortical infarcts associated with MCA atherosclerotic disease than in those without. However, if the strictly unilateral, single infarction is considered, the presence of MCA disease does not seem to be associated with severe symptoms.37 Rather, the location of vascular stenosis could be one of the determinants for clinical severity. A recent study49 suggested that proximal M1 stenosis tends to produce infarct in the lower part of the pyramidal tract (internal capsule), while distal M1 stenosis tends to result in infarcts located in the upper part of the pyramidal tract (corona radiata). This observation seems to agree with alleged anatomical characteristics of lenticulostriate arteries: those arising from the proximal M1 supply the lower part while those from distal M1 perfuse the upper part of the pyramidal tract.50 The authors also reported that the motor symptoms were more severe in patients with proximal stenosis than in those with distal stenosis possibly because of the involvement of densely packed motor fibers in the lower part of the pyramidal tract in the former group of patients.
Anterior cerebral artery disease General features ACA infarction accounts for less than 3% of ischemic stroke.51–54 Since the first description of autopsy results in the early twentieth century,55,56 several studies have investigated the etiology and clinical features of ACA infarctions using CT51–53 or MRI.54,57 Clinically, ACA infarction is characterized by limb weakness, worse in the leg than in the arm. A small lesion may produce isolated lower limb weakness. However, arm weakness equal to or even greater than leg weakness may be observed, at least in the early stage, due possibly to the extension of the infarction to the lateral convexity,58 a partial involvement
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of arm-presenting motor fibers in the subcortical area,52,58 or motor neglect phenomenon.59,60 Sensory dysfunction is usually less severe and occurs almost always in the paretic limbs. Hypobulia/apathy characteristically occurs and has been shown to be related to callosal61,62 or anteromedial frontal lobe damage.63,64 This symptom is more severe and prevalent in patients with bilateral lesions than in those with unilateral lesions.64 Other symptoms include urinary incontinence, alien hand sign, and limb apraxia. When the infarct involves the left brain, aphasia may develop. Although various types of aphasia may occur, transcortical aphasia is most characteristic in these patients.65,66 Other miscellaneous symptoms include emotional lability/incontinence,67 drowsiness/somnolence, acute confusion/agitation, motor perseveration, amnesia, and parkinsonian features (hypokinesia and cogwheel rigidity with or without tremor).68,69 ACA atherosclerosis as a cause of ACA territory infarction As in MCA territory infarction, intrinsic ACA atherosclerosis has been considered to be a rare etiology of ACA territory infarction. In an autopsy series of 55 patients with ACA territory infarcts, 10 had probable cardiac embolization and only five had atherosclerosis primarily involving the ACA.70 In a study using CT scan, Gacs et al.51 proposed the following stroke mechanisms: embolization, propagation of thrombotic material from an occluded ICA into the intracranal branches, and vasospasm or propagating thrombosis associated with anterior communicating aneurysm. Thus, they did not even mention intrinsic ACA atherosclerosis. More recently, Bogousslavsky and Franco52 reported that among 27 patients with ACA territory infarction embolism from either the ICA disease or the heart was found in 17 patients (63%), whereas in situ thrombotic occlusion of ACA was detected in only one. On the other hand, studies from Asia showed strikingly different results. Kazui et al.53 reported 17 Japanese patients assessed by CT and angiography. The majority (10 patients, 59%) were caused by intrinsic ACA atherosclerosis, whereas cardiogenic infarction occurred only in three patients (18%). A recent study from Korea showed a similar result. Kang and Kim64 studied 100 consecutive patients with ACA territory infarction assessed by MRI and angiography
(mostly MRA). Presumed etiologies were large artery atherosclerosis in 73, cardiogenic embolism in 10, either large artery disease or cardiogenic embolism in two, and unknown in 15 patients. Among the patients with large artery atherothrombosis, there were local ACA atherosclerotic diseases in 61, ICA diseases in six, and either ICA or ICA diseases in six patients. Thus, in contrast to Western countries, intrinsic ACA atherothrombosis seems to be the most frequent etiology of ACA infarction, whereas embolism from the heart or ICA is uncommon in Asians. A study from Turkey revealed intermediate results.54 Aside from atherosclerosis or embolism, uncommon causes of ACA territory infarction include vasospasm secondary to aneurysmal rupture, arterial dissection, moyamoya disease, and fibromuscular dysplasia. These rare etiologies are discussed in Chapters 18– 20. Although rare, ACA occlusion may occur because of vessel compression secondary to intracranial hemorrhages, which may produce either ipsilateral71 or contralateral72 ACA infarction. The mechanism of stroke in intracranial ACA atherosclerotic disease has rarely been investigated. In a series of 100 patients with ACA infarction, Kang and Kim64 reported that local ACA atherosclerotic disease ipsilateral to the infarct was observed in 68 patients: 40 with occlusions and 28 with stenoses. The atherosclerotic change occurred most frequently in A2 (n = 38), followed by A1 (n = 22), A2–A3 junction (n = 5), and A1–A2 junction (n = 3). The reason why atherosclerosis more often occurs in A2 than in A1 remains unknown. Perhaps, A1 atherosclerosis may more often remain silent in the presence of the anterior communicating artery. Based on the analysis of the MRI and angiographic findings, they proposed the following mechanisms of stroke in ACA infarction. Local branch occlusion (LBO) The infarct is located in the area adjacent to the atherosclerotic vessel, whereas other areas of ACA territory are spared. The mechanism of stroke was considered to be an occlusion of the orifice of one or more of the perforators supplying adjacent structures by the local thrombus formation at the area of stenosis.21,32 The infarcts are usually localized to the anterior part of the corpus callosum and/or the cingulate gyrus (Fig. 6.1). Occlusion of the frontopolar or anterior inferior frontal branch, which usually stems from A2,73 75
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Fig 6.1 T2-weighted magnetic resonance imaging shows an infarct localized to the right anterior portion of the corpus callosum (small arrows), which was caused by left anterior cerebral artery stenosis) (large arrow) that probably
occluded perforating branches. (From Kang SY, Kim JS. Anterior cerebral artery infarction: stroke mechanism and clinical-imaging study in 100 patients. Neurology 2008; 70: 2386–2393, with permission)
may produce extension of the lesion to the anterior part of the superior frontal gyrus.
usually extensive. However, some cortical areas may be spared because of collateralization from the MCA or contralateral ACA.
In situ thrombotic occlusion (ITO) The extension of infarct is beyond the area adjacent to the diseased vessel and therefore cannot be explained by LBO. The infarcts can be explained by occlusion of the main ACA trunk or pericallosal artery, which results in infarcts affecting the whole or the most part of the ACA territory (Fig. 6.2). Thus, the infarct is
Artery-to-artery embolism The infarct is located in the remote area from the stenosed vessel. They are usually small, sometimes scattered, and are located at the areas supplied by cortical branches. The mechanism of stroke can be explained by artery-to-artery embolism (Fig. 6.3).
Fig 6.2 Diffusion-weighted magnetic resonance imaging shows a large infarct involving whole left anterior cerebral artery territory including the corpus callosum, frontal pole, cingulate gyrus, superior frontal lobe, supplementary motor area, paracentral lobule and precuneus. MR angiogram shows thrombotic occlusion of left anterior cerebral artery (arrow). There was an absent right A1, and the right anterior cerebral artery is supplied by a branch from the left A1. (From Kang SY, Kim JS. Anterior cerebral artery infarction: stroke mechanism and clinical-imaging study in 100 patients. Neurology 2008; 70: 2386–2393, with permission)
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Fig 6.3 Diffusion weighted MRI shows scattered infarcts in ACA–MCA (anterior cerebral artery– middle cerebral artery) borderzone area. MR angiogram shows significant stenosis in the A2–A3 junction of left anterior cerebral artery that probably caused artery-to-artery embolism. Distal hypoperfusion may have played a role in development of embolic infarcts in the borderzone area. (From Kang SY, Kim JS. Anterior cerebral artery infarction: stroke mechanism and clinical-imaging study in 100 patients. Neurology 2008; 70: 2386–2393, with permission)
Combination of LBO and artery-to-artery embolism Infarcts are located adjacent to the atherosclerotic vessel as in LBO. However, there are additional, usually scattered infarcts in the remote area. Unlike infarcts caused by ITO, the infarcts are not in continuity with each other. Using these criteria, Kang and Kim64 identified the mechanisms of stroke from ACA atherosclerosis (n = 61) as LBO in 20, ITO in 20, artery-to-artery embolism in 12, and combined in nine patients. Since the lesions tend to involve the anterior frontal cortex or the anterior part of the corpus callosum, patients with LBO and ITO more often had hypobulia/apathy than those with artery-to-artery embolism. In patients with artery-to-artery embolism, embolism tends to produce small, scattered lesions in the MCA and ACA borderzone area probably due to impaired clearance of emboli in the presence of severe perfusion deficits74 (Fig. 6.3). Unlike MCA infarction, embolism from the diseased heart does not necessarily produce massive ACA territory infarction, probably due to the presence of abundant collaterals connecting both ACA systems. Thus, the diverse pattern of clinical manifestations in these patients is related to the distinct topographic patterns of infarction, which in turn is de-
termined by various pathogenic mechanisms and the status of collateral circulations.
Intracranial internal carotid artery disease In contrast to proximal ICA disease, atherosclerosis occurring at the intracranial ICA has not drawn much interest. This is partly because intracranial ICA disease has not been considered to be an important cause of stroke and partly because the diseased vessel is surgically inaccessible and is therefore not of interest to surgeons. Indeed, in the Joint Study of Extracranial Arterial Occlusion, carotid bifurcation disease was six times more common than the intracranial ICA disease.75 Although pathologic studies have found occasional cases with distal ICA thrombotic occlusion associated with either anterograde or retrograde thrombus extension, whether the thrombosis was caused by embolic occlusion or by intrinsic atherosclerosis remains frequently uncertain.76,77 However, subsequent studies have shown that intracranial ICA atherosclerosis is more common in black people and Asians than in Caucasians.15 In a 77
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Fig 6.4 A 79-year-old diabetic man suddenly developed left arm weakness. Fluid attenuated inversion recovery MRI shows infarcts in the right frontal area. Angiogram shows stenosis in the distal portion of the right internal carotid artery (arrow). Diamox-challenged single photon emission computed tomography shows normal findings (not shown). The infarction was considered to be caused by artery-to-artery embolism.
recent study from Korea, out of 215 patients with significant (≥50% stenosis or occlusion) ICA disease, the frequency of intracranial atherosclerotic ICA disease was about one-quarter of proximal ICA disease (Park et al. unpublished observation). As in patients with proximal ICA disease, intracranial ICA disease may produce stroke or TIA by way of artery-to-artery embolism, hemodynamic insufficiency, or the combination of the two.78 (Figs 6.4 and 6.5). In this regard, the mechanism of stroke in distal ICA disease seems to be similar to that in proximal ICA disease. However, DWI studies have suggested that intracranial ICA disease tends to produce more often single infarct patterns and less often complex patterns (embolic + hemodynamic) than in those with extracranial ICA disease. 78
Perhaps, different hemodynamic status related to different degree of collaterals, either through ophthalmic artery/posterior communicating artery or vasa vasoum formation, might explain these differences. In addition, the thrombus occurring at the site of intracranial ICA atherosclerosis may extend distally to occlude the MCA or ACA, causing MCA and ACA territory infarcts, respectively.51 Although traditional studies have reported that amaurosis fugax is caused by severe proximal ICA occlusive disease, the intracranial ICA disease at or proximal to the origin of the ophthalmic artery can produce ocular ischemia causing transient or permanent blindness (Fig. 6.6). According to Craig et al.,79 who reviewed 47 symptomatic patients with angiographically documented intracranial ICA stenosis, there were 15 (26%) patients presenting with major stroke, seven (12%) with partial non-progressing stroke, 9 (15%) with reversible ischemic neurologic deficits, and 16 (28%) with TIAs. As in proximal ICA disease, the symptoms may be precipitated by patients’ hemodynamic alteration. Kim and Kang80 observed patients with intracranial ICA disease who developed embolic or hemodynamic infarction after gastrointestinal bleeding and subsequent anemia. Using scanning electron microscopy, Saunders and Shedden81 found evidence of damaged endothelium along with attached red blood cells and platelet debris in 30% of specimens of carotid siphon and in 80% of specimens from carotid bifurcation. This observation suggests that the embolic potential of the carotid siphon might be smaller than that of the carotid bifurcation. Nevertheless, clinical studies have shown that the prognosis of significant intracranial ICA stenosis is not favorable, and may even be worse than that of proximal ICA stenosis. Previous studies on patients with significant (>50%) stenosis have shown that ischemic symptoms occurred in 27–40% (stroke ipsilateral to the stenosed artery in 17–33%) during the average follow-up period of 30–51 months.78,79,82 The presence of tandem extracranial ICA stenosis significantly increased the risk. The mortality rate was also fairly high ranging from 33% to 50%, approximately half of them being related to cardiac events. Thus, intracranial ICA disease not only produces embolic or hemodynamic strokes per se but also serves as an important marker for generalized atherosclerosis, carrying a high risk of recurrent stroke or other vascular events.
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Fig 6.5 A 72-year-old woman with hypertension and diabetes mellitus developed left hemiparesis. T2-weighed MRI shows infarcts in the internal borderzone area (short arrows). Angiogram shows occlusion of the distal internal carotid artery just above the origin of the ophthamic artery
(long arrow). Diamox-challenged single photon emission computed tomography shows decreased perfusion reserve in the left middle cerebral artery and anterior cerebral artery territories.
Intracranial ICA disease is usually treated by antiplatelet agents, and angioplasty/stenting and bypass surgery are tried in selected patients. However, whether these treatments have any influence on the outcome of the patients remains unclear. Indeed, studies focusing on the intracranial ICA disease have so far been too limited, and the mechanism of stroke, treatment modality, and prognosis in intracranial ICA disease needs to be investigated more meticulously in the future, especially in countries where this condition is prevalent.
References
Fig 6.6 A 56-year-old hypertensive man developed transient blindness in his right eye. Contrast-enhanced MR angiography shows severe focal stenosis in the right petrous portion of the internal carotid artery (arrow).
1 Lhermitte F, Gautier JC, Derouesne C, Guiraud B. Ischemic accidents n the middle cerebral artery territory (a study of the causes in 122 cases). Arch Neurol 1968; 19: 248–256. 2 Lhermitte F, Gautier JC, Derouesne C. Nature of occlusions in the middle cerebral artery. Neurology 1970; 20: 82–88.
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3 Fisher CM, Gore I, Okabe N, et al. Atherosclerosis of the carotid and vertebral arteries. J Neuropathol Exp Neurol 1965; 24: 455. 4 Allcock JM. Occlusion of the middle cerebral artery: serial angiography as a guide to conservative therapy. J Neurosurg 1967; 27: 353–363. 5 Lascelles RG, Burrows EH. Occlusion of the middle cerebral artery. Brain 1965; 88: 85–96. 6 Silverstein A, Hollin S. Internal carotid vs middle cerebral artery occlusion. Arch Neurol 1965; 12: 468–471. 7 Sindermann F, Dichigans J, Bergleiter R. Occlusion of the middle cerebral artery and its branches. Angiographic and clinical correlates. Brain 1969; 92: 607–620. 8 Hinton RC, Mohr JP, Ackerman RH, Adair LB, Fisher CM. Symptomatic middle cerebral artery stenosis. Ann Neurol 1979; 5: 152–175. 9 Gorelick PB, Caplan LR, Hier DB, et al. Racial differences in the distribution of anterior circulation occlusive disease. Neurology 1984; 34: 54–57. 10 Inzitari D, Hachinski VC, Wayne Taylor D, Barnett HJM. Racial differences in the anterior circulation in cerebrovascular disease: how much can be explained by risk factors? Arch Neurol 1990; 47: 1080–1084. 11 Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Raceethnicity and determinants of intracranial atherosclerotic cerebral infarction: The Northern Manhattan Stroke Study. Stroke 1995; 26: 14–20. 12 Yoo K-M, Shin H-K, Cahng H-M, Caplan LR. Middle cerebral artery occlusive disease: the New England Medical Center Stroke Registry. J Stroke Cerebrovasc Dis 1998; 7: 344–351. 13 Heyden S, Heyman A, Goree J. Nonembolic occlusion of the middle cerebral and carotid arteries: A comparison of predisposing factors. Stroke 1970; 1: 363–369. 14 Min WK, Park KK, Kim YS, et al. Atherothrombotic middle cerebral artery territory infarction: topographic diversity with common occurrence of concomitant small cortical and subcortical infarcts. Stroke 2000; 31: 2055– 2061. 15 Lee PH, Oh SH, Bang OY, et al. Isolated middle cerebral artery disease: clinical and neuroradiological features depending on the pathogenesis. J Neurol Neurosurg Psychiatry 2004,75: 727–732. 16 Lee DK, Kim JS, Kwon SU, Kang DW. Lesion patterns and stroke mechanism in atherosclerotic middle cerebral artery disease: early diffusion-weighted MRI study. Stroke 2005; 36: 2583–2588. 17 Caplan L, Babikian V, Helgason C, et al. Occlusive disease of the middle cerebral artery. Neurology 1985; 35: 975– 982. 18 Bogousslavsky J, Barnett HJ, Fox AJ, et al. Atherosclerotic disease of the middle cerebral artery. Stroke. 1986; 17: 1112–1120.
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19 Lyrer PA, Engelter S, Radu EW, Steck AJ. Cerebral infarcts related to isolated middle cerebral artery stenosis. Stroke 1997; 28: 1022–1027. 20 Warach S, Gaa J, Siewert B, et al. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol 1995; 37: 231– 241. 21 van Everdingen KJ, van der Grond J, Kappelle LJ, et al. Diffusion-weighted magnetic resonance imaging in acute stroke. Stroke 1998; 29: 1783–1790. 22 Kim JS. A diffusion-weighted MRI study of acute ischemic distal arm paresis. Neurology 2002; 59; 650. 23 Hacke W, Schwab S, Horn M, et al. Malignant middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol 1996; 53: 309–315. 24 Fisher CM. Lacunes: small, deep cerebral infarcts. Neurology 1965; 15: 774–784. 25 Fisher CM. The arterial lesions underlying lacunes. Acta Neuropathol 1969; 12: 11–15. 26 Horowitz DR, Tuhrim S, Weiberger JM, Rudolph SH. Mechanisms in lacunar infarction. Stroke 1992; 23: 325– 327. 27 Fisher CM. Capsular infarcts. The underlying vascular lesions. Arch Neurol 1979; 36: 65–73. 28 Adams HP, Demasio HC, Putman SF, Demasio AR. Middle cerebral artery occlusion as a cause of isolated subcortical infarction. Stroke 1983; 14: 948–952. 29 Kappelle LJ, Koudstaal PJ, Gijin JV, et al. Carotid angiography in patients with lacunar infarction. Stroke 1988; 19: 1093–1096. 30 Waterston JA, Brown MM, Butler P, Swash M. Small deep cerebral infarcts associated with occlusive internal carotid artery disease. Arch Neurol 1990; 47: 953–957. 31 Mead GE, Lewis SC, Wardlaw JM, et al. Severe ipsilateral carotid stenosis and middle cerebral artery disease in lacunar ischaemic stroke: innocent bystanders? J Neurol 2002; 249: 266–271. 32 Donnan GA, Bladin PF, Berkovic SF, et al. The stroke syndrome of striatocapsular infarction. Brain 1991; 114 ( Pt 1A): 51–70. 33 Donnan GA, Norving B, Bamford JM, Bogousslavsky J. Subcortical infarction: classification and terminology. Cerebrovasc Dis 1993; 3: 248–251. 34 Adachi T, Kobayashi S, Yamaguchi S, Okada K. MRI findings of small subcortical ‘lacune-like’ infarction resulting from large vessel disease. J Neurol 2000; 247: 280–285. 35 Nakano S, Yokogami K, Ohta H, et al. CT-defined large subcortical infarcts: correlation of location with site of cerebrovascular occlusive disease. Am J Neuroradiol 1995,16: 1581–1585. 36 Bang OY, Heo JH, Kim JY, et al. Middle cerebral artery stenosis is a major clinical determinant in striatocapsular small, deep infarction. Arch Neurol 2002; 59: 259–263.
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37 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. 38 Mok VCT, Fan YH, Lam WWM, et al. Small subcortical infarct and intracranial large artery disease in Chinese. J Neurol Sci 2003; 216: 55–59. 39 Fisher CM. Lacunar infarcts: a review. Cerebrovasc Dis 1991; 1: 311–320. ˜ M, Castellanos M. Deteriora40 Serena J, Rodr´ıguez-Ya´ nez tion in acute ischemic stroke as the target for neuroprotection. Cerebrovasc Dis 2006; 21 (Suppl 2): 80–88. 41 Steinke W, Ley SC. Lacunar stroke is the major cause of progressive motor deficits. Stroke 2002; 33: 1510–1516. 42 Lodder J, Gorsselink EL. Progressive stroke caused by CTverified small deep infarcts; relation with the size of the infarct and clinical outcome. Acta Neurol Scand 1985; 71: 328–330. 43 Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS. Effect of blood pressure and diabetes on stroke in progression. Lancet 1994; 344: 156–159. 44 Nakamura K, Saku Y, Ibayashi S, Fujishima M. Progressive motor deficits in lacunar infarction. Neurology 1999; 52: 29–33. 45 Audebert HJ, Pellkofer TS, Wimmer ML, Haberl RL. Progression in lacunar stroke is related to elevated acute phase parameters. Eur Neurol 2004; 51: 125–131. 46 Bang OY, Joo SY, Lee PH, et al. The course of patients with lacunar infarcts and a parent arterial lesion: similarities to large artery vs small artery disease. Arch Neurol 2004; 61: 514–519. 47 Cho KH. Radiological and clinical features of single subcortical infarction in middle cerebral artery territory. Thesis for Doctoral Dissertation, University of Ulsan, 2007. 48 Wang X, Lam WWM, Fan YH, et al. Topographic patterns of small subcortical infarcts associated with MCA stenosis: a diffusion-weighted MRI study. J Neuroimaging 2006; 16: 266–271. 49 Cho KH, Kang DW, Kwon SU, Kim JS. Location of single subcortical infarction due to middle cerebral artery atherosclerosis: proximal vs distal arterial stenosis. J Neurol Neurosurg Psychiatry (in press). 50 Donzelli R, Marinkovic S, Brigante L, et al. Territories of the perforating (lenticulostriate) branches of the middle cerebral artery. Surg Radiol Anat 1998; 20: 393–398. 51 Gacs G, Fox AJ, M. Barnett HJM, Vinuela F. Occurrence and mechanisms of occlusion of the anterior cerebral artery. Stroke 1983; 14: 952–959. 52 Bogousslavsky J, Franco R. Anterior cerebral artery territory infarction in the Lausanne stroke registry. Arch Neurol 1990; 1: 144–150.
53 Kazui S, Sawada T, Naritomi H, Kuriyama Y. Angiographic evaluation of brain infarction limited to the anterior cerebral artery territory. Stroke 1993; 24: 549– 553. 54 Kumral E, Bayulkem B, Evyapan D, Yunten N. Spectrum of anterior cerebral artery territory infarction: clinical and MRI findings. Eur J Neurol 2002; 9: 615–624. 55 Foix C, Hillemand P. Les syndromes de l’art`ere ant´erieure. Enc´ephale 1925; 20: 209–232. 56 Critchley M. The anterior cerebral artery and its syndromes. Brain 1930; 53: 120–165. 57 Kubis N, Guichard J-P. Isolated anterior cerebral artery infarcts: a series of 16 patients. Cerebrovasc Dis 1999; 9: 185–187. 58 Brust JCM. Anterior cerebral artery disease. In: Barnett HJM, Mohr JP, Yatsu F and Stein B, (eds) Stroke: pathophysiology, diagnosis, and treatment. Philadelphia, PA: Churchill Livingstone, 1998: 401–425. 59 Brust JCM. Lesions of the supplementary motor area. In: Luders HO (ed.) Supplementary sensorimotor area, vol. 70. New York, NY: Raven Press, 1996: 237–248. 60 Chamorro A, Marshall RS, Valls-Sole J, et al. Motor behavior in stroke patients with isolated medial frontal ischemic infarction. Stroke 1997; 28: 1755–1760. 61 Sussman NM, Gur RC, Gur RE, O’Connor MJ. Mutism as a consequence of callosotomy. J Neurosurg 1983; 59: 514–519. 62 Ross MK, Reevers AG, Roberts DW. Postcommissurotomy mutism. Ann Neurol 1984; 16: 114. 63 Brust JCM, Sawada T, Kazui S. Anterior cerebral artery. In: Bogousslavsky J, Caplan LR (eds) Stroke syndromes. New York, NY: Cambridge University Press, 2001: 439– 450. 64 Kang SY, Kim JS. Anterior cerebral artery infarction: stroke mechanism and clinical-imaging study in 100 patients. Neurology 2008; 70: 2386–2393. 65 Masdeu JC Schoene WC, Funkenstein H. Aphasia following infarction of the left supplementary motor area. Neurology 1978; 28: 1220–1223. 66 Alexander MP, Schmitt MA. The aphasia syndrome of stroke in the left anterior cerebral artery territory. Arch Neurol 1980; 37: 97–100. 67 Kim JS, Choi-Kwon S. Poststroke depression and emotional incontinence: correlation with lesion location. Neurology 2000; 54: 1805–1810. 68 Kim JS. Involuntary movements after anterior cerebral artery territory infarction. Stroke 2001; 32: 258– 261. 69 Klatka LA, Depper MH, Marini AM. Infarction in the territory of the anterior cerebral artery. Neurology 1998; 17: 69–75. 70 Castaigne P, Lhermitte F, Escourelle R, et al. Etude anatomopathologique de 74 infarcts de l’art`ere c´er´ebrale
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anterieure (55 observations). Rev Med Toulouse 1975; (Suppl): 339. Rothfus WE, Goldberg AL, Tabas JH, Deeb ZL. Callosomarginal infarction secondary to transfalcial herniation, AJNR 1987; 8; 1073. Kim CH, Kim JS. Development of cerebral infarction shortly after intracerebral hemorrhage. Eur Neurol 2007; 57: 145–149. Perlmutter D, Rhoton AL, Jr. Microsurgical anatomy of the distal anterior cerebral artery. J Neurosurg 1978; 49: 204–228. Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55: 1475–1482. Hass WK, Fields WS, North RR, et al. Joint study of extracranial arterial occlusion II. Arteriography, techniques, sites and complications. JAMA 1968; 203: 961–968. Hutchinson EC, Yates PO. Carotico-vertebral stenosis. Lancet 1957; 1: 2–8.
¨ 77 Torvik A, Jorgensen L. Ischemic cerebrovascular disease in an autopsy series. Part 1. Prevalence, location and predisposing factors in verified thrombo-embolic occlusion and their significance in the pathogenesis of cerebral infarction. J Neurol Sci 1966; 3: 490–509. 78 Wechsler LR, Kistler JP, Davis KR, Kaminski M. The prognosis of carotid siphon stenosis. Stroke 1986; 17: 714–718. 79 Craig DR, Meguro K, Watridge C, et al. Intracranial internal carotid artery stenosis. Stroke 1982; 13: 825– 828. 80 Kim JS, Kang SY. Bleeding and subsequent anemia: a precipitant for cerebral infarction. Eur Neurol 2000; 43: 201–208. 81 Saunders FW, Shedden P. The carotid siphon: a scanning electron microscope assessment if its embolic potential. Can J Neurol Sci 1985; 12: 263–266. 82 Marzewski DJ, Furlan AJ, Louis PS, et al. Intracranial internal carotid artery stenosis: longterm prognosis Stroke 1982; 13: 821–824.
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Posterior circulation disorders Louis R Caplan, Pierre Amarenco and Jong S Kim
Cerebral infarcts occurring in the posterior circulation are caused by intrinsic intracranial atherosclerosis, embolism from proximal artery or diseased heart, or small vessel occlusive disease. Generally, infarcts developing in areas supplied by distal branches such as the cerebellum and occipital area are produced by embolism whereas infarcts occurring in the brainstem are caused by either small vessel occlusion or intracranial atherosclerosis. Intrinsic atherosclerosis may produce multiple lesions in the same vascular territory such as the medulla and cerebellum, or lateral thalamus and occipital area. However, multiple lesions involving different vascular territories (i.e., pons, thalamus, and occipital area) strongly suggest that an embolism is the underlying etiology. As in the anterior circulation, the importance of intracranial atherosclerosis seems to be greater in Asians than in Caucasians in posterior circulation stroke. However, this issue has not yet been sufficiently investigated. In this chapter, we review clinical and pathophysiological aspects of infarcts occurring in the posterior circulation and discuss the role of intracranial vascular occlusive diseases.
Localization of brain lesions within the posterior circulation Localization within the posterior circulation is simplified by dividing the vertebrobasilar territory into proximal, middle, and distal territories.1,2 The proximal intracranial posterior circulation territory includes regions supplied by the intracranial vertebral arteries (ICVAs), the medulla oblongata, and the posterior inferior cerebellar artery (PICA)-supplied region of the
cerebellum. The ICVAs join together to form the basilar artery at the medullopontine junction. The middle intracranial posterior circulation territory includes the portion of the brain supplied by the basilar artery and its penetrating artery branches up to its superior cerebellar artery (SCA) branches: the pons and the anterior inferior cerebellar artery (AICA)-supplied portions of the cerebellum. The distal intracranial posterior circulation territory includes all the territory supplied by the rostral basilar artery and the SCA, posterior cerebral artery (PCA) and their penetrating artery branches – midbrain, thalamus, SCA-supplied cerebellum, and PCA territories. This distribution is shown diagrammatically in Fig. 7.1. Lesions within the medulla are most often unilateral and predominantly lateral tegmental. When an infarct is found in the medulla on one side, the ipsilateral ICVA or its branches must have been obstructed at one time. Infarcts in the pons are most often bilateral and medial-tegmentobasal when the basilar artery is occluded. When a penetrating branch is occluded, the infarcts are unilateral and in the territory of a branch. Infarction in the midbrain, thalamus, and posterior portions of the cerebral hemispheres supplied by the PCAs are due to disease within the distal basilar artery or its branches.
Proximal intracranial posterior circulation territory Clinical syndromes Lateral medullary infarction Lateral medullary infarction (LMI) is characterized by a constellation of symptoms and signs related
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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Fig 7.1 Sketch of the base of the brain showing the intracranial vertebral and basilar arteries and their branches. The section is divided into proximal intracranial territory, middle intracranial territory, and distal intracranial territory. AICA, anterior inferior cerebellar artery; ASA, anterior spinal artery; PCA, posterior cerebral artery; PICA, posterior inferior cerebellar artery; SCA, superior cerebellar artery. Reproduced with permission from Laurel Cook-Lowe from Caplan LR. Posterior Circulation disease, clinical findings, diagnosis and management, Boston, Blackwell Science, 1996.
to involvement of compactly organized nuclei or tracts in a small part of the brain, the medulla oblongata. The symptoms/signs may be categorized as very common (90% or more) ones, including sensory symptoms/signs, Horner sign, and gait instability; moderately common (50–70%) ones, including dysphagia, hoarseness, nystagmus, vertigo, limb ataxia, nausea/vomiting, and headache; and less common (<40%) ones including skew deviation, diplopia, facial paresis, gaze deviation, and respiratory difficulty.3 The clinical presentations depend on the dorsal– ventral, medial–lateral, and rostro–caudal topographic location of the infarcts. According to a recent study investigating a large number of LMI patients, vertigo, diplopia nystagmus, skew deviation, nausea/vomiting, and severe gait instability tend to 84
co-occur.3 This is understandable because these symptoms are related to the involvement of vestibular nuclei, nucleus prepositus hypoglossi, inferior cerebellar peduncle, and related structures at the superficial dorsal part of the medulla. Most patients with LMI describe feeling dizzy or off-balance. Others report frank vertigo-turning, rotating, whirling, or moving in relation to their environment. Some patients feel as if they are being pulled or are falling towards one side (most often ipsilateral to the lesion); others describe a swaying, rolling feeling as if they are moving from side to side. Patients with vestibular system abnormalities often describe blurred or double vision. Some report oscillopsia characterized by a rhythmic motion or oscillation of objects on which they attempt to focus. Less common is tilting or inversion of the visual environment. In many patients standing or walking is impossible during the acute period and others may need to support patients in the erect position. Compared with gait instability, limb ataxia is relatively uncommon and less severe if the cerebellum is spared. The nystagmus usually has both horizontal and rotational components. The rapid phase of the rotatory nystagmus usually moves the upper border of the iris towards the side of the lesion. Larger amplitude, slower nystagmus is usually present on gaze to the side of the lesion, whereas smaller amplitude quick nystagmus is found on gaze directed to the contralateral side. Ocular torsion is often present; the ipsilateral eye and ear may rest in a down position below the contralateral eye and ear.1,4 At times, ocular torsion noted on lateral eye movements is accompanied by a head tilt and skew deviation with the ipsilateral eye positioned downward. This combination of findings is referred to as the ocular tilt reaction.5,6 These patients often have difficulty judging correctly the visual-vertical axis. A rarer oculomotor abnormality is ocular lateropulsion, a forced conjugate deviation of the eyes to one side.1,7,8 Dysphagia, hoarseness, and dysarthria constitute another group of symptoms that tends to co-occur in the same patient.3 These symptoms are generally caused by lesions involving the nucleus ambiguous, located in the deep portion (ventral medial) of the medulla. Paralysis of the muscles of the oropharynx results in food being trapped in the piriform recess of the pharynx. Food and secretions have relatively free access into the air passages. Patients try to extricate the food with a cough or throat-clearing maneuver that makes a characteristic crowing-like sound.
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Examination shows paralysis of the ipsilateral vocal cord and a lack of elevation of the ipsilateral palate on phonation. The uvula often deviates to the contralateral side. Dysarthria and a hoarse breathy voice are common. Clinical-imaging correlation studies,3,9,10 have shown that dysphagia but not dysphonia is more frequent and more severe in patients with rostral lesions than in those with caudal lesions. This is probably explained by the pattern of viscerotopic organization of the nucleus ambiguous; the esophageal and pharyngeal motor system is regulated by the compact and semi-compact formation located in the rostral intermediate area of the nucleus ambiguous whereas muscles related to phonation, such as cricothyroid and other intrinsic laryngeal muscles are regulated by semi-compact and loose formation in the intermediate caudal areas.11 In patients with severe dysphagia, aspiration pneumonia is an important complication that may affect the patient’s prognosis adversely. Regarding sensory symptoms and signs, the loss of pain and thermal sensation involving the ipsilateral trigeminal area and contralateral body/limbs is the most typical pattern (ipsilateral trigeminal pattern). The corneal reflex is usually reduced in the ipsilateral eye. However, recent studies have found that other patterns such as contralateral trigeminal– contralateral limb/body (contralateral trigeminal pattern), bilateral trigeminal–contralateral limb/body (bilateral trigeminal pattern), limb/body involvement without trigeminal involvement (isolated limb/body pattern) are nearly as common as the classical pattern if the patients are examined early.3,12 Trigeminal involvement without limb/body involvement (isolated trigeminal pattern) also occurs in about 10% of the patients. The diverse patterns of sensory abnormalities are related to the different location of structures related to sensory perception: spinothalamic tract in the lateral superficial area, descending trigeminal tract in the dorsal area, and ascending secondary trigeminal tract in the ventral area. Accordingly, typical, ventral, large, lateral, and dorsal lesions are related to ipsilateral trigeminal, contralateral trigeminal, bilateral trigeminal, isolated limb/body sensory loss, and isolated trigeminal sensory loss patterns, respectively.3,12 Sensory gradient or level is observed in approximately one-quarter of the patients, which is related to a partial involvement of laminated sensory fibers in the spinothalamic tract.13 Although many patients with
hypalgesia are unaware of their sensory loss until they are tested, pain or unpleasant dysesthetic feelings in the face are sometimes the earliest and most prominent feature of the LMI. The facial pain is usually described as sharp jolts or stabs of pain most often in the ipsilateral eye or face. More often, however, the painful or burning symptoms appear as a delayed manifestation. Approximately one-quarter of the patients develop central post-stroke pain, usually in the area of most severely impaired sensory perception.14,15 Hiccups are less common, but can be an annoying complaint. Although the neural substrate for hiccups remains unknown, involvement of the nucleus ambiguus or adjacent reticular areas regulating respiration may be responsible for the generation of hiccups. Overt respiratory dysfunction is even less common but can be a clinically important symptom.1,16 Control of inspiration and expiration and their automaticity lies within the ventrolateral medullary tegmentum and the medullary reticular zone. The best known abnormality described in patients with LMI is failure of automatic respiration, a phenomenon especially apparent during sleep (Ondine’s curse). Signs of other autonomic dysfunction are also occasionally present, such as abnormalities of sweating, thermal regulation, and vasomotor control. Cardiovascular abnormalities (tachycardia, bradycardia, or orthostatic hypotension) and gastrointestinal autonomic dysfunctions (decreased esophageal motility, gastroesophageal reflux, or gastric retention) may be present. Medial medullary infarction Medial medullary infarction (MMI) was once thought as a grave disorder characterized by quadriparesis, sensory deficits and tongue weakness. After the introduction of MRI, it has now been realized that unilateral MMIs presenting with relatively benign sensorimotor stroke are much more common than severe, bilateral cases.17 The most consistent finding in patients with MMI is a contralateral hemiparesis.1,18,19 When the degree is severe, the hemiparesis is complete and flaccid at onset. The hand and foot are most severely involved. Later, increased tone and spasticity develop in the arm and leg. Facial weakness, usually mild and transient, may be observed, especially if the infarct involves the rostral medulla. Corticobulbar fibers to the face travel in the pyramid and can extend caudally until the mid medulla before crossing and ascending to the contralateral seventh nerve nucleus.1 At 85
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times hemiparesis is the only clinical finding related to infarction localized to the medullary pyramid.1,20,21 Sensory symptoms are the second most common symptoms related to ischemia of the medial lemniscus. In about one half of patients, the face is also involved. Many patients report paresthesias or less often dysesthesias in the contralateral limbs without significant objective signs of touch, vibration, or position sense loss. In others, proprioceptive dysfunction such as the loss of position and vibration sense is detected in the contralateral limbs, usually more marked in the foot than in the hand. Ipsilateral tongue paralysis is the least common but most topographically localizing sign of MMI. Tongue paresis causes slurring of speech especially of lingual consonants, and difficulty manipulating food in the mouth. Hemimedullary infarction Occasionally, patients have infarction that involves both the lateral and the medial medullary territories on one side. Symptoms are identical to those found in patients with LMI with the addition of a hemiparesis contralateral to the lesion. The hemiparesis may develop concurrently with lateral medullary symptoms and signs or can occur later. Cerebellar infarction in PICA distribution PICA cerebellar infarcts can be divided into (1) infarction in the territory of the medial branch of PICA (mPICA) affecting mostly the inferior cerebellar vermis, (2) infarction limited to the lateral branch of PICA (lPICA) affecting mostly the lateral surface of the posterior inferior cerebellar hemisphere, and (3) full PICA territory infarcts involving both the mPICA and lPICA territories.1,22,23 Full PICA territory infarcts are often accompanied by edema formation and mass effect – socalled pseudotumoral cerebellar infarcts. These large cerebellar infarcts are almost always due to embolism from the heart, aorta, or ipsilateral vertebral artery in the neck. About one-fifth of PICA territory cerebellar infarcts are accompanied by infarction in the dorsal or dorsolateral medulla.1 The combination of lateral medullary and PICA cerebellar infarction occurs when the ICVA is occluded and blocks the orifice of both PICA and the lateral medullary penetrators. Most often mPICA territory infarcts are accompanied by dorsal medullary infarcts since the mPICA branch has some supply to the dorsal medulla.1,23,24 86
Infarcts limited to the medial vermis in mPICA territory usually cause a vertiginous labyrinthine syndrome that closely mimics a peripheral vestibulopathy. Severe vertigo with prominent nystagmus are the major findings.1,22,25,26 Some patients also have truncal lateropulsion characterized by feelings of magnetic pulling of the trunk to the ipsilateral side. Ocular lateropulsion may also be present. Lateral cerebellar hemisphere PICA territory infarcts are usually characterized by minor degrees of dizziness and gait incoordination with veering to the side of the lesion. Minor limb hypotonia and incoordination are found. A common syndrome is acute unsteadiness with ataxia but without vertigo or dysarthria. When the full PICA cerebellar territory is involved, headache is usually present in the occiput or high neck on the ipsilateral side. The head may also be tilted with the occiput tending ipsilaterally. Vomiting, gait ataxia, truncal lateropulsion, and limb incoordination are other common findings. The body is often tilted or pulled ipsilaterally upon sitting or standing. The limb incoordination consists mostly of hypotonia rather than a rhythmic intention tremor. Herniation is the most feared complication in patients with a large PICA infarction. After the first day or so, patients develop increased headache, vomiting, and decreased consciousness. At first they become drowsy and later stuporous. Bilateral Babinski signs are an early sign of the cerebellar mass effect. Oculomotor abnormalities develop: the most common one being a conjugate gaze paresis to the side of the lesion or a paresis of abduction limited to the ipsilateral eye. Bilateral sixth nerve paresis may occur. Later, bilateral horizontal gaze palsies may develop often accompanied by ocular bobbing. These signs are due to compression of the pontine tegmentum by the swollen cerebellar infarct. Stupor, coma, and respiratory arrest follow if patients are not adequately treated.
Vascular lesions and stroke mechanisms in patients with proximal intracranial territory infarction LMI is the one of the best examples of intrinsic intracranial diseases, either atherosclerotic (superimposed by thrombosis) or dissecting, producing small infarcts by way of perforator occlusion1,3,27,28 (Fig. 7.2). Less often, cardiogenic or artery-to-artery
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Fig 7.2 An example of a patient with lateral medullary infarction due to distal vertebral artery occlusive disease. A 66-year-old man with hypertension and diabetes mellitus developed sudden onset of dizziness, vertigo, gait disturbances, and dysarthria. There was a left Horner syndrome, decreased pinprick and temperature sensation in the right limbs, and ataxia in the left extremities. Diffusion-weighted MRI showed an infarct in the left lateral medulla. MR angiogram showed thrombotic occlusion of the left distal vertebral artery (arrow) that probably occluded penetrating branches supplying the lateral medulla.
emboli usually from the extracranial vertebral artery (ECVA) explain LMI. According to a study examining 123 Korean patients with MRI and angiogram (mostly MR angiogram),3 the angiogram findings were abnormal in 77%. There was vertebral artery (VA) stenosis/occlusion in 67%, and isolated PICA disease in 10%. Among the patients with VA disease, approximately half had ICVA diseases and the other half had whole VA diseases. ECVA diseases with intact ICVA were rare. The presumed pathogenic mechanisms of infarction were large vessel atherosclerosis in 50%, arterial dissection in 15%, small vessel occlusion in 13%, cardiac embolism in 5%, and unknown in 15%. MMI usually results from atherothrombosis occurring in the ICVA1,29 or less often in the proximal basilar artery. Although uncommon, the vascular pathology within the penetrating anterior spinal artery branches explains the MMI, in such cases the infarct is usually limited to the lower portion of the medullary pyramid. When the lesion is located lower than crossed pyramidal fibers, ipsilateral hemiparesis may develop.30 Aside from causing LMI or MMI, atherosclerosis in the ICVA may produce embolism in distal areas of the posterior circulation. Severe stenosis or occlusion of bilateral ICVA may produce recurrent minor infarcts or transient ischemic attacks (TIAs) by way of embolization, hemodynamic failure, or both. Unilateral ICVA disease may also be problematic if the contralateral ICVA is hypoplastic or absent. Transient dizzi-
ness, gait instability, dysarthria, or diplopia are common symptoms in these patients, which often occur when patients are exhausted or dehydrated. In these patients, MRI often shows multiple scattered infarcts of various ages in the posterior circulation. Sometimes, atrophy of the brainstem or the cerebellum is noted. Endovascular therapy such as stenting may be of help in these patients although the long-term outcome of the procedure remains unclear. The most common cause of PICA territory cerebellar infarction is embolism to the ICVA from the heart or the proximal ECVA.1,25,27,30 PICA branch infarcts limited to either mPICA or lPICA territories are usually embolic, from cardiac, aortic, or ECVA sources.1 Less often occlusion of the ICVA is due to in situ atherosclerosis with superimposed thrombosis. It seems that PICA infarcts caused by intrinsic atherosclerosis of the ICVA or proximal PICA are more common in Asians than in Caucasians. Although rare, PICA Dissection may produce PICA infarction.
Middle intracranial posterior circulation territory Clinical syndromes Bilateral pontine infarction Most patients with pontine ischemia related to basilar artery occlusion have some transient or persistent degree of paresis and corticospinal tract 87
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abnormalities.1,31–34 The initial motor weakness is often lateralized and has been referred to as the “herald hemiparesis” of basilar artery occlusion.35 Hemiparetic patients with basilar artery occlusion almost always show some motor or reflex abnormalities on the non-hemiparetic side: slight weakness, hyperreflexia, an extensor plantar reflex or abnormal spontaneous movements such as shivering, twitching, shaking, or jerking on the relatively spared side. Painful stimuli may precipitate a flurry of abnormal movements. Large repetitive jerking and twitching limb movements are often misdiagnosed as seizures.36 If successful therapy (such as recanalization) is not performed, asymmetrical motor disturbances frequently progress to severe quadriplegia. Ataxia or incoordination of limb movements is another common finding observed in the limbs that are not severely paretic. The ataxia is invariably bilateral but is frequently asymmetric. Weakness of bulbar muscles is very common and is an important cause of morbidity and mortality. Bulbar symptoms include bilateral facial weakness, dysphonia, dysarthria, dysphagia, and limited jaw movements. Some patients become totally unable to speak, open their mouth, protrude their tongue, swallow, or move their face at will or on command. Secretions pool in the pharynx, and aspiration is a potentially serious complication. Patients may show exaggerated crying and laughing spells and are hypersensitive to emotional stimuli. Despite the inability to voluntarily move the muscles, the jaw, face, and pharyngeal reflexes may be hyperactive and even clonic. The mouth may be tightly closed and difficult to open. When all voluntary movement other than the eyes is lost but consciousness is retained, the deficit is referred to as the “locked-in syndrome.”37,38 Some patients with pontine ischemia develop delayed-onset palatal myoclonus, a rhythmic involuntary jerking movement of the soft palate and pharyngopalatine arch which can involve the diaphragm and larynx.1,39 Occasionally, rhythmic, jerky movements are also observed in the extremities (mostly hand) or eyes, although they are not synchronous with palatal movements. The movements of the palate vary in rate between 40 to 200 beats per minute. The movements involve the eustachian tube and make a click that the patient and doctor can hear. The posited anatomical lesion involves the “Guillain–Mollaret triangle,” which includes the dentate nucleus of the cerebellum, 88
the red nucleus in the midbrain, and the inferior olivary nucleus in the medulla and their interconnections. Chronic involvement of the central tegmental tract, and consequent hypertrophic degeneration of the inferior olive is considered to be related to this palatal myoclonus. Oculomotor symptoms and signs are very common. Few patients with pontine infarction due to basilar artery occlusion have normal eye movements. The findings depend on whether the lesions involve the tegmentum of the pons unilaterally or bilaterally. Abnormalities include complete horizontal gaze palsy, unilateral horizontal conjugate gaze palsy, sixth-nerve palsies, unilateral or bilateral internuclear opthalmoplegia (INO), and a one-and-a-half syndrome (conjugate gaze palsy and an INO).1,40–45 Lesions affecting the abducens nucleus or the pontine paramedian reticular formation (PPRF) on one side often cause a unilateral conjugate gaze palsy.40–42 Horizontal, gaze paretic nystagmus is common and, when asymmetric, usually is more prominent when the gaze is directed to the side of a unilateral pontine tegmental lesion. Lesions involving the medial longitudinal fasciculus (MLF) cause an INO that is characterized during conjugate lateral gaze to the contralateral side by weakness of adduction to the contralateral side along with nystagmus of the abducting eye. Dissociated nystagmus, that is nystagmus that is more severe in one eye and not rhythmically concordant in the two eyes, and vertical nystagmus are found in patients with an INO. When the PPRF and MLF are involved on the same side, the only preserved gaze is in the abducting eye when looking contralaterally (one-and-a-half syndrome).40–45 Ocular bobbing is sometimes present in patients with bilateral pontine infarction.40,46 Miller Fisher40 used the term to describe a characteristic vertical motion of the eyes, “The eyeballs intermittently dip briskly downwards through an arc of a few millimeters and then return to the primary position in a kind of bobbing action.” Bobbing can be bilateral and symmetric or can be predominantly unilateral or simply slightly asymmetric.40,46–48 Asymmetric bobbing is common in patients with cerebellar lesions and those in whom there is an asymmetric paralysis of either conjugate gaze or ocular abduction. When bobbing is asymmetric, usually the eye ipsilateral to the side of limited gaze bobs when the gaze is directed to that side. Ptosis of the upper eyelids is also very frequent.49 The
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pupils may remain normal or become small. In some patients the pupils are bilaterally very small (“pinpoint”). Use of a magnifying glass can show that, despite their very small size, the pupillary response to light is preserved, although the amplitude of the response is slight. Somatosensory abnormalities are common but usually cannot be precisely assessed in patients with basilar artery occlusions. Occasionally, patients complain of uncomfortable paresthesias because of involvement of the medial lemniscus in the paramedian dorsal portion of the basis pontis. Symptoms such as tinnitus, hearing loss, and auditory hallucination are related to involvement of the central auditory tracts and nuclei (auditory nuclei, lateral lemnisci, trapezoid bodies, inferior colliculi) or to ischemia of the eighth nerves or the cochlea. Alteration in the level of consciousness is an important sign in patients with basilar artery occlusion and is related to bilateral medial tegmental pontine ischemia.
Anterior inferior cerebellar artery territory infarction When infarction is limited to unilateral AICA territory, the clinical findings are similar to those found in patients with LMI, except that seventh and eighth nerve findings are present rather than symptoms and signs related to the tenth nerve (nucleus ambiguus) dysfunction.1,22,24,50–53 The lesion may involve the facial, vestibular and cochlear nuclei, the seventh nerve fibers within the lateral tegnentum and base, the eighth nerve peripheral fibers, or the cochlea and vestibule. Weakness of the contralateral limbs and an extensor plantar sign are found when the infarct extends to the pontine base The internal auditory artery is most often a branch of AICA. In some patients, especially those with diabetes, ischemia of the inner ear structures supplied by the internal auditory artery can herald a full AICA territory infarct.54 Tinnitus, hearing loss, and vertigo are the most common symptoms related to inner-ear ischemia.
Unilateral pontine infarction Unilateral pontine infarction is usually caused by small vessel occlusion or basilar artery stenosis. The symptoms and signs consist of parts of the various pontine syndromes described above. Lesions involving the ventral part of the pons produce lacunar syndromes such as pure motor hemiparesis, sensorimotor stroke, ataxic hemiparesis, or dysarthria– clumsy hand syndrome. The combinations are determined by the degree of involvement of the pyramidal tract, corticobulbar tract, corticopontocerebllar tract, and ascending lemniscal sensory tract. Both lesion size and lesion location determine the severity of the symptoms. Usually, lesions in the rostral pons tend to produce less severe motor dysfunction, probably because of relatively sparsely arranged corticospinal fibers in this region.50 For this reason, dysarthria–clumsy hand syndrome is usually encountered in patients with lesions affecting the rostral pons. Deep, localized infarction mostly involving the lemnsical sensory tract produces pure or predominant hemisensory syndrome whereas far dorsal lesions involving abducens nuclei complex, PPRF, or medial longitudinal fasciculus produce various ocular signs such as one-and-a-half syndrome, INO, or sixth nerve palsy. Mild ataxia, dysarthria, or gait disturbances are usually also present.
Vascular lesions and stroke mechanisms in patients with middle intracranial territory ischemia When pontine ischemia is bilateral, the causative vascular lesion is usually an intrinsic occlusive lesion within the basilar artery, most often atherosclerosis with or without superimposed thrombosis. Dissection of the basilar artery can produce a similar syndrome. Sometimes thrombosis begins in one distal ICVA and extends into the basilar artery or the occlusion involves a basilarized ICVA, the contralateral ICVA being hypoplastic or ends in PICA.1,33 Occasionally, however, mid-basilar occlusion is caused by embolism either from the diseased heart or proximal artery.55,56 The reason why the embolus does not move further to the distal part of the basilar artery may be explained by the presence of posterior communicating arteries in these patients; when an embolus enters the basilar artery, the downstream perfusion pressure may decline. In the presence of the posterior communicating artery, retrograde flow through this artery interferes with the progression of embolism towards the distal basilar artery, and an embolus may lodge in the proximal or middle part of the basilar artery.56 Basilar artery occlusion, whatever the cause, is an ominous sign leading to quadriparesis and locked-in 89
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Fig 7.3 An example of locked-in syndrome caused by basilar artery atherothrombotic occlusion. A 73-year-old man with hypertension and a history of cigarette smoking developed recurrent episodes of dizziness followed by stupor and quadriparesis 10 days later. Initial diffusion-weighted magnetic resonance imaging (MRI) showed tiny, scattered, recent infarcts involving the right occipital area (A, arrow), and the cerebellum (B and C, arrows). No definite lesions were identified in the pons. MR
angiogram showed occlusion of both distal vertebral arteries and non-visualization of the basilar artery (D, arrow). Intra-arterial thrombolysis was attempted, but failed to recanalize the vessel (not shown). Follow up diffusion weighted MRI showed bilateral pontine infarction (E, F, G). MR angiogram showed persistent occlusion of the basilar artery (not shown). The patient remained in a locked-in state.
syndrome. Patients with intrinsic basilar artery atherosclerosis often show minor signs or symptoms of posterior circulation ischemia that precede the major stroke (Fig. 7.3). In some patients, however, the basilar artery occlusion may end up with minor or transient symptoms and signs because of welldeveloped collateral circulation (Fig. 7.4). In some patients, basilar artery occlusion may even be detected as an incidental finding. In still others, chronic stenosis or occlusion of the basilar artery with insufficient collateralization, produces recurrent minor strokes, or TIAs. Dizziness, gait instability, dysarthria, or visual disturbances due to ischemia on the occipital area are commonly encountered symptoms, especially when the patients are exhausted, hungry, or dehydrated. Aside from medications, endovascular procedures are occasionally tried in these patients (Fig. 7.5).
In patients with unilateral pontine infarction, total occlusion of the basilar artery is rare. However, basilar artery stenosis was found in 23% of unilateral paramedian pontine lesions,57 and in 50% of those with lesions extending to the basal pial surface.58 Thus, basilar artery stenosis seems to be an important cause of pure pontine infarction, especially when the lesion abuts on the basal surface (Fig. 7.6). In contrast, localized, deep pontine lesions presenting with predominant sensory symptoms are usually caused by small vessel occlusion related to lipohyalinosis.59 However, far dorsal lesions producing predominantly ocular motor abnormalities are occasionally associated with basilar artery atherosclerosis.60 When infarction is limited to the territory of one AICA, the cause is almost always atheromatous
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Fig 7.4 An example of a patient with basilar artery occlusion showing benign outcome due to well-developed collateral circulation. A 66-year-old man with hypertension and diabetes mellitus suddenly developed dizziness and dysarthria that lasted for 10 minutes. Neurologic examination showed no abnormal signs. Diffusion-weighted magnetic resonance imaging showed two small recent infarcts in the left pons and right cerebellum (A, arrows). MR angiogram showed non-visualization of the basilar artery due to thrombotic occlusion (B, arrow). Conventional angiogram 4 days later showed occlusion of
the vertebrobasilar junction on both sides. AP view (C) and lateral view (D) showed occlusion of the distal left vertebral artery (arrows). The left posterior inferior cerebellar artery was well developed to supply much of the left cerebellum. The right cerebellum was also supplied by vermian branches from the left posterior inferior cerebellar artery. A lateral view of the carotid system showed that the rostral portion of the posterior circulation system (posterior cerebral artery, superior cerebellar artery, and upper portion of the basilar artery) (E, arrow) is supplied by the posterior communicating artery (arrowhead).
branch disease. When there is AICA territory infarction accompanied by other infarcts within the pons or other posterior circulation regions, then basilar artery or bilateral ICVA occlusions are usually present.
Sometimes symptoms of AICA such as tinnitus or hearing loss may herald catastrophic bilateral pontine infarction associated with progressive basilar artery occlusion. 91
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Fig 7.5 A 45-year-old man with hypertension, diabetes, and a history of coronary heart disease developed recurrent attacks of dizziness, diplopia, and gait instability that lasted usually for a few minutes. Magnetic resonance imaging showed no abnormal findings. Angiogram shows occlusion of the right vertebral artery just above the posterior inferior
cerebellar artery (A, arrow) and severe stenosis of the basilar artery just above the anterior inferior cerebellar artery (B, arrow). Angioplasty and stenting was performed and the stenosis was improved. The patient had no symptoms during the 2 months after the procedure.
Fig 7.6 An example of pontine infarction caused by intrinsic atherosclerotic basilar artery stenosis. A 65-year-old hypertensive and diabetic man developed dysarthria, left facial paresis, and left hemiparesis.
Diffusion-weighted magnetic resonance imaging showed right pontine base infarction. MR angiogram showed atherosclerotic narrowing of the basilar artery (arrow).
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Distal posterior circulation intracranial intracranial territory Clinical syndromes Top of the basilar syndrome Occlusion of the rostral portion of the basilar artery can cause ischemia of the midbrain and thalami as well as the temporal and occipital lobe cerebral hemispheral territories supplied by the PCAs. The major abnormalities associated with the rostral brainstem ischemia involve alertness, behavior, memory, and oculomotor and pupillary functions. The most common abnormalities of eye position and movement involve vertical gaze and convergence.1,61,62 Some patients have a loss of all voluntary and reflex vertical eye movements. Reflex movements are sometimes preserved despite loss of voluntary vertical eye movements. Either up gaze or down gaze can be selectively involved, but in most patients both directions of vertical gaze are involved. Upgaze and vertical gaze palsies are more common than down gaze palsies.1 Monocular elevation palsies, ipsilateral or contralateral to the lesion and vertical one-and-ahalf syndromes (bilateral upgaze palsy and monocular downgaze palsy or bilateral downgaze palsy and monocular upgaze palsy) also occur. Asymmetric or unilateral lesions in the midbrain tegmentum and posterior thalami can cause contraversive ocular tilt reactions in which the contralateral eye and ear are down. The abnormalities include skew deviation, ocular torsion, and abnormal estimation of the visual vertical.6 Convergence abnormalities are also very common. Usually one or both eyes are hyperconverged. One or both eyes may rest inward or down and in at rest. On attempted upgaze, the eyes may show adductor contractions causing convergence movements. Retraction of the upper eyelid to widen the palpebral fissure has been called Collier’s sign when the abnormality is due to a rostral mesencephalic lesion near the level of the posterior commissure. In some patients both lids are retracted but one eye may have normal lid position or ptosis. Lesions in the rostral brainstem often affect the pupillary light reflex so that the pupils react slowly and incompletely, or not at all to light. The pupils are often small at rest in patients with diencephalic lesions and may be fixed and dilated if the lesions involve the third nerve Edinger–Westphal nuclei. A combination of diencephalic and midbrain lesions
cause mid-position fixed pupils. In midbrain lesions, the pupil may become eccentric (“corectopia”)1,61,63 or oval.64 Hypersomnolence and abulia are common in patients with rostral brainstem infarcts. Abnormal reports and hallucinations are probably related to the altered sleep–wake dreaming cycle.61 Reports made by patients often consist of replies to queries that have no relation to reality. The patient may mislocate themselves in place giving the names of far distant geographical locations, and in the personal time dimension, saying that they are presently performing activities that they only had done in their childhood, adolescence, or much earlier in their adult life. Peduncular hallucinations are predominantly visual, and are often quite vivid and contain colors, objects, and scenes. The hallucinations occur predominantly after sundown.1,61,65 Some patients with rostral paramedian brainstem infarcts that include the thalamus have prominent and sometimes persistent memory deficits. The amnesia involves both anterograde and retrograde memory and usually includes both verbal and non-verbal memory. Sensory and motor abnormalities are usually absent in patients with top of the basilar infarction unless there are concomitant infarcts in the pontine base, midbrain peduncle, or lateral thalamus. Pure midbrain infarction The midbrain is supplied by branches arising from the PCA, upper basilar artery, and the SCA, and is frequently involved in patients with top of the basilar syndrome. However, an infarct limited to the midbrain is rare accounting for 0.6–2.3% of admitted stroke patients.66,67 (Fig. 7.7) Although the syndromes of third nerve palsy with contralateral hemiparesis (Weber syndrome), tremor (Benedikt syndrome), or ataxia (Claude syndrome) have been well described, a recent study with MRI examination showed that third nerve palsy is observed in only one-third of the patients. The third nerve palsy is usually partial and pupillary involvement is less common than in patients with top of the basilar artery syndrome. In this series, clinical manifestations included gait instability (68%), dysarthria (55%), limb ataxia (50%), sensory symptoms (43%), third nerve palsy (35%) definitive limb weakness (23%), and INO (13%).67 According to the pattern of lesion location, midbrain infarcts can be categorized into four groups.67 93
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Anteromedial infarction is characterized by lesions involving the third nerve nuclei/fascicles or medial longitudinal fasciculus and adjacent cerebellar tracts. Patients show ocular motor disturbances and ataxia but without significant motor dysfunction. Sensory abnormalities usually restricted to the perioral and hand areas may be present. Anterolateral infarction is characterized by lesions that include the cerebral peduncle. Patients have hemiparesis and/or hemiataxia. Ocular motor dysfunction is rare. Some patients show features of combined anteromedial and anterolateral infarction. Dorsolateral infarction is uncommon and is characterized by prominent sensory symptoms because of involvement of the laterally situated ascending sensory tract causing a pure sensory stroke syndrome. The most dorsal part of the midbrain is rarely involved in isolation; it is almost always accompanied by superior cerebellar artery territory involvement. Superior cerebellar artery territory infarction Most often SCA territory infarcts are accompanied by other infarcts in regions supplied by other arteries that arise at the rostral end of the basilar artery. Early reports described the so-called classic SCA syndrome that developed when the rostral pontine tegmentum and a portion of the midbrain was infarcted as well as the superior aspect of the cerebellum. The syndrome was said to consist of ipsilateral limb ataxia; ipsilateral Horner syndrome; contralateral loss of pain, and temperature sensibility of the face, arm, leg, and trunk; and a contralateral fourth nerve palsy.1,22,65,67–70 Abnormal ipsilateral spontaneous involuntary movements also occur. The classic
syndrome is quite rare. The classic syndrome is present when the pontine and midbrain tegmentum and superior cerebellar surface are infarcted. The full syndrome is quite rare. Slight dizziness, vomiting, ipsilateral limb dysmetria, gait ataxia, and dysarthria are common. Vertigo is usually not prominent in patients with isolated SCA territory infarcts. Limb incoordination, limb ataxia, intention tremor, and dysarthria are more common in SCA territory cerebellar infarcts than in either AICA or PICA territory cerebellar infarcts.1 Patients with infarcts in the territory of the lateral branch of the SCA have prominent limb ataxia, varying from slight clumsiness to severe incoordination and dysmetria, and dysarthria. Cerebellar gait ataxia and veering and pulling of the trunk to the ipsilateral side, so-called axial lateropulsion, also occur. Dysarthria and abnormal speech rhythm are common in patients with SCA territory infarcts, no matter whether the lesion involves the full territory or the medial or lateral branches.1,22,71
Posterior cerebral artery territory infarction When the PCA is stenosed or occluded, the commonest symptoms and signs relate to the hemispheral distribution of the artery – the occipital and medial temporal lobes. However in some patients, PCA disease causes predominantly deep infarcts or both hemispheral and deep infarcts. Deep infarcts involve decreased flow through penetrating branches to the lateral thalamus from the thalamogeniculate arteries and through the peduncular penetrating branches to the cerebral peduncle. Fig 7.7 An example of pure midbrain peduncular infar due to intrinsic atherothrombosis occurring in the posterior cerebral artery. A 76-year-old hypertensive woman developed dizziness, diplopia, ataxia with slight weakness in the left extremities, and gait instability. Magnetic resonance imaging showed right midbrain infarction mainly involving the cerebral peduncle (A). MR angiogram showed atherosclerotic narrowing in the P2 portion of the right posterior cerebral artery (B, arrow).
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Lateral thalamic infarcts can be caused by occlusive lesions within the PCA or by intrinsic occlusive lesions within the thalamogeniculate branches themselves. The clinical findings are (1) a slight hemiparesis usually rapidly regressive, (2) paresthesia on the contralateral side with variable objective loss of touch, pain, and temperature sensation, (3) slight hemiataxia and dystonic hand postures both contralateral to the side of infarction.72 Sometimes there are abnormal movements involving the contralateral arm and hand. Some patients with lateral thalamic infarcts later develop pain in the limbs that were paresthetic acutely. Hemiplegia can develop because of infarction that involves the cerebral peduncle.73 Patients with large infarcts related to occlusion of the proximal PCA (mostly embolic) can present with severe hemiplegia, hemisensory loss, and hemianopia mimicking MCA occlusions. These infarcts involve both the deep and superficial supply territories of the PCA. The most common finding in patients with PCA territory infarction is a hemianopia.1,74–76 If just the lower bank of the calcarine fissure is involved – the lingual gyrus – a superior quadrant field defect results. An inferior quadrantanopia results if the lesion affects the cuneus on the upper bank of the calcarine fissure. When infarcts are restricted to the striate cortex and do not extend into adjacent parietal cortex, patients are aware of the visual defect. Usually described as a void, blackness, or a limitation of vision to one side, patients usually recognize that they must focus extra attention to the hemianopic field. When given written material or pictures, patients with hemianopia due to occipital lobe infarction are able to see and interpret stimuli normally, although it may take them a bit longer to explore the hemianopic visual field. In patients with occipital lobe infarcts, physicians can reliably map out the visual fields by confrontation. At times, the central or medial part of the field is spared – so-called macular sparing. Optokinetic nystagmus is preserved. Some patients, although they accurately report motion or the presence of objects in their hemianopic field, cannot identify the nature, location, or color of those objects. When the full PCA territory is involved, visual neglect can accompany the hemianopia. In patients with PCA territory infarcts, lateral thalamic ischemia is the major reason for somatosensory symptoms and signs.77 Patients describe paresthesias or numbness in the face, limbs, and trunk. On examination, touch, pinprick, and position sense may be
reduced. The combination of hemisensory loss with hemianopia without paralysis is virtually diagnostic of infarction in the PCA territory. The occlusive lesion is within the PCA before the thalamogeniculate branches to the lateral thalamus. When the left PCA territory is infarcted, alexia without agraphia,1,78 anomic or transcortical sensory aphasia,1,79 and Gerstmann syndrome may be found. Defective acquisition of new memories is common when both medial temporal lobes are damaged but also occurs in lesions limited to the left temporal lobe.1,78,80–82 The memory deficit in patients with unilateral lesions is usually not permanent but may last up to 6 months. Patients cannot recall what has happened recently, and when given new information, they cannot recall it moments later. They often repeat statements and questions spoken only minutes before. Some patients with left PCA territory infarction have difficulty in understanding the nature and use of objects presented visually (associative visual agnosia).1,78 They can trace with their fingers and copy objects, demonstrating that visual perception is preserved and can name objects presented in their hand and explored by touch or when verbally described. Infarcts of the right PCA territory are often accompanied by prosopagnosia, difficulty in recognizing familiar faces.1,83 Disorientation to place and an inability to recall routes or to read or revisualize the location of places on maps are also common.1,84 Patients with right occipitotemporal infarcts also may have difficulty revisualizing what a given object or person look like. Dreams may also be devoid of visual imagery. Visual neglect is much more common after lesions of the right than of the left PCA territory.
Vascular lesions and stroke mechanisms in patients with distal intracranial territory infarcts Top of the basilar artery syndrome is almost always caused by embolism from the heart, aorta, and ECVAs and ICVAs.1,85–87 Rostral brainstem infarcts that are unilateral and are within the territory of single penetrating branches such as the polar artery, thalamic– subthalamic artery, posterior choroidal artery, and midbrain penetrating arteries are caused by disease of those branches – lipohyalinosis or atheromatous branch disease. 95
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Fig 7.8 A 60-year-old man with a history of hypertension, diabetes, and coronary heart disease had sudden blurred vision followed by clumsiness of the left hand. On examination, he showed right homonymous hemianopia, and slight weakness and moderately decreased sensation in the left arm and leg. Initial diffusion-weighted magnetic resonance imaging (MRI) showed a few scattered, tiny infarcts in the left medial temporal and occipital area (A). Initial MR angiogram showed occlusion of the P2 portion
of the left posterior cerebral artery (B). Diffusion MRI taken one day later showed expansion of the lesion to the left lateral thalamus, medial temporal area and occipital area (C). A follow-up MR angiogram 6 days later showed persistent occlusion of the left posterior cerebral artery. This patient showed normal vertebral artery and normal echocardiographic findings and thus was considered to have infarction due to intrinsic posterior cerebral artery atherothrombotic occlusion.
Infarction localized to the midbrain is mostly caused by small vessel occlusion or intrinsic atherosclerotic lesions in the proximal PCA or SCA. As in pontine infarction, lesions restricted to the deep area are usually related to small vessel disease whereas those involving the medial surface are often associated with atherosclerotic disease at proximal PCA, SCA, or BA (Fig. 7.7). Overall, approximately 40% of patients with pure midbrain infarction have relevant intracra-
nial large artery atherosclerosis. Embolism is a rare cause of pure midbrain infarction.67 Most infarcts that are limited to the lateral thalamus in the territory of the thalamogeniculate artery are caused by small vessel occlusion. However, MR angiogram shows that approximately 30% of the patients show stenosis, usually of mild degree, at the P2 portion of the PCA. Although rare, PCA stenosis may produce recurrent transient ischemic attacks of dominant sensory manifestations
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due to recurrent ischemia on the thalamogeniculate artery territory.88 Superior cerebellar artery territory infarcts are predominantly embolic especially when infarction is limited to mSCA or lSCA branches. Occasional patients with bilateral SCA territory have a stenosing lesion involving the basilar artery affecting the region of the artery from which the SCAs originate. Unilateral PCA territory infarcts are also predominantly embolic. Emboli most often have been documented to arise from the heart and the ECVAs and ICVAs, but the aorta may also be a frequent source.1,74–76 Occasional patients have an intrinsic atherostenotic lesion within the PCA. It seems that intrinsic atherosclerosis as a cause of PCA infarction is more common in Asians than in Caucasians (Fig. 7.8). These patients often have TIAs characterized by visual, sensory, or visual and sensory symptoms before the major strokes.
References 1 Caplan LR. Posterior circulation disease: clinical findings, diagnosis, and management. Boston, MA: Blackwell Science, 1996. 2 Caplan LR. Stroke syndromes in diseases of the nervous system. In: Asbury AK, McKhann GM, McDonald WI, Goadsby PJ, McArtheur JC (eds) Clinical neuroscience and therapeutic principles, 3rd edn. Cambridge: Cambridge University Press, 2002: pp. 1345–1360. 3 Kim JS. Pure lateral medullary infarction: clinicalradiological correlation of 130 acute, consecutive patients. Brain 2003; 126: 1864–1872. 4 Morrow MJ, Sharpe JA. Torsional nystagmus in the lateral medullary syndrome. Ann Neurol 1988; 24: 390– 398. 5 Keane JR. Ocular tilt reaction following lateral pontomedullary infarction. Neurology 1992; 42: 259– 260. 6 Brandt T, Dieterich M. Vestibular syndromes in the roll plane: topographic diagnosis from brainstem to cortex. Ann Neurol 1994; 36: 337–347. 7 Kommerell G, Hoyt WF. Lateropulsion of scaccadic eye movements. Arch Neurol 1973; 28: 313–318. 8 Meyer K, Baloh R, Krohel G, et al. Ocular lateropulsion as a sign of lateral medullary disease. Arch Opthalmol 1980; 98: 1614–1616. 9 Kim JS, Lee JH, Suh DC, Lee MC. Spectrum of lateral medullary syndrome: correlation between clinical findings and magnetic resonance imaging in 33 subjects. Stroke 1994; 25: 1405–1410.
10 Kim H, Chung CS, Lee KH, Robbins J. Aspiration subsequent to a pure medullary infarction: lesion sites, clinical variables, and outcome. Arch Neurol 2000; 57: 478– 483. 11 Bieger D, Hopkins DA. Viscerotopic representation of the upper alimentary tract in the medulla oblongata in the rat: the nucleus ambuguus. J Comp Neurol 1987; 262: 546–562. 12 Kim JS, Lee JH, Lee MC. Patterns of sensory dysfunction in lateral medullary infarction: clinical-MRI correlation. Neurology 1997; 49: 1557–1563. 13 Matsumoto S, Okuda B, Imai T, Kameyama M. A sensory level on the trunk in lower lateral brainstem lesions. Neurology 1988; 38: 1515–1519. 14 MacGowan GJL, Janal MN, Clark WC, et al. Central poststroke pain and Wallenberg’s lateral medullary infarction: frequency, character, and determinants in 63 patients. Neurology 1997; 49: 120–125. 15 Kim JS, Choi-Kwon S. Sensory sequelae of medullary infarction: differences between lateral and medial medullary syndrome. Stroke 1999; 30: 2697–2703. 16 Bogousslavsky J, Khurana R, Deruaz JP, et al. Respiratory failure and unilateral caudal brainstem infarction. Ann Neurol 1990; 28: 668–673. 17 Kim JS, Kim HK, Chung CS. Medial medullary syndrome: report of 18 new patients and a review of the literature. Stroke 1995; 26; 1548–1552. 18 Tyler K, Sandberg E, Baum KF. Medial medullary syndrome and meningovascular syphyls: a case report in an HIV-infected man and a review of the literature. Neurology 1994; 44: 2231–2235. 19 Sawada H, Seriu N, Udaka F, Kameyama M. Magnetic resonance imaging of medial medullary infarction. Stroke 1990; 21: 963–966. 20 Ropper AH, Fisher CM, Kleinman GM. Pyramidal infarction in the medulla: a cause of pure motor hemiplegia sparing the face. Neurology 1979; 29: 91–95. 21 Milandre L, Arnaud O, Khalil R. Infarction of the medullary pyramid identified on MRI. Cerebrovasc Dis 1992; 2: 183–184. 22 Caplan LR. Cerebellar Infarcts: key features. Rev Neurol Dis 2005; 2: 51–60. 23 Amarenco P, Hauw J-J, Henin D, et al. Les infarctus du territoire de l’artere cerebelleuse postero-inferieure, etude clinico-pathologique de 28 cas. Revue Neurologique 1989; 145: 277–286. 24 Amarenco P, Hauw J-J. Anatomie des arteres cerebelleuses. Revue Neurologique 1989; 145: 267– 276. 25 Amarenco P, Roullet E, Hommel M, et al. Infarction in the territory of the medial branch of the posterior inferior cerebellar artery. J Neurol Neurosurg Psychiatry 1990; 53: 731–735.
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26 Huang CY, Yu YL. Small cerebellar strokes may mimic labyrinthine lesions. J Neuropl Neurosurg Psychiatry 1985; 48: 263–265. 27 Graf KJ, Pessin MS, DeWitt LD, Caplan LR. Proximal intracranial territory posterior circulation infarcts in the New England Medical Center Posterior Circulation Registry. Eur Neurol 1997; 37: 157–168. 28 Mueller-Kuypers M, Graf KJ, Pessin MS, DeWitt LD, Caplan LR. Intracranial vertebral artery disease in the New England Medical Center Posterior Circulation Registry. Eur Neurol 1997; 37: 146–156. 29 Caplan LR. Intracranial branch atheromatous disease: a neglected understudied and underused concept. Neurology 1989; 39: 1246–1250. 30 Amarenco P, Levy C, Cohen A, et al. Causes and mechanisms of territorial and non-territorial cerebellar infarcts in 115 consecutive patients. Stroke 1994; 25: 105–112. 31 Kubik CS, Adams RD. Occlusion of the basilar artery: a clinical and pathological study. Brain 1946; 69: 73–121. 32 Labauge R, Pages M, Marty-Double C, et al. Occlusion of the basilar artery. A review with 17 personal cases. Revue Neurologique 1981; 137: 545–571. 33 Voetsch B, DeWitt LD, Pessin MS, Caplan LR. Basilar artery occlusive disease in the New England Medical Center Posterior Circulation Registry. Arch Neurol 2004; 61: 496–504. 34 Ferbert A, Bruckman H, Drummen R. Clinical features of proven basilar artery occlusion. Stroke 1990; 21: 1135– 1142. 35 Fisher CM. The “herald hemiparesis” of basilar artery occlusion. Arch Neurol 1988; 45: 1301–1303. 36 Ropper AH. “Convulsions” in basilar artery occlusion. Neurology 1988; 38: 1500–1501. 37 Nordgren RE, Markesbery WR, Fukuda K, Reeves AG. Seven cases of cerebromedullospinal disconnection: the “locked-in” syndrome. Neurology 1971; 21: 1140–1148. 38 Feldman M. Physiological observations in a chronic case of “locked-in” syndrome. Neurology 1971; 21: 459–478. 39 Tahmoush A, Brooks J, Keltner J. Palatal myoclonus associated with abnormal ocular and extremity movements: a polygraphic study. Arch Neurol 1972; 27: 431–440. 40 Fisher CM. Some neuro-opthalmologic observations. J Neurol Neurosurg Psychiat 1967; 30: 383–392. 41 Pierrot-Deseilligny C, Chain F, Serdaru M, et al. The “one-and-a-half” syndrome: electro-oculographic analyses of five cases with deductions about the physiological mechanisms of lateral gaze. Brain 1981; 104: 665–699. 42 Bronstein AM, Morris J, Du Boulay G, et al. Abnormalities of horizontal gaze: clinical, oculographic and magnetic resonance imaging findings. I abducens palsy. J Neurol Neurosurg Psychiat 1990; 53: 194–199. 43 Bronstein AM, Rudge P, Gresty MA, et al. Abnormalities of horizontal gaze. Clinical, oculographic and magnetic
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resonance imaging findings. II. Gaze palsy and internuclear opthalmoplegia. J Neurol Neurosurg Psychiat 1990; 53: 200–207. Wall M, Wray SH. The one-and-a-half syndrome. A unilateral disorder of the pontine tegmentum: a study of 20 cases and review of the literature. Neurology 1983; 33: 971–980. Sharpe J, Rosenberg M, Hoyt W, et al. Paralytic pontine exotropia. Neurology 1974; 24: 1076–1081. Fisher CM. Ocular bobbing. Arch Neurol 1964; 11: 543– 546 Nelson J, Johnston C. Ocular bobbing. Arch Neurol 1970; 22: 348–356. Newman N, Gay A, Heilbrun M. Dysjugate ocular bobbing: its relation to midbrain, pontine, and medullary function in a surviving patient. Neurology 1971; 21: 633– 637. Caplan LR. Ptosis. J Neurol Neurosurg Psychiat 1974; 37: 1–7. Km JS, Lee JH, Lee MC. Syndromes of pontine basis infarction: a clinical-radiological correlation study. Stroke 1995; 26: 950–955 Adams RD. Occlusion of the anterior inferior cerebellar artery. Arch Neurol Psychiatry 1943; 49: 765–770. Amarenco P, Hauw J-J. Cerebellar infarction in the territory of the anterior and inferior cerebellar artery. Brain 1990; 113: 139–155. Amarenco P, Rosengart A, DeWitt LD, et al. Anterior inferior cerebellar artery territory infarcts. Mechanisms and clinical features. Arch Neurol 1993; 50: 154–161. Oas JG, Baloh RW. Vertigo and the anterior inferior cerebellar artery syndrome. Neurology 1992; 42: 2274– 2279. Kubik CS, Adams RD. Occlusion of basilar artery: a clinical and pathological study. Brain 1946; 69: 73–121 Ferbert A, Bruckmann H, Drummen R. Clinical features of proven basilar artery occlusion. Stroke 1990; 21: 1135–1142 Bassetti C, Bogousslavsky J, Barth A, Regli F. Isolated infarcts of the pons. Neurology 1996; 46: 165–175. Kataoka S, Hori A, Shirakawa T, Hirose G. Paramedian pontine infarction: neurological/topographical correlation. Stroke 1997; 28: 809–815. Kim JS, Bae YH. Pure or predominant sensory stroke due to brainstem lesion. Stroke 1998; 28: 1761–1764. Kim JS. Internuclear ophthalmoplegia as an isolated or predominant symptom of brainstem infarction. Neurology 62: 1491–1496, 2004 Caplan LR. Top of the basilar syndrome: selected clinical aspects. Neurology 1980; 30: 72–79. Mehler MF. The neuro-ophthalmologic spectrum of the rostral basilar artery syndrome. Arch Neurol 1988; 45: 966–971.
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63 Selhorst J, Hoyt W, Feinsod M, et al. Midbrain corectopia. Arch Neurol 1976; 33: 193–195. 64 Fisher CM. Oval pupils. Arch Neurol 1980; 37: 502–503. 65 Mills CK. Preliminary note on a new symptom complex due to a lesion of the cerebellum and cerebello-rubrothalamic system. The main symptoms being ataxia of the upper and lower extremities on one side, and on the other side deafness, paralysis of emotional expression in the face, and loss of the senses of pain, heat, and cold over the entire half of the body. J Nerv Ment Dis 1912; 39: 73–76. 66 Bogousslavsky J, Maeder P, Regli F, Meuli R. Pure midbrain infarction: clinical syndromes, MRI, and etiologic patterns. Neurology 1994; 44: 2032–2040. 67 Kim JS, Kim JY. Pure midbrain infarction: clinical, radiological and pathophyiological findings. Neurology 2005; 64: 1227–1232. 68 Davison C, Goodhart SP, Savitsky N. The syndrome of the superior cerebellar artery and its branches. Arch Neurol Psychiatry 1935; 33: 1143–1174. 69 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. 70 Amarenco P. Cerebellar stroke syndromes. In: Bogousslavsky J, Caplan LR (eds) Stroke syndromes. Cambridge: Cambridge University Press, 1996: pp. 344–357. 71 Lechtenberg R, Gilman S. Speech disorders in cerebellar disease. Ann Neurol 1978; 3: 285–290. 72 Caplan LR, DeWitt LD, Pessin MS, et al. Lateral thalamic infarcts. Arch Neurol 1988; 45: 959–964. 73 Hommel M, Besson G, Pollak P, et al. Hemiplegia in posterior cerebral artery occlusion. Neurology 1990; 40: 1496–1499. 74 Pessin MS, Kwan ES, DeWitt LD, et al. Posterior cerebral artery stenosis. Ann Neurol 1987; 21: 85–89. 75 Pessin MS, Lathi E, Cohen M, et al. Clinical features and mechanism of occipital infarction. Ann Neurology 1987; 21: 290–299. 76 Yammamoto Y, Georgiadis AL, Chang H-M, Caplan LR. Posterior Cerebral Artery territory infarcts in the New
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England Medical Center Posterior Circulation Registry. Arch Neurology 1999; 56: 824–832. Georgiadis AL, Yamamoto Y, Kwan ES, et al. Anatomy of sensory findings in patients with posterior cerebral artery (PCA) territory infarction. Arch Neurol 1999; 56: 835– 838. Caplan LR, Hedley-White T. Cueing and memory dysfunction in alexia without agraphia. Brain 1974; 97: 251– 262. Kertesz A, Sleppard A, MacKenzie R. Localization in transcortical sensory aphasia. Arch Neurol 1982; 39: 475–479. Victor M, Angevine J, Mancall E, et al. Memory loss with lesion of hippocampal formation. Arch Neurol 1961; 5: 244–263. Ferro JM, Martins IP. Memory loss in stroke syndromes, 2nd edn. In: Bogousslavsky J, Caplan LR (eds) Stroke Syndromes Cambridge: Cambridge University Press, 2001: pp. 242–251. Benson F, Marsden C, Meadows J. The amnestic syndrome of posterior cerebral artery occlusion. Acta Neurol Scand 1974; 50: 133–145. Damasio A, Damasio H, Van Hoesen G. Prosopagnosia: anatomic basis and behavioral mechanisms. Neurology 1982; 32: 331–341. Fisher CM. Disorientation to place. Arch Neurol 1982; 39: 33–36. Caplan LR. Posterior circulation ischemia: then, now, and tomorrow [The Thomas Willis Lecture – 2000] Stroke 2000; 31: 2011–2013. Caplan LR, Wityk RJ, Glass TA, et al. New England Medical Center Posterior Circulation Registry. Ann Neurol 2004; 56: 389–398. Caplan LR, Wityk RJ, Pazdera L, et al. New England Medical Center posterior circulation stroke registry: II. Vascular lesions. J Clin Neurol 2005; 1: 31– 49. Kim JS. Pure or predominantly sensory transient ischemic attacks associated with posterior cerebral artery stenosis. Cerebrovasc Dis 2002; 14: 136–138.
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Cognitive dysfunction, dementia and emotional disturbances Jae-Hong Lee, Alex E Roher, Thomas G Beach and Jong S Kim
Intracranial atherosclerosis and cognitive dysfunction Cognitive dysfunction in extracranial atherosclerosis Cognitive dysfunction is being increasingly recognized as an important symptom or sequelae of cerebrovascular disease. It is well known that extracranial carotid artery stenosis causes cognitive impairment or even dementia.1–3 According to a systematic review of 18 studies on cognitive deficits in patients with internal carotid artery (ICA) occlusive disease prior to surgery,4 14 studies showed that there were cognitive deficits in patients with symptomatic or asymptomatic ICA obstruction, whereas only four studies reported there was no significant cognitive dysfunction. In a cohort of over 1200 people with age ranging from 59 to 71 years, both poor attentional function and impaired performance on the mini-mental state examination (MMSE) were associated with the presence of carotid plaques, with a direct relationship between global cognitive impairment and carotid wall thickness.5 ICA atherosclerosis is often associated with chronic periventricular and/or deep subcortical white matter ischemic lesions6 and accompanying cerebral atrophy.7 These silent infarcts or cerebral atrophy may be related to a cognitive decline in patients who did not experience overt stroke syndromes.8 In patients without brain lesions, uncompensated, chronic hypoperfusion due to severe ICA disease seems to contribute to cognitive impairment as well. Cognitive impairment in these patients is generally global and diffuse in nature and mild or moderate in sever100
ity. Such a critical cerebral hypoperfusion may interact with age and even play a role in the development of Alzheimer’s pathology, further facilitating cognitive impairment and dementia.9 Amelioration of cognitive function is occasionally observed in patients who undergo carotid endarterectomy or stenting.10 However, peri-procedural complications such as embolism or hyperperfusion syndrome may aggravate cognitive dysfunction. The use of intraoperative shunting may be one of the factors for this complication by way of increasing the risk of microembolism and silent infarction.11 Finally, ICA stenosis may be one of the predictors for future cognitive impairment. The Cardiovascular Health Study showed that about one-third of patients with ICA stenosis developed a significant cognitive decline over 5 years of follow-up.12 Cognitive dysfunction in patients with intracranial atherosclerosis Unlike in extracranial ICA disease, there are few data on the impact of intracranial atherosclerosis (ICAS) on cognitive function. Nevertheless, it seems likely that ICAS is causally related to cognitive dysfunction through several pathophysiologic mechanisms, as in extracranial occlusive diseases. First, as discussed in Chapters 5 and 6, ICAS often produces deep subcortical infarcts by occluding the orifice of the deep perforators (i.e., lenticulostriate arteries). Even a small subcortical lesion may produce sudden, severe cognitive impairment. The best-known example of this so-called “strategic infarct dementia” is the capsular genu infarction that
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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frequently produces confusion, memory loss, and frontal lobe dysfunction. Functional brain imaging demonstrated ipsilaterally reduced perfusion in the frontal or temporal lobe, suggesting the functional disconnection of the cortical–subcortical pathway as a possible mechanism for cognitive impairment.13,14 An infarct occurring in the caudate nucleus is an another example. Patients with caudate infarction often show deficits in attention, memory, and frontal lobe function such as set shifting. Patients with dorsal caudate lesions are generally abulic, apathetic, and frontal lobish, whereas those with ventral caudate lesions tend to be more disinhibited, irritable, and euphoric.15 In clinical practice, we observe patients with abulia more often than those with euphoria.16 The cognitive impairment is more severe when the lesion is located on the left side, where aphasic symptoms may be superimposed. In addition, striatal or pallidal infarction can also produce significant cognitive impairments characterized by frontal–subcortical executive dysfunction, especially when the lesion is large. The involvement of the anterior limb of the internal capsule seems to be critical in this condition.17 Frontotemporal hypoperfusion has been demonstrated in these patients.18 Bilateral lesions produce more severe symptoms, sometimes mimicking akinetic mutism. Second, ICAS can develop cortical infarcts by way of artery-to-artery embolization or main trunk occlusion. Various cortical dysfunctions can be observed depending on the location or the side of the involved hemisphere, such as dysphasia, acalculia, dyspraxia, or neglect. Although these symptoms are not categorized as dementia, cognitive decline on more broad dimensions can be caused by a combined effect of multiple or recurrent strokes. Clinically silent cortical infarcts may also contribute to the cognitive decline. A single infarction in the anterior cerebral artery (ACA) territory or in the medial temporal lobe may cause severe frontal executive dysfunction and memory loss, respectively, especially when the lesion is located on the left side. Third, severe ICAS can produce chronic cerebral hypoperfusion. In this condition, silent, small infarcts may develop in the borderzone area, which is often unnoticed clinically. As in carotid artery disease, these silent lesions contribute to cognitive decline. Moreover, diminished cerebral perfusion may lead to regional cerebral dysfunction even in the absence of a structural lesion. The role of perfusion failure on cog-
nitive dysfunction in patients with ICAS has not been firmly established, but can be inferred from observing the efficacy of EC/IC bypass surgery for cognitive function. Since 1974, it has been suggested that bypass surgery will improve the cognitive function of the patients.19 However, studies investigating this issue with the use of appropriate neuropsychological tests are uncommon and have shown controversial results. For instance, Binder et al.20 observed improved cognitive function in patients undergoing bypass surgery, which, however, was not significantly different from that observed in medically treated patients. Younkin et al.21 studied 44 patients who had undergone bypass surgery, and observed a significant cognitive improvement along with an improvement of cerebral blood flow. However, the possibility of natural improvement could not be ruled out in the absence of control subjects. The study by Nielsen et al.22 seems to provide more reliable evidence on the relationship between cognitive impairment and ICAS. They performed neuropsychological tests in 12 patients who presented with transient ischemic attacks (TIAs). The majority (n = 8) had ICAS (intracranial ICA or MCA stenosis). Preoperatively, the patients showed cognitive dysfunction characterized by impaired visuomotor function, immediate visual recall, visual learning, general knowledge, and mental arithmetic tests compared with age- and sex-matched control subjects. Three months after the bypass surgery, the cognitive function in the patients had significantly improved compared with the preoperative states, albeit not to the level of normal, control subjects. More recently, Sasoh et al.23 studied 25 patients with occlusive vascular disease who had undergone EC/IC bypass surgery. There were 13 patients with ICA occlusion and 12 with MCA occlusion. Fifteen were neurologically normal preoperatively. Cognitive function was assessed using the Japanese Wechsler Adult Intelligence Scale 2 weeks before surgery and 6 months postoperatively. Preoperatively, the level of cognitive function, either verbal or performance IQ, was significantly lower in patients than in control subjects. There was a significant improvement in cognitive function after the surgery, although postoperative cognitive function was still somewhat poorer than in control subjects. They also demonstrated that cognitive impairment was closely related to the presence of an elevated regional oxygen extraction fraction (rOEF) 101
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detected by positron emission tomography (PET). On the basis of these observations, they hypothesized that, in the presence of misery perfusion, patients would be unable to increase cerebral blood flow and metabolism further in response to the increased metabolic demand from complex tasks, which may manifest clinically as cognitive dysfunction. The relationship between cognitive dysfunction and cerebral hypoperfusion due to ICAS can also be inferred from studies on moyamoya disease, a progressive vasculo-occlusive disorder involving the intracranial ICA/or proximal MCA and ACA (see Chapter 20). According to studies from Japan, the intelligence of affected children declined after the onset of moyamoya disease probably due to long-standing, uncompensated cerebral hypoperfusion.24,25 Hogan et al.26 showed that moyamoya syndrome may be associated with intellectual decline in a Western population as well. A report of a preoperative longitudinal study showed that 16 out of 27 children with moyamoya disease had a lower full-scale IQ than the baseline at follow-up.27 According to unpublished data from South Korea, patients with moyamoya syndrome showed impairments in executive function and visuoconstructive skills with relatively spared verbal memory, reflecting interruption of frontostriatal circuitry. In patients with moyamoya disease, the cognitive decline may be caused by underlying chronic hypoperfusion, silent ischemic lesions, or the combination of both. The role of perfusion failure on cognitive function can be inferred from a report describing a woman with moyamoya syndrome who had experienced right hemispheric stroke.28 She showed a remarkable improvement in her cognitive deficit after unilateral EC– IC bypass surgery to augment perfusion in the cerebral hemisphere. Prior to surgery, her performance of tasks involving right hemispheric functions, such as visuospatial perception, organization, and construction, was markedly impaired. The postoperative neuropsychological assessment showed that these functions had improved to almost normal levels. In addition, verbal learning and delayed recall performances improved dramatically as well. These were believed to be mediated by the left hemisphere, unrelated to the original right hemispheric stroke. This observation suggests that perfusion augmentation following surgical revascularization may result in cognitive improvement beyond focal regions of established ischemia. 102
Summary The accumulated data suggest that cognitive impairment is present in patients with ICAS, and is attributed to subcortical infarcts in the strategic areas or multiple, sometimes silent, ischemic lesions, or uncompensated, chronic hypoperfusion. Indeed, according to a study from Hong Kong, China,29 patients with subcortical infarction due to MCA atherosclerotic disease had a tendency to have a lower MMSE score than those without. However, in that study, multiple infarcts were more common in patients with ICAS than in those without, and the more severe cognitive dysfunction may therefore be attributed to greater brain damage rather than to the presence of ICAS itself. Further studies are warranted to elucidate to what extent vascular cognitive impairments are related to the location or amount of infarcted tissue or cerebral hypoperfusion, and to establish reasonable therapeutic approaches for cognitive impairment in patients with ICAS. As discussed in Chapter 15, transluminal angioplasty and stenting has recently been developed to treat ICAS. In a retrospective series, soft neurologic findings, such as word-finding difficulties that were presumably related to cerebral hypoperfusion, improved after angioplasty and stenting in some patients.30 With the wide availability of these therapeutic procedures, cognitive function in patients with ICAS should be closely monitored so that intervention can be used as a potential strategy to improve cognitive dysfunction in these patients.
Intracranial atherosclerosis and Alzheimer’s disease The literature has shown a close relationship between Alzheimer’s disease (AD) and cardiovascular diseases such as myocardial infarction, critical coronary artery disease, cardiac arrest, and atherosclerosis of ICA. Vascular risk factors such as hypertension, hypercholesterolemia, hyperhomocysteinemia, and diabetes also represent definite risk factors for dementia.31 Patients with AD have higher levels of plasma cholesterol than non-demented (ND) age- and gender-matched control individuals. Amyloid-beta (Aβ) 42, the peptide that accumulates in the brains of AD subjects, is positively correlated with total serum cholesterol and
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apolipoprotein B100 and negatively correlated with HDL levels.32 It has been well established that severe hypoperfusion of the brain is prevalent in AD, which is suggestive of the presence of a significant amount of ischemia/hypoxia. The sum of the blood flow through the carotids and basilar arteries, as measured by phase-contrast MRI, was significantly decreased (443 mL/minute) in patients with AD than in a ND age-matched cohort (551 mL/minute).33 The total cerebral blood flow evaluated by Duplex ultrasound of the carotids and vertebral arteries was lower in AD (475 mL/minute) than in ND controls (744 mL/minute).34 These pieces of evidence suggest a direct causal or additive association between cerebral atherosclerotic vascular disease and AD. However, the role of cerebral artery pathology in the pathophysiology of AD has long been controversial.35 Moreover, in most of the previous studies, the arteries of the circle of Willis were not evaluated precisely or appropriate statistical analyses were lacking.36 Thus, the relationship between ICAS and AD has remained unclear until recently. Pathological study results supporting the relationship In order to determine potential associations between atherosclerotic vascular disease of the circle of Willis and the AD pathology, Roher et al.31 performed computer-assisted vessel measurements to calculate the stenosis index of the intracranial arteries from 54 consecutive autopsies: 22 ND control individuals with a mean age of 85.5 years and 32 AD subjects with a mean age of 85.2 years. A total of almost 1000 cross-sections from the circle of Willis were microscopically examined, including the anterior communicating artery, basilar artery, ACA, ICA, MCA, posterior cerebral artery (PCA), posterior communicating arteries, and vertebral arteries. The stenosis index was calculated by subtracting the luminal area from the outer area, dividing the difference by the outer area and multiplying the quotient by 100. Figure 8.1 shows contrasting examples of the degrees of atherosclerosis occurring in AD and ND control arteries. In the autopsy-confirmed AD cases, 22% of the examined arteries were 80% occluded, whereas in the ND group only 4.5% were as extensively blocked ( p < 0.001). Moreover, in AD, 3.6% vs 1.1% of the
Fig 8.1 Cross-sections of the circle of Willis arteries. (A) Arteries from the control non-demented individuals. (B) Arteries from Alzheimer’s disease subjects showing advanced atherosclerotic plaques with a significant degree of stenoses and total occlusion in some instances. In both A and B, the arteries also demonstrate a variable degree or arteriosclerosis.
ND cases arteries were totally occluded. In the ND population, 73% of the subjects had more than 50% stenosis, 23% had greater than 60% stenosis, and none exhibited stenoses greater than 70%. By contrast, in the AD cohort, 97% of the subjects had more than 50% stenosis, 81% had greater than 60% stenosis, and in 38% the extent of stenosis was greater than 70%. When each of the arteries was considered independently, the difference between AD and ND was also significant. The degree of cerebral hypoperfusion is directly proportional both to the number of stenoses along the intracranial arterial path and to the overall degree of stenosis revealed by the severity of arterial atherosclerosis. In patients with AD, the intracranial arterial stenosis positively and directly correlated with the degree of AD neuropathology that included the total plaque score, neurofibrillary tangle (NFT) score, The Consortium to Establish a Registry for Alzheimer’s Disease neuritic plaque 103
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score, Braak stage score, and white matter rarefaction score.31 Severe atherosclerotic vascular disease is not only confined to the circle of Willis arteries, but in many cases it continues into the leptomeningeal arteries such as the ACA, MCA, PCA, and their major branches,37 adding to brain hypoperfusion and promoting cerebral infarcts and dementia. In this study, the major leptomeningeal arteries from 10 AD cases (7 female and 3 male patients; average age, 89.7 and 83.6 years, respectively) and 10 ND control subjects (7 female and 3 male individuals; average age, 87.6 and 84.7 years, respectively) were dissected and fixed. More than 600 cross-sections were electronically measured to obtain their indices of stenosis. In the AD cases, the leptomeningeal arteries demonstrated an average of 75% occlusion, whereas in the ND control cohort the mean extent of occlusion was only 44% ( p < 0.00001). The major cause of occlusion was clearly due to the extensive deposition of atheroma plaque. Some atheroma plaques were almost continuous along the total length of the artery and, in some occasions, totally blocked the artery. As in the case of the arteries of the circle of Willis, there was a positive correlation between the severity of the leptomeningeal atherosclerosis and the total plaque score, NFT score, Braak stage, CERAD neuritic plaque score, white matter rarefaction, and the total number of stenoses.37 In another study, postmortem gross anatomical grading of circle of Willis atherosclerosis was performed in 397 subjects classified by neuropathological assessment, including 92 ND elderly control subjects, 215 with AD, 30 with vascular dementia (VaD), and 60 with non-AD dementias.38 The diagnosis of VaD was made neuropathologically according to the National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurosciences criteria,40 and the patients with VaD comprised 23 cases with a coexistent neuropathologic diagnosis of AD and 7 “pure” VaD cases. All non-AD dementia cases had clinically established dementia and included 29 cases with Parkinson’s disease, 10 with progressive supranuclear palsy, 4 with hippocampal sclerosis, 3 with dementia lacking distinctive histology, 3 with dementia with Lewy bodies, 3 with argyrophilic brains, 3 with multiple system atrophy, 2 with motor neuron disease, and 1 each with Huntington’s disease, cerebral tauopathy due to tau mutation, and non-specific, sporadic 104
tauopathy. Circle of Willis atherosclerosis was graded by gross visual inspection. The extent of atheromatous involvement was rated as none, mild, moderate, or severe. The method was validated by comparison with detailed cross-sectional measurements of arterial lumen narrowing, performed on 54 cases as mentioned above. The diagnostic groups differed significantly from each other in terms of the circle of Willis atherosclerosis score. The AD group had significantly higher mean circle of Willis scores than the nonAD dementia and control groups, whereas the VaD group had significantly higher scores than all the other groups. Severe circle of Willis atherosclerosis was most common in the VaD group (53%), followed by the AD cases (34%) and the ND control and non-AD dementia groups (both 18%). In addition, the atherosclerosis scores from the AD, VaD, and non-AD dementia groups were each compared with those of the ND control group to derive odds ratios for the diagnosis of each disease, based on increasing circle of Willis atherosclerosis grade. The results were adjusted for age, gender, and the presence of the apolipoprotein E (apoE) ε4 allele. The circle of Willis atherosclerosis score was not a significant predictor for the diagnosis of non-AD dementia but did predict the diagnoses of both AD and VaD, with increased odds ratios (ORs) of 1.31 (95% CI 1.04– 1.69) and 2.50 (95% CI 1.52–4.10), respectively, for each corresponding unit of increase in circle of Willis grade. Moreover, increasing circle of Willis atherosclerosis was associated with an increased likelihood for higher neuritic plaque scores and Braak neurofibrillary stages, with ORs ranging between 1.13 and 1.36 for each unit increase in the atherosclerosis score. Both the diagnosis and characteristic histopathologic lesions of AD were significantly associated with circle of Willis atherosclerosis. The results suggest that the statistical association between ICAS and AD is not an artifact from diagnostic misclassification or from unequal distribution of the apoE ε4 allele. An increase in the atherosclerosis score from 0 to 3 would be associated with a 3.9-fold increased likelihood for the presence of AD. This is similar to the risk associated with a single apoE ε4 allele. Additional data supporting the role of atherosclerosis in AD have also been provided by the National Alzheimer’s Coordination Center. Clinical and neuropathological data concerning 1054 subjects (921 AD and 133 ND cases) indicated that atherosclerosis
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of the circle of Willis scores correlated with a higher degree of neuritic plaque scores (OR of 5.8 for severe score; p < 0.0001, adjusted for age and gender).40 Further confirmation of the potential role of atherosclerosis in AD was recently provided by the Asia-Honolulu Aging Study.41 In this study, decreased cross-sectional luminal areas of circle of Willis arteries were significantly correlated with the number of neuritic plaques and vascular amyloid. Transcranial Doppler ultrasonography studies The relationship between ICAS and AD was also deducted from transcranial Doppler (TCD) studies. Roher et al.36 examined the status of the arteries of the circle of Willis in living patients by means of TCD. In this study, 25 AD patients (13 female and 12 male patients; average age, 79.1 years; MMSE score, 22.5) and 30 ND elderly control subjects (18 female and 12 male individuals; average age, 80.6 years; MMSE score, 29.6) were assessed for the mean flow velocity (MFV) and mean pulsatility index (PI), a measurement of the degree of arterial rigidity, of the right and left intracranial arterial segments. The insonated arteries comprised the proximal and distal MCA, ACA, PCA, carotid siphons, ICA, vertebral arteries, and the proximal and distal segments of the basilar artery. In the AD patients, the MFV was decreased in 13 out of the 16 insonated segments, albeit without a statistical significance ( p = 0.22), whereas the PI was elevated in 15 of the 16 arterial segments ( p = 0.005). The average systolic pressure was higher in the ND cohort than in the AD group (134 vs 123 mm Hg, p = 0.011). When corrected for pharmacological treatment for hypertension, the difference between the ND and the AD groups remained statistically significant ( p = 0.03). The diastolic pressure was also low in the AD group compared with the ND cohort, but the difference was not statistically significant. Other important correlations indicated that the PI increases and the MFV decreases with age. In the course of the TCD studies, other important and previously uncovered cardiovascular abnormalities common in the elderly population were observed, including spontaneous emboli, hypoplastic arteries, arterial occlusions with flow diversions, bruits, severe arterial stenoses, atrial fibrillation, atrioventricular block, irregular heart rate, tachycardia, and subclavian steal. Remarkably, all these cardiovascular alterations are potentially capa-
ble of modifying the ejection fraction or decreasing the blood flow to the brain causing chronic cerebral hypoperfusion and loss of memory. Summary Atherosclerosis of the cerebral arteries is more severe in AD patients than in ND age-matched control subjects. Clinical, experimental, and epidemiological data have demonstrated that chronic and escalating brain hypoperfusion underlies dementia. Although the “amyloid cascade” hypothesis may be central to the pathophysiology of AD, it is not necessarily the sole instigator of AD pathogenesis. Instead, sporadic AD and occlusive arterial disease may have synergistic or interdependent relationships. The presence of soluble and insoluble Aβ peptide pools in AD may be the consequence of brain hypoperfusion, hypoxia,42 and blood– brain barrier disruption.43,44 Vascular inflammation has an important role in the development of both atherosclerosis and vascular amyloidosis in AD. The clinical and pathological consequences of atherosclerosis have proven to be addressable by lifestyle modifications and pharmacological therapy. Whether the relationship between ICAS and AD is causal or additive, it seems reasonable to postulate that these therapies may also delay the clinical appearance and progression of AD.
Depression and other emotional disturbances in intracranial atherosclerosis Depression There is a complex relationship between depression and stroke; stroke may cause, predispose to, or perpetuate depressive disorders, whereas depression, in turn, has been shown to be a risk factor for stroke.45 Post-stroke depression The prevalence of post-stroke depression (PSD) has been reported to range from 12 to 64%.46–59 The wide variation in the frequency may be related to methodological heterogeneity regarding the criteria for depression, the timing of assessment, and the sampled population. There has been intense controversy regarding the relationship between PSD and the location of stroke. Although the importance of left-sided brain lesion in producing depression has been emphasized by Robinson’s group,46,60–64 studies showing opposite 105
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results have also been published.54,55,65 Other reports,52,57,66,67 including a meta-analysis,68 suggest that PSD is not related to a specific location of the brain. However, a review of MRI-based studies found that lesions involving left prefrontosubcortical circuits were mainly associated with PSD.69 Moreover, a recent report70 illustrated that the association between left anterior lesion and PSD is stronger in acute, admitted patients than in chronic patients recruited from the community. Thus, the left frontosubcortical area seems to be an important structural basis of PSD. The importance of subcortical structures of the anterior circulation such as the caudate, putamen, or pallidum in producing PSD has also been stressed in the literature.62,63,69 According to Cummings,71 these lesions may produce depressive symptoms by way of disrupting the prefrontosubcortical circuits or their projections, which participate in controlling emotion and behavior. The ischemic lesions occurring in the anterior subcortical structures, either symptomatic or asymptomatic, are also important determinants for late-onset depression.72 Based on this observation, a so-called “vascular depression hypothesis” has been addressed.73 Literatures have shown that patients with late-onset depression more often have vascular risk factors,74 cognitive dysfunction,75 and neuroradiologic abnormalities72,76 than those with early-onset depression. The brain lesions in these patients are generally considered to be caused by small vessel occlusive diseases.77 However, in the studied population, large cerebral vessels, especially intracranial large arteries, have been investigated rarely. Thus, the role of large cerebral artery atherosclerosis in the development of late-onset depression remains less clear. Depression and cerebral atherosclerosis Recently, there have been suggestions that large cerebral vessel atherosclerosis is closely related to latelife depression. Studies have shown that depression is closely associated with intimamedial thickness (IMT) or carotid plaque assessed by Doppler studies in elderly subjects.78–80 A recent community-based study has provided a more solid line of evidence on this argument; Tiemeier et al.81 assessed IMT of the common carotid artery, ankle brachial blood pressure index, and aortic atherosclerosis in 4019 subjects, and found that depression was closely associated with more severe atherosclerosis. In addition, Thomas et al.82 stud106
ied postmortem findings of 20 patients with a history of depression and 20 control subjects, and demonstrated a close association of depression with atheromatous vascular diseases. These series of observations are not mutually independent of the aforementioned findings that silent, small ischemic lesions are importantly linked to late-life depression. Bots et al.83 studied the association of white matter ischemic lesions and the carotid IMT in subjects recruited from the Rotterdam study, and found that IMT thickness and atherosclerotic plaques were significantly greater in subjects with white matter lesions than in those without; an increase of 0.1 mm in the wall thickness was associated with a 50% increase in the probability of white matter lesions. Although the causal relationship between white matter lesions and cerebral artherosclerosis remains uncertain, cerebral atherosclerosis might lead to late-life depression by way of producing ischemic lesions in the frontal subcortical area. In addition, large vessel atherosclerosis may produce depression by way of inducing severe cerebral perfusion defect. This argument may be supported by a recent study result that demonstrated improvement of depressive symptoms along with improved perfusion after stenting procedures in patients with severe carotid atherosclerosis.84 However, the cause–effect relationship between depression and cerebral atherosclerosis has not always been clear, since depression may be the cause rather than the result of atherosclerosis. It has been shown that depression plays a role as a risk factor of vascular disease, with the possible links being altered platelet activation, cardiac arrhythmia, enhanced inflammatory process, and noradrenergic hyperactivity in depressive persons.85–87 Moreover, depressionrelated behavior may render the subject vulnerable to vascular diseases, which includes the lack of exercise, poor adherence to medical treatment, lack of enthusiasm in controlling risk factors such as cigarette smoking or alcohol drinking, etc. Considering all these facts, it seems reasonable to assume that the causal pathway between depression and cerebral atherosclerosis is bidirectional. Depression and intracranial atherosclerosis Unfortunately, previous studies did not specifically investigate the association between ICAS and depression. Moreover, the study subjects included in autopsy and Doppler studies were usually Caucasians in whom
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ICAS is uncommon. Therefore, the role of ICAS in late-life depression is still unknown. However, given the aforementioned fact that frontosubcortical vascular lesions are an important structural base of PSD or late-onset depression and that ICAS is an important cause of subcortical infarction, at least in Asian countries (see Chapter 6), ICAS, especially that occurring in the anterior circulation, is likely to contribute to PSD or late-life depression. Recent community-based studies have provided data supporting this argument. As a part of the Rotterdam epidemiologic study, Tiemeier et al.88 studied blood flow velocity of the MCA and CO2 -induced vasomotor reactivity in 2093 subjects. Depression was diagnosed by the Dutch version of the original Center for Epidemiology Studies Depression scale (CES-D) with a cut off-score of ≥16. The Dutch version of the present state examination (PSE-10) and DSM-IV criteria were also applied. A total of 116 subjects (5.5%) were screened positive for depression as measured by CES, and 111 of them underwent psychiatric work. A depressive disorder as defined by the DSM-IV criteria was established in 42 cases, eight were considered to have other psychiatric disorders, and the remainder (n = 61) were considered to have “subthreshold depressive disorder.” The authors found that subjects with depressive symptoms had significantly reduced blood flow velocities and lower vasomotor reactivity than those without depression. The blood flow velocity was reduced mostly in subjects suffering from a DSM-IV depressive disorder, whereas the overall reduction in the vasomotor reactivity was accounted for by subjects with subthreshold depressive disorder. In a subsequent study, the authors reported that arterial stiffness was also related to latelife depression.89 Again, interpretation of these results should be made with caution, since depression may be the cause of the vascular changes, and the decreased blood flow may simply reflect the diminished cognitive demand in the depressive state. Nevertheless, considering the importance of frontal subcortical ischemic lesions as an organic basis of depression and the importance of ICAS as a cause of ischemic lesions occurring in this area, ICAS seems to play a role in PSD or late-life depression. The results from a recent study on blood flow also support this possibility. Certainly, further studies are needed to elucidate more clearly the relationship between ICAS and depression.
Emotional disturbances other than depression Emotional incontinence In 1923, Wilson used a term “pathological laughing and crying” in describing uncontrollable outbursts of emotion characterized by “exaggerated, forced, uncontrollable, spasmodic, and unrelated with true emotion”.90 Although the term has been used until recently,91–93 others favor terms such as “emotionalism,”94 “lability of mood,”95,96 or emotional incontinence97–100 to include milder forms of emotional disturbances. Patients suffering from post-stroke emotional incontinence (PSEI) are not necessarily depressed or elated during their emotional display. PSEI is usually evoked by certain social or emotional triggering, such as when the patient suddenly encounters a person or undergoes neurologic tests. In severe cases, the emotional response is quite incongruous with the situation: the patient may laugh during a funeral ceremony. Usually, patients more often cry than laugh but may cry and laugh alternately. PSEI may start at the onset of stroke,101 but more often manifests itself weeks or months after the stroke.92,98 PSEI occurs more frequently and more severely in patients with bilateral or diffuse ischemic strokes.90, However, careful examination reveals that mild PSEI is not uncommon in unilateral stroke.98 Autopsy102 and imaging92,94,98,99,101 studies have shown that strokes occurring in the basal ganglia or pontine base frequently produce PSEI, although cortical strokes, especially those occurring in the anterior frontal area, are also related to PSEI.98 According to Kim and Choi-Kwon,98 the location of the lesions related to PSEI is similar to that related to PSD, but seems to be related more closely to subcortical structures such as the basal ganglia or pontine base. Although the relationship between ICAS and PSEI has rarely been investigated, the association may be strong when considering the important role of ICAS in producing subcortical infarction. The prevalence of PSEI has been shown to be 15– 20%.94,95 In a study from Korea, the prevalence of PSEI assessed at approximately 3 months after stroke was 34%, which was even higher than that of PSD.98 One of the reasons for the differences in prevalence is the different criteria of PSEI used in each study. For instance, a study from Hong Kong, China, showed that the prevalence of PSEI at 3 months after stroke 107
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onset was 17.9% when Kim’s criteria were applied, whereas it was 6.3% when the more strictly defined House criteria were used.100 Another explanation is the relatively high prevalence ICAS and consequent subcortical lesions in Asian populations. As for the mechanism of pathological laughter or crying, Wilson90 proposed disinhibition of the laughing/crying center at the brainstem from the cortex due to the presence of subcortical lesions, which would release inappropriate emotional responses. In addition, there is ample evidence that PSEI is closely related to serotonin system dysfunction; studies have shown that selective serotonin re-uptake inhibitors (SSRI) improve PSEI.97,103,104 Perhaps, SSRI either attenuates an emotional trigger in these patients or improves dysfunctional serotonergic pathways that destabilized the input sent from the basotemporal limbic cortex to the amygdala and the lateral limbic circuit. Anger proneness Patients showing overt outbursts of anger after stroke are rarely observed.105 On the other hand, if carefully examined, more subtle symptoms such as increased irritability, intolerability, loss of generosity and an inability to control anger are much more prevalent. Kim et al.106 prospectively studied 145 patients (97 men and 48 women; mean age, 60 years) with single, unilateral stroke at 3–12 months post stroke. The poststroke anger proneness (PSAP) or inability to control anger or aggression was assessed by a standardized interview using the 10-item Spielberger Trait Anger Scale. They found that as many as 47 patients (32%) were prone to anger, either evoked after trivial provocation or spontaneous. Interestingly, PSAP was closely correlated with the presence of PSEI but not PSD. The lesion distribution was also very similar; both PSAP and PSEI were closely associated with the lesions affecting the anterior frontal lobe, lenticulocapsular area, and the pontine base, but not parietal, medullary, or cerebellar regions. In other words, patients with lenticulocapsular or pontine strokes often had both PSAP and PSEI. Similar to PSEI, PSAP dramatically improves after fluoxetine treatment.104 Thus, PSAP may be a spectrum of neuropsychological manifestations related to serotonergic system dysfunction along with PSEI. As is the case with depression, the causal pathway between anger proneness and vascular disease 108
seems to be bidirectional. It has been shown that anger proneness is closely associated with peripheral arterial atherosclerotic disease.107 Anger108 or A-type behavior (tenseness trait)109 has been shown to play a role as a risk factor for carotid atherosclerosis and atherosclerotic subtype of ischemic stroke, respectively. Panic disorders There is evidence showing that abnormalities in the autonomic dysregulation of intracranial artery are related to anxiety or panic disorder. Using TCD, Faravelli et al.110 studied the mean flow velocity of the MCA during a 70◦ tilting-table test in three groups: 11 patients with a diagnosis of panic disorder, 9 patients asymptomatic (at least for 6 months) for panic disorders, and 10 normal control subjects. They found that both patients with acute panic disorder and those with remitted disorder showed a greater reduction of mean flow velocity compared with normal subjects. Other investigators111,112 showed that patients with panic disorder had a greater reduction in flow rates of the basilar artery after hyperventilation. These studies do not necessarily imply that ICAS is related to panic disorder, but suggest that autonomic dysregulation of intracranial arteries may be a trait marker of panic disorder. Summary and conclusions Emotional disturbances such as depression are important, yet frequently overlooked complications of stroke. They adversely influence physical and cognitive function and decrease the quality of life of patients as well as caregivers.113 The literature has provided evidence that cerebrovascular diseases, sometimes asymptomatic ones, are closely related to latelife depression. Depression in turn is associated with cognitive impairment,114 vascular dementia, or even AD.115 Considering the importance of frontotemporal basal ganglionic circuitry in regulating emotions and fontal executive functions, ICAS seems to contribute to both depression and cognitive dysfunction especially in elderly subjects. In addition, a series of studies by Roher et al.31,37 has elegantly demonstrated that ICAS is closely related to AD. There has been a dramatic change in life expectancy during the last 100 years. In 1900, the average life expectancy was about 48 years, whereas in 2007 it is almost 80 years in developed countries. Prolonged
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life-span and lifestyle changes have definitely increased atherosclerotic as well as degenerative brain diseases. The consequent cognitive and emotional disturbances in an aged population are nowadays prevalent, and their impact on our society is already enormous. The impact will be even greater in the future with increasing life expectancy. As has been discussed, emotional disturbances, cognitive changes, and dementia are closely interrelated phenomena, and the degenerative and atherosclerotic processes appear to be mutually synergistic. Future studies should be aimed to elucidate more clearly the nature of the complex link connecting these disorders. The efficacy of preventive or therapeutic strategies for cerebrovascular diseases such as lifestyle modifications, antithrombotic agents, angioplasty/stenting, and bypass surgery on cognitive or emotional disturbances should be investigated. In addition, since emotional disturbances are one of the most readily treatable conditions, it should also be determined whether therapeutic trials targeting the emotional disorders can intervene this pathologic link and improve vascular and cognitive impairment.
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102 Poeck K. Pathological laughter and crying. In: Vinken PJ, Bruyn GW, Klawans HL (eds) Handbook of neurology, vol. 45 Amsterdam: Elsevier, 1985: pp. 219–225. 103 Derex L, Ostrowsy K, Nighoghossian N, Trouillas P. Severe pathological crying after left anterior choroidal artery infarct: reversibility with paroxitine treatment. Stroke 1997; 28: 1464–1466. 104 Choi-Kwon S, Han SW, Kwon SU, Kang DW, Choi JM, Kim JS. Fluoxetine treatment in post-stroke depression, emotional incontinence and anger-proneness: a double-blind placebo-controlled study Stroke 37; 156– 161, 2006. 105 Paradiso S, Robinson RG, Arndt S. Self-reported aggressive behavior in patients with stroke. J Nerv Ment Dis 1996; 184: 746–753. 106 Kim JS, Choi-Kwon S, Kwon SU, Seo YS. Inability to control anger or aggression after stroke. Neurology 2002; 58: 1106–1108. 107 Wattanakit K, Williams JE, Schreiner PJ, et al. Association of anger proneness, depression and low social support with peripheral arterial disease: the Atherosclerosis Risk in Communities Study. Vascular Medicine 2005; 10: 199–206. 108 Matsumoto Y, Uyama O, Shimizu S, et al. Do anger and aggression affect carotid atherosclerosis? Stroke 1993; 24: 983–986. 109 Kim JS, Yoon SS, Lee SI, et al. Type A behavior and stroke : high tenseness dimension may be risk factor for cerebral infarction. Eur Neurol 1998; 39: 168–173. 110 Faravelli C, Marinoni M, Spiti R, et al. Abnormal brain hemodynamic responses during passive orthostatic challenge in panic disorder. Am J Psychiatry 1997; 154: 378– 383. 111 Gibbs DM. Hyperventilation induced cerebral ischemia in panic disorder and effect of nimodipine. Am J Psychiatry 1992; 149: 1589–1591. 112 Ball S, Shekhar A. Basilar artery response to hyperventilation in panic disorder. Am J Psychiatry 1997; 154: 1603–1604. 113 Choi-Kwon S, Kim HS, Kwon SU, Kim JS. Factors affecting the burden on caregivers of stroke survivors in Seoul, South Korea. Arch Phy Med Rehab 2005; 86: 1043–1048. 114 Ownby RL, Crocco E, Acevedo A, et al. Depression and risk for Alzheimer disease. Arch Gen Psychiatry 2006; 63: 530–538. 115 Barnes DE, Alexopoulos GS, Lopez OL, Williamson JD, Yaffe K. Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study. Arch Gen Psychiatry 2006; 63: 273–279.
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Natural course and prognosis Juan F Arenillas, Louis R Caplan and KS Lawrence Wong
Atherosclerosis is a systemic, chronic and dynamic disease characterized by the genesis, progression, and complication of atherosclerotic vessels.1 Unfortunately, atherosclerotic lesions become clinically expressive abruptly, unexpectedly, and often provoke dramatic consequences for patients. Therefore, rational preventive strategies should attempt to identify and evaluate the risk of atherosclerotic plaques to become symptomatic in each patient, and to therapeutically target the basic mechanisms involved in the progression and complication of these lesions. Although the process of atherogenesis may share common mechanisms across diverse arterial territories, there are important regional differences regarding the relative contribution of basic mechanisms to the progression and complication of atherosclerotic plaques.2 Atherosclerosis in intracranial arteries has unique characteristics related to the anatomical and hemodynamic peculiarities of the intracranial arterial system, reviewed elsewhere in this book.3 For instance, intracranial arteries are extraordinarily sensitive to the loss of antioxidant capacity and to oxidative stress.4 Therefore, specific research may be needed to elucidate to what extent the molecular pathways implicated in the development of extracranial atherosclerosis are also involved in the progression of intracranial artery atherosclerosis (ICAS). The diagnosis of ICAS was traditionally dependent on conventional angiography, still considered the gold standard for its detection.5,6 In the last decades, several reliable non-invasive diagnostic methods have been developed, including transcranial Doppler ultrasound (TCD),7,8 transcranial color duplex (TCCD),9 magnetic resonance angiography (MRA),10,11 and com-
puted tomography angiography.12 With these techniques, evaluation of the status of intracranial arteries has become much easier nowadays. However, these are still expensive and not widely available especially in developing countries where high prevalence of ICAS is expected. Moreover, imaging diagnosis of ICAS is based on the detection of arterial stenosis rather than the wall itself, and is therefore restricted to an advanced stage of the disease. Another major diagnostic problem of ICAS derives from the fact that none of these imaging techniques provides information regarding the histopathological nature of the lesion responsible for arterial narrowing. Although atherosclerosis may be the most frequent cause of intracranial stenosis, many different entities are able to produce stenoses affecting intracranial large arteries, as described in Chapters 18, 19 and 20. Further references to intracranial stenosis in this chapter will be restricted to stenoses caused by intracranial atherosclerosis. After reviewing these conceptual premises, we will dedicate the rest of this chapter to summarizing the updated knowledge about the natural course of ICAS and about its main prognostic factors.
Natural course of intracranial atherosclerosis ICAS is a major cause of ischemic stroke worldwide,13–16 as has been reviewed in Chapter 3. Like atherosclerosis occurring elsewhere, atherosclerotic lesions in intracranial vessels develop silently over the years before they give rise to clinical symptoms.17–19 However, the natural history of asymptomatic ICAS
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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is still poorly understood, and population-based studies addressing the prognostic impact of asymptomatic ICAS are lacking. Here we will focus on the main features that characterize the natural history of this disease once it has become symptomatic. Risk of clinical recurrence in symptomatic intracranial atherosclerosis Symptomatic ICAS is burdened with a high risk of clinical recurrence. The recurrence risk is especially high during the first days, weeks, and months after the initial clinical episode.20 The risk of having a subsequent ischemic stroke in the territory of a symptomatic stenosis varies depending on its location. Patients with a first-ever symptomatic intracranial internal carotid artery (ICA) stenosis have an annual recurrence risk rate around 8% for an ischemic stroke affecting the stenosed artery territory and between 4 and 12% for any ischemic stroke.21–23 Regarding symptomatic middle cerebral artery (MCA) stenosis, the annual recurrence risk observed among patients included in the medical arm of the Extracranial/Intracranial Bypass Study was 7.8% for an ischemic stroke within the stenosed MCA territory and 9.5% for any ischemic stroke.24 Finally, the retrospective Warfarin– Aspirin Symptomatic Intracranial Disease (WASID) study group showed that clinical recurrence rates in patients with symptomatic intracranial stenoses affecting the vertebrobasilar territory are also high.25 The reported annual risk of having a new ischemic stroke within the territory of the stenosed artery was 10.7% for symptomatic basilar artery stenoses, 7.8% for symptomatic intracranial vertebral artery stenoses, and 6% for symptomatic posterior cerebral artery (PCA) stenoses. The annual recurrence rate for a new ischemic stroke involving any cerebrovascular territory in patients with symptomatic basilar artery, vertebral artery or PCA stenoses was 15%, 13.7%, and 6%, respectively. The WASID prospective trial included 569 patients with symptomatic stenosis located in any intracerebral large artery.20 After a median follow-up of 1.8 years, the annual recurrence rate of a new ischemic stroke in the territory of the stenosed artery was 12% in the aspirin arm and 11% in the warfarin arm. The annual recurrence rates for any ischemic stroke were as high as 15% and 14% in the aspirin and warfarin arms, respectively. In line with these observations, 114
ˆ the Groupe d’Etude des Stenoses Intra-Craniennes Ath´eromateuses symptomatigues (GESICA) study investigators reported that during a median follow-up of 23.4 months, 38.2% of the 102 included patients had a stroke or a transient ischemic attack (TIA) in the same territory of the stenotic artery.26 Moreover, recurrent cerebrovascular events were observed with a median time of 2 months after the initial episode. From these studies, we can conclude that currently available antithrombotic therapies do not provide sufficient protection against the high risk of clinical recurrence in patients with symptomatic ICAS.
Global vascular disease risk in patients with intracranial atherosclerosis Symptomatic ICAS patients are also exposed to an elevated risk of having coronary ischemic events and vascular death. In the WASID study, 30 (5.3%) patients had a major cardiac event (myocardial infarction or sudden death) during the study period.20 The rate of fatal cardiac events has been shown to be extraordinarily high among patients with symptomatic intracranial ICA stenoses.21–22 Marzewski et al.22 reported that 50% of the patients included in their series died during follow-up, 55% of them due to cardiac diseases. Thus, a significant proportion of patients with symptomatic ICAS may develop coronary artery disease within a few years after the initial event, often with fatal consequences. Therefore, coronary risk evaluation in patients with TIA and ischemic stroke caused by ICAS should be optimized. Arenillas et al.27 reported that up to 52% of patients with symptomatic ICAS who had no history of cardiac disease show abnormal myocardial perfusion single photon emission computed tomography (SPECT) studies, suggesting the presence of occult coronary artery disease, as shown in Fig. 9.1. This observed prevalence of occult coronary artery disease is as high as that reported in patients with symptomatic cervical ICA stenosis.28 Existence of a stenosed intracranial ICA, location of the symptomatic stenosis in the vertebrobasilar arteries, and the presence of high plasma levels of lipoprotein (a) (Lp(a)) and homocysteine (Hcy) were factors that predicted the presence of occult coronary artery disease.27 Another prospective study performed by the same group concluded that the presence of moderate to severe perfusion defects
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Fig 9.1 Assessment of coronary risk using myocardial perfusion GATED-SPECT. (A) Time of flight cranial magnetic resonance angiography showing four severe stenoses affecting both intracranial internal carotid arteries (1 and 3) and both middle cerebral arteries (2 and 4). (B) In the myocardial perfusion SPECT a moderate-severe reversible defect is observed in the inferior wall of the left ventricle. (C) In GATED-SPECT systolic thickening is preserved but volumes are slightly increased, and ejection fraction is decreased. EDV, end-diastolic volume; ESV, end-systolic volume; HLA, horizontal long-axis; R, rest; S, stress; SA, short-axis; VLA, vertical long-axis. Courtesy of Dr. Candell-Riera and Dr Rovira, from the Nuclear Cardiology Department and Magnetic Resonance Unit, Vall d’Hebron Hospital, Barcelona, Spain, respectively.
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on baseline myocardial perfusion scintigraphy was a powerful predictor of future major coronary events in symptomatic ICAS patients.29 Taken together, these findings suggest that patients affected by symptomatic ICAS should be considered as having an equivalent risk for coronary artery disease. Intracranial atherosclerosis: a dynamic and multifocal disease Intracranial stenoses may progress or regress over time. In a retrospective review of serial angiograms in patients with ICAS, Akins et al.30 showed that 20% of intracranial ICA lesions progressed during a 7-year follow-up period compared with 61% of the anterior cerebral artery (ACA), MCA, and PCA lesions (based on a minimum 10% change). On the other hand, regression occurred in 14% of intracranial ICA lesions and 28% of the ACA–MCA–PCA lesions. Two prospective, long-term follow-up studies using TCD also showed that symptomatic MCA stenoses were dynamic lesions that progressed and regressed over time.31–32 The progression rate reported by the Barcelona group31 was 32.5%, higher than the 9% observed by the Hong Kong investigators.32 Both studies showed that progression of symptomatic MCA stenosis was associated with an increased risk of recurrent ischemic stroke. A more recent study by the same European group showed that progression of ICAS involved all ICAS and not solely the clinically relevant stenosis.33 Seventy-five consecutive patients with symptomatic ICAS underwent TCD followup during a median time of 23 months. ICAS was found to progress in 25 (33%) patients, to regress partially in 5 (7%), and to remain stable in 45 (60%) patients. According to the Cilostazol Prevents the Progression of the Symptomatic Intracranial Arterial Stenosis (TOSS) study from Korea,34 during 6 months’ follow-up, MRA-defined progression of symptomatic ICAS was noted in 29% and regression in 15% of patients receiving aspirin monotherapy. The MRA results were consistent with the TCD-defined progression or regression rate. Therefore, although the definition of progression and regression was not identical among different studies, it seems clear that symptomatic intracranial stenoses show dynamic changes and that they more often progress than regress. Figure 9.2 shows the MRA finding of an illustrative patient showing progression of atherosclerosis. 116
ICAS is also a multifocal disease. A substantial proportion of patients affected by symptomatic ICAS have coexistent asymptomatic ICAS besides the culprit lesion, as shown in Asian and European–Mediterranean populations.26,35–37 In the GESICA study, associated intracranial stenoses were observed in 41% of the included patients.26 Histopathologic studies have also confirmed that ICAS is a diffuse process affecting multiple intracranial arteries. Figure 9.3 shows the MRA finding of an illustrative patient with multiple atherostenoses. As will be discussed later, coexisting asymptomatic ICAS progresses less often than the symptomatic one.
Intracranial atherosclerosis: prognostic factors Patients who have symptomatic ICAS constitute a high-vascular risk group. The next part of the chapter will be dedicated to review the factors that characterize those patients that are at highest risk for progression and recurrence. The proposed culprit factors for the progressive–recurrent course of ICAS will be divided into two main categories. First, those local factors and mechanisms that confer vulnerability to the intracranial atherosclerotic plaque itself, which may be called vulnerable intracranial stenosis. Second, the systemic factors and basic pathways that render a patient more prone to develop the complications of ICAS in the near future. These high-risk patients will be referred to as vulnerable intracranial atherosclerosis patients, following the terminology used for coronary disease.38–39 Local factors: vulnerable intracranial stenosis Severity of the culprit intracranial stenosis In the WASID prospective study, Kasner et al.40 demonstrated that the severity of the symptomatic intracranial stenosis was independently associated with a higher risk of subsequent stroke in the territory of the stenosed artery. The risk of recurrent stroke in the territory of the symptomatic stenotic artery was the highest with stenosis ≥70% (hazard ratio 2.03; 95% CI 1.29–3.22). The prognostic impact of stenosis severity had been previously shown for basilar artery stenosis in the WASID retrospective study, but not for other intracranial arteries.26 Other investigators have found
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Fig 9.2 Progression of intracranial atherosclerosis. A 72-year-old hypertensive man developed right hemiparesis and hemihypesthesia. T2-weighted magnetic resonance imaging (MRI) showed a left medial medullary infarction (A). Magnetic resonance angiography showed thrombotic occlusion of the left distal vertebral artery (short arrow) that was considered to be responsible for the infarction. A clinically silent lower basilar artery indentation was also
observed (long arrow) (B). 14 months later, the patient developed dysarthria and dizziness. Diffusion-weighted MRI showed small, scattered infarcts in the right and left occipital areas, cerebellum, and the pons (C and D). Magnetic resonance angiography markedly increase in the basilar artery stenosis (long arrow), while distal vertebral artery occlusion was unchanged (short arrow (E)).
Fig 9.3 Intracranial atherosclerosis: a multifocal disease. A 44-year-old hypertensive man with a history of cigarette smoking developed recurrent, transient left hemiparesis. Magnetic resonance angiography showed severe stenosis at the M1 portion of the right middle cerebral artery (thick arrow) that was considered to be responsible for the patient’s symptoms. In addition, there were multiple intracranial stenoses located at the A2 portion of the right anterior cerebral artery, A1 portion of the left anterior cerebral artery, diffuse narrowing of the basilar artery, and occlusion of the left posterior cerebral artery and left distal vertebral artery (thin arrows).
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that the severity (>70%) of symptomatic intracranial stenosis is associated with early recurrent ischemic lesions on diffusion-weighted imaging.41 Severe MCA stenoses often show a higher progression rate during TCD follow-up.42 On the other hand, although theoretically considered a severe condition, the long-term prognosis of chronic, bilateral MCA occlusion was reported to be reasonable at least in the patients who did not present with a devastating stroke.43 Location of the symptomatic stenosis No differences in recurrence risk according to the location of symptomatic intracranial stenosis have been found, either considering each intracranial artery individually21–24,26 or categorizing the involved vessels with respect to their location as the anterior or posterior circulation stenosis.40 The presence of concomitant stenoses in the extracranial and intracranial portions of the same artery (tandem lesions) carries a higher recurrence risk.44 Extent of intracranial atherosclerosis The number of diseased vessels within the cerebral arterial circulation has been shown to be associated with a higher risk of stroke recurrence and vascular death.44–45 Those patients with atherosclerotic stenoses affecting both extracranial and intracranial large arteries are exposed to a higher risk than patients with isolated intracranial stenoses. The number of intracranial stenoses is also associated with a higher risk of future ICAS progression, as shown by recent TCD studies.33 Nonetheless, other relevant studies failed to show an association between the number of intracranial stenoses and a higher risk of recurrent stroke.26 Symptomatic vs asymptomatic intracranial stenoses Paralleling extracranial ICA stenosis, the risk of recurrent ischemic events appears to be much higher in patients with symptomatic intracranial stenoses than in patients with asymptomatic stenoses.19,46–47 Kern et al.46 reported an annual overall stroke risk of 12.5% vs 2.8% in patients with symptomatic vs asymptomatic MCA stenoses. In patients with symptomatic ICAS, coexistent asymptomatic intracranial stenosis is frequently observed. The risk of future ischemic stroke caused by these asymptomatic lesions appears to be low.26 Progression of stenosis in asymptomatic vessels
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is also much less frequent than that of symptomatic ones.34 Progression of intracranial atherosclerosis Two long-term follow-up studies using TCD showed that progression of symptomatic MCA stenosis was associated with a higher risk of further ischemic events, either related to the stenosed artery or not.31–32 Another study by Arenillas et al.33 showed a strong relationship between TCD-detected progression of ICAS, globally defined and not focused only on the evolution of the symptomatic stenoses, and a higher risk of further brain ischemic events during followup.33 Thus, identifying the progression of ICAS by TCD may help us to characterize patients with an aggressive clinical course, and to direct secondary prevention strategy. Stenosis causing hemodynamic compromise The hemodynamic compromise caused by a symptomatic intracranial stenosis has recently emerged as an independent prognostic factor associated with an increased recurrence risk.26 From a clinical standpoint, patients with hemodynamic compromise affecting the territory of a stenosed artery characteristically report fluctuations in the intensity of the neurological deficits after changes in body position or with blood pressure drops. This clinical pattern may be present in around 15–20% of patients with symptomatic ICAS who have an extremely high risk of recurrent stroke (60.7%).26 Apart from clinical observation, other ancillary examinations allow assessment of cerebral hemodynamic reactivity (TCD, Xenon SPECT, Xenon CT, perfusion CT, and MRI) or oxygen extraction fraction assessed by positron emmission tomography (PET), and provide useful information in identifying patients who have a greater hemodynamic impairment.48–50 This subgroup of patients may theoretically benefit from endovascular treatment or bypass surgery.51 Microembolic signals In patients with symptomatic MCA stenosis, detection of microembolic signals using TCD monitoring within 3 days after onset of symptoms has been described as a predictor of future ischemic events in the stenotic MCA territory.52 Moreover, a positive relationship has been found between the number of detected microembolic signals and the number of acute ischemic lesions
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visible on diffusion-weighted imaging.53 These results suggest that microembolic signals detected during the acute phase of ischemic stroke might be considered an indirect sign of intracranial plaque instability. However, the presence of microembolic signals may imply that the stenosis is actually a partial recanalization of an embolic occlusion rather than intrinsic atherosclerosis, and therefore may require thorough diagnostic work-up to rule out this possibility.54 Plaque composition It is well accepted that the histological composition of the atherosclerotic plaque may determine its vulnerability. The so-called unstable atherosclerotic plaque, rich in lipid deposits and inflammatory components and with a thin fibrous cap, may cause a clinical event as a result of its destabilization. The importance of vulnerable plaque may be different among different vascular trees; several histopathological studies have shown that the relevance of the unstable atherosclerotic plaque might be greater in extracranial than in intracranial arteries.55–56 In addition, plaques rich in inflammatory components have often been described in the intracranial vertebral and basilar arteries,57–58 whereas they seem to occur less commonly in MCA disease, where fibrous stable plaques predominate.59 However, complicated plaques affecting the MCA showing rupture or intraplaque hemorrhage have been also reported.60 Besides the evaluation of indirect evidences of plaque instability, such as microembolic signals or diffusion-weighted imaging lesion pattern, there is a need to develop noninvasive diagnostic methods to characterize the intracranial vulnerable atherosclerotic plaque. In this context, high-resolution MRI seems to be the most promising technique.61 With the advancement of technologies, the prognostic relevance of the morphological characteristics of intracranial plaques will need to be determined in the future.
Systemic factors: vulnerable intracranial atherosclerosis patients Classical vascular risk factors The role of vascular risk factors in the development of ICAS has been reviewed in Chapter 4. Among the classical risk factors, diabetes mellitus seems to
play a pre-eminent role in intracranial atherogenesis. In European–Mediterranean patients, type 2 diabetes mellitus has been associated with a greater extent of ICAS, and consequently patients with diabetes have a higher number of intracranial stenoses than nondiabetics patients.37 Diabetes has also been found to be associated with a higher risk of recurrent stroke and vascular death among Asian symptomatic ICAS patients.44 On the other hand, Chaturvedi et al.62 recently studied patients recruited from the WASID trial and found that elevated blood pressure and cholesterol levels are associated with an increased risk of stroke and other major vascular events in symptomatic ICAS patients.
Metabolic syndrome The metabolic syndrome (MetS) consists of a constellation of vascular risk factors and metabolic abnormalities comprising (1) centrally distributed obesity; (2) atherogenic dyslipidemia, characterized by elevated triglycerides and decreased highdensity lipoproteins; (3) high blood pressure, and (4) hyperglycemia.63 This cluster of highly interrelated factors increases the individual’s risk of vascular disease including stroke.64 The increase in the risk of incident brain ischemic events observed in patients with MetS may derive mostly from the potential capacity of MetS to enhance the development and progression of atherosclerotic lesions. Insulin resistance, the underlying pathophysiological mechanism in MetS, is known to cause multiple pro-atherothrombotic effects both on the fibrinolytic system and on the vascular endothelium. The relationship between MetS and ICAS has been addressed by several recent studies,65–67 and is extensively reviewed in Chapter 4. Among patients with ischemic stroke who are of Asian ancestry, the highest prevalence of MetS was observed in the subgroup of patients with ICAS (55%), even higher than the frequency of MetS observed in patients with extracranial carotid atherosclerosis (40%).65 In the WASID study the MetS patients with symptomatic ICAS had an excess risk of recurrent ischemic events.67 Taken together, these studies suggest that intracranial arteries are vulnerable to the MetS, and that the MetS has a profound impact on the development, progression, and complication of ICAS. In line with these findings, it has been
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recently reported that the blood level of adiponectin, a protein secreted by adipose cells that improves insulin sensitivity and possesses anti-atherogenic properties, is significantly lower in patients with ICAS than in those with other stroke subtypes.68 Thus, the role of MetS and insulin resistance on the progression and clinical recurrence of ICAS has emerged as an important area of investigation. Gender WASID study investigators have shown that there is gender difference in the risk for outcome events among patients enrolled in this clinical trial. Women with symptomatic ICAS appeared to be at significantly greater risk for ischemic stroke and for the combined end-point of stroke or vascular death.69 The 2-year rates of the primary end-point were 28.4% and 1.6% for women and men, respectively. In order to explain these findings, the authors suggest that elderly women may be vulnerable to factors associated with poor outcome, such as social isolation, lower socioeconomic status, and greater clustering of vascular risk factors. Failure of antithrombotic therapy Patients with symptomatic ICAS who fail to respond to antithrombotic therapy have extremely high rates of recurrent brain ischemic events or death. Recurrent ischemic events typically occur within a few weeks or months after failure of standard medical therapy.70 The high recurrence risk observed makes it important to consider alternative treatment strategies such as intracranial angioplasty or stenting in this subgroup of patients. Inflammation Inflammation is known to play a crucial role in all stages of atherogenesis, from early lesion formation to plaque progression and destabilization.71 A growing body of evidence supports the involvement of inflammation in the progression and complication of symptomatic ICAS. First, patients with ICAS show high plasma concentrations of inflammatory markers such as adhesion molecules and monocyte chemoattractant protein-1 (MCP-1), reflecting the existence of an inflammatory endothelial activation in this condition.72 Second, C-reactive protein (CRP), a sensitive indicator of systemic inflammation, has been shown to be
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a powerful predictor of future major ischemic events, either related to ICAS or not, in first-ever symptomatic patients with ICAS.73 Third, progression of symptomatic ICAS has been found to be associated with a proinflammatory state, as reflected by high circulating levels of inflammatory markers, such as CRP, E-selectin, MCP-1, intercellular adhesion molecule-1 (ICAM-1), and matrix metalloproteinase 9 (MMP-9), of which CRP emerged as an independent predictor of a progressive course of the disease.33 Finally, an elevated white blood cell (WBC) count at study entry was associated with an increased risk of stroke and vascular death in patients with symptomatic ICAS enrolled in the WASID trial.74 Elevated inflammatory markers such as CRP and WBC count may help identify those patients with a persistently enhanced subclinical inflammatory response and an increased propensity to plaque progression and complication. Prothrombotic state and impaired endogenous fibrinolysis Thrombosis and defective endogenous fibrinolysis may also contribute to progression of atherosclerotic lesions systemically. Their potentially deleterious role on ICAS has been suggested by several recent studies. First, an elevated circulating level of Lp(a), an atherothrombogenic cholesterol-rich lipoprotein that inhibits endothelial surface fibrinolysis by competing with plasminogen binding, was independently associated with a greater extent of ICAS.37 Second, a positive correlation between homocysteine concentration and the number of intracranial stenosis has been reported. Homocysteine is known to exert prothrombotic effects on the endothelial surface.75 Finally, a high level of plasminogen activator inhibitor-1 (PAI-1) emerged as a powerful predictor of the risk of ICAS progression.33 In this setting, an increased PAI-1 expression in atherosclerotic vessels may cause an impaired fibrinolytic response to mural thrombi, leading to a greater extent and persistence of thrombi in the arterial lumen. Increased exposure to clot-associated mitogens in the artery wall may in turn accelerate atherosclerosis.76 Inhibited endogenous angiogenic response Angiogenesis (the sprouting of new blood vessels from pre-existing vascular structures77 ) is a complex and finely regulated process triggered by hypoxia. The
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endogenous angiogenic response to ischemia is the result of a complex balance between stimulant and inhibitor factors that interact in an orchestrated manner. A high level of the angiogenesis inhibitor endostatin was independently associated with a higher recurrence risk and a higher progression rate of ICAS.78 Therefore, symptomatic ICAS patients with an angiogenic balance skewed towards a predominance of inhibitors may be at a higher risk of progression and clinical recurrence. Inhibitors of angiogenesis such as endostatin impair re-endothelization processes leading to plaque growth through excessive neointima formation. Research is needed to elucidate the relationship between angiogenesis and the hemodynamic compromise caused by ICAS, and to evaluate whether the stimulation of angiogenesis may be a therapeutic alternative for patients with progressive ICAS. Genetic factors It remains unclear to what extent the risk of progression and complication of symptomatic ICAS might be genetically predetermined. There is a need to investigate the genetic factors implicated in the genesis and outcome of ICAS.
Therapeutic implications Analysis of these proposed risk factors has practical implications for the prevention and treatment of symptomatic ICAS.79 Factors such as symptomatic, severe, progressive, medically refractory stenosis, along with MetS, and increased inflammatory markers characterize patients that are at a higher risk for progression and recurrence. These patients would benefit from more strict vigilance, more exhaustive risk factor control, and more aggressive medical therapy. In selected cases with severe (>70%) symptomatic stenoses causing hemodynamic impairment and those in whom best medical therapy has failed may benefit from interventional (endovascular or bypass) therapy. Regarding plaque composition, those patients with a predominance of fibrous stable stenotic plaques with hemodynamic impairment may be more likely to benefit from therapies that target arterial narrowing, such as stenting. In contrast, patients with unstable plaques in which the relative contribution of inflammation and other basic mechanisms to the progression and com-
plication of intracranial atherosclerosis is greater may benefit more from optimal medical therapy. However, these suggestions need to be substantiated or refuted in randomized clinical trials comparing stenting vs best medical therapy.80 The biomarkers analyzed in this chapter might also be useful in the field of secondary prevention of patients with symptomatic ICAS in three main ways. First, as prognostic tools in the selection of high-risk patients who may benefit from more intensive preventive approaches. Second, they could be used to monitor the efficacy of anti-atherosclerotic therapies or to help optimize risk factor and metabolic control. And third, given that some of these molecules have been proposed as direct mediators of atherogenesis, their therapeutic inhibition may represent a promising new approach for the medical treatment of patients affected by this condition. In this context, a CRP inhibitor has been newly developed.81
References 1 Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999; 340: 115–126. 2 Kiechl S, Willeit J. The natural course of atherosclerosis. Part I: incidence and progression. Arterioscler Thromb Vasc Biol 1999; 19: 1484–1490. 3 D’Armiento FP, Bianchi A, de Nigris F, et al. Age-related effects on atherogenesis and scavenger enzymes of intracranial and extracranial arteries in men without classic risk factors for atherosclerosis. Stroke 2001; 32: 2472– 2479. 4 Napoli C, Witztum JL, de Nigris F, et al. Intracranial arteries of human fetuses are more resistant to hypercholesterolemia-induced fatty streak formation than extracranial arteries. Circulation 1999; 99: 2003– 2010. 5 Samuels OB, Joseph GJ, Lynn MJ, et al. A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol 2000; 21: 643–646. 6 Feldmann E, Wilterdink JL, Kosinski A, et al for 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. 7 Lindegaard K-F, Bakke SJ, Aaslid R, Nornes H. Doppler diagnosis of intracranial occlusive disorders. J Neurol Neurosurg Psychiatry 1986; 49: 510–518.
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8 Ley-Pozo J, Ringelstein EB. Noninvasive detection of occlusive disease of the carotid siphon and middle cerebral artery. Ann Neurol 1990; 28: 640–647. 9 Baumgartner RW, Mattle HP, Schroth G. Assessment of ≥50% or <50% intracranial stenoses by transcranial color-coded Duplex sonography. Stroke 1999; 30: 87–92. ¨ 10 Furst G, Hofer M, Steinmetz H, et al. Intracranial stenooclusive disease: MR angiography with magnetization transfer and variable flip angle. Am J Neuroradiol AJNR 1996; 17: 1749–1757. 11 Korogi Y, Takahashi M, Mabuchi N, et al. Intracranial vascular stenosis and occlusion: diagnostic accuracy of three-dimensional, Fourier transform, tone-of-flight MR angiography. Radiology 1994; 193: 187–193. ¨ 12 Skutta B, Furst G, Eilers J, et al. Intracranial stenoocclusive disease: double-detector helical CT angiography versus digital subtraction angiography. Radiology 1999; 20: 791–799. 13 Huang YN, Gao S, Li SW, Huang Y, Li JF, Wong KS, Kay R. Vascular lesions in Chinese patients with transient ischemic attacks. Neurology 1997; 48: 524–525. 14 Wong KS, Huang YN, Gao S, Lam WWM, Chan YL, Kay R. Intracranial stenosis in Chinese patients with acute stroke. Neurology 1998; 50: 812–813. 15 Sacco R, Kargman DE, Quiong Gu, Zamanillo MC. Raceethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke 1995; 26: 14–20. 16 Wityk RJ, Lehman D, Klag M, et al. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996; 27: 1974–1980. 17 Huang HW, Guo MH, Lin RJ, et al. Prevalence and risk factors of middle cerebral artery stenosis in asymptomatic residents in Rongqi County, Guangdong. Cerebrovasc Dis 2007; 24: 111–115. 18 Wong KS, Ng PW, Tang A, et al. Prevalence of asymptomatic intracranial atherosclerosis in high-risk patients. Neurology 2007; 68: 2035–2038. 19 Takahashi W, Ohnuki T, Ide M, et al. Stroke risk of asymptomatic intra- and extracranial large-artery disease in apparently healthy adults. Cerebrovasc Dis 2006; 22: 263–270. 20 Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. 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. 21 Craig DR, Meguro K, Watridge C, et al. Intracranial internal carotid artery stenosis. Stroke 1982; 13: 825–828. 22 Marzewski DJ, Furlan AJ, St. Louis P, et al. Intracranial internal carotid artery stenosis: long term prognosis. Stroke 1982; 13: 821–824.
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23 Wechsler LR, Kistler JP, Davis KR, Kaminski MJ. The prognosis of carotid siphon stenosis. Stroke 1986; 714– 718. 24 Bogousslavsky J, Barnett HJM, Fox AJ, et al. For the EC/IC Bypass Study Group. Atherosclerotic disease of the middle cerebral artery. Stroke 1986; 17: 1112–1120. 25 The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Study Group. Prognosis of patients with symptomatic vertebral or basilar artery stenosis. Stroke 1998; 29: 1389–1392. 26 Mazighi M, Tanasescu R, Ducrocq X, et al. Prospective study of symptomatic atherothrombotic intracranial stenoses: the GESICA study. Neurology 2006; 66: 1187– 1191. 27 Arenillas JF, Candell-Riera J, Romero-Farina G, et al. Silent myocardial ischemia in patients with symptomatic intracranial atherosclerosis: associated factors. Stroke 2005; 36: 1201–1206. 28 Chimowitz MI, Poole RM, Starling MR, et al. Frequency and severity of asymptomatic coronary disease in patients with different causes of stroke. Stroke 1997; 28: 941–945. 29 Candell-Riera J, Arenillas JF, Romero-Farina G, et al. Prognostic Value of Myocardial Perfusion Gated SPECT in Patients with Symptomatic Intracranial Large-Artery Atherosclerosis. Cerebrovasc Dis 2007; 24: 247–254. 30 Akins PT, Pilgram TK, Cross III DT, Moran CJ. Natural history of stenosis from intracranial atherosclerosis by serial angiography. Stroke 1998; 29: 433–438. 31 Arenillas JF, Molina CA, Montaner J, et al. Progression and clinical recurrence of symptomatic middle cerebral artery stenosis. A long-term follow-up transcranial Doppler ultrasound study. Stroke 2001; 32: 2898–2904. 32 Wong KS, Li H, Lam WWM, et al. Progression of middle cerebral artery occlusive disease and its relationship with further vascular events after stroke. Stroke 2002; 33: 532–536. ´ 33 Arenillas JF, Alvarez-Sab´ ın J, Molina CA, et al. Progression of symptomatic intracranial large-artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis. Stroke 2008; 39: 1456–1463. 34 Kwon SU, Cho YJ, Koo JS, et al. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke 2005; 36: 782–786. 35 Wong KS, Li H, Chan YL, et al. Use of transcranial Doppler ultrasound to predict outcome in patients with intracranial large-artery occlusive disease. Stroke 2000; 31: 2641–2647. 36 Yoo JH, Chung CS, Kang SS. Relation of plasma homocyst(e)ine to cerebral infarction and cerebral atherosclerosis. Stroke 1998; 29: 2478–2483.
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´ P, et al. High lipoprotein 37 Arenillas JF, Molina CA, Chacon (a), diabetes and the extent of symptomatic intracranial atherosclerosis. Neurology 2004; 63: 27–32. 38 Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003; 108: 1664–1672. 39 Naghavi M, Libby P, Falk E, et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 2003; 108: 1772–1778. 40 Kasner SE, Chimowitz MI, Lynn MJ, et al. 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. 41 Kang DW, Kwon SU, Yoo SH, et al. Early recurrent ischemic lesions on diffusion-weighted imaging in symptomatic intracranial atherosclerosis. Arch Neurol 2007; 64: 50–54. 42 Jeon HW, Cha JK. Factors related to progression of middle cerebral artery stenosis determined using transcranial Doppler ultrasonograhy. J Thromb Thrombolysis 2008; 25: 265–269. 43 Bogousslavsky J, Wong W, Barnett HJ, Fox AJ. Bilateral occlusion of the trunk of the middle cerebral artery. Results of an international randomized trial. The EC/IC Bypass Study Group. Stroke 1986; 17: 1107–1111. 44 Wong KS, Li H. Long-term mortality and recurrent stroke risk among Chinese stroke patients with predominant intracranial atherosclerosis. Stroke 2003; 34: 2361–2366. 45 Asil T, Balci K, Uzunca I, et al. Six-month follow-up study in patients with symptomatic intracranial arterial stenosis. J Clin Neurosci 2006; 13: 913–916. 46 Kern R, Steinke W, Daffertshofer M, et al. Stroke recurrences in patients with symptomatic vs asymptomatic middle cerebral artery disease. Neurology 2005; 65: 859– 864. 47 Kremer C, Schaettin T, Georgiadis D, Baumgartner RW. Prognosis of asymptomatic stenosis of the middle cerebral artery. J Neurol Neurosurg Psychiatry 2004; 75: 1300– 1303. 48 Haubrich C, Kruska W, Diehl RR, et al. Dynamic autorregulation testing in patients with middle cerebral artery stenosis. Stroke 2003; 34: 1881–1885. 49 Uzunca I, Asil T, Balci K, Utku U. Evaluation of vasomotor reactivity by transcranial doppler sonography in patients with acute stroke who have symptomatic intracranial and extracranial stenosis. J Ultrasound Med 2007; 26: 179–185. 50 Lu J, Li K, Zhang M, Jiao L. Dynamic susceptibility contrast perfusion magnetic resonance imaging in patients
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with symptomatic unilateral middle cerebral artery stenosis or occlusion. Acta Radiol 2007; 48: 335–340. Ecker RD, Levy EI, Sauvageau E, et al. Current concepts in the management of intracranial atherosclerotic disease. Neurosurgery 2006; 59 (Suppl 3): 210–218. Gao S, Wong KS, Hansberg T, et al. Microembolic signal predicts recurrent cerebral ischemic events in acute stroke patients with middle cerebral artery stenosis. Stroke 2004; 35: 2832–2836. Wong KS, Gao S, Chan YL, et al. Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diffusion-weighted imaging and microemboli monitoring study. Ann Neurol 2002; 52: 74– 81. Segura T, Serena J, Castellanos M, et al. Embolism in acute middle cerebral artery stenosis. Neurology 2001; 56: 497–501. Lammie GA, Sandercock PAG, Dennis MS. Recently occluded intracranial and extracranial carotid arteries. Relevance of the unstable atherosclerotic plaque. Stroke 1999; 30: 1319–1325. Lhermitte F, Gautier JC, Derouesne C, Guiraud B. Ischemic accidents in the middle cerebral artery territory: a study of causes in 122 cases. Arch Neurol 1968; 19: 248–256. Castaigne P, Lhermitte F, Gautier JC, et al. Arterial occlusions in the vertebro-basilar system. A study of 44 patients with post-mortem data. Brain 1973; 96: 133– 154. Caplan L. Posterior circulation ischemia: then, now, and tomorrow. The Thomas Willis Lecture-2000. Stroke 2000; 31: 2011–2023. Schumacher HC, Tanji K, Mangla S, et al. Histopathological evaluation of middle cerebral artery after percutaneous intracranial transluminal angioplasty. Stroke 2003; 34: 170–173. Ogata J, Masuda J, Yutani C, Yamaguchi T. Mechanisms of cerebral artery thrombosis: a histopathological analysis on eight necropsy cases. J Neurol Neurosurg Psychiatry 1994; 57: 17–21. Klein IF, Lavall´ee PC, Touboul PJ, et al. In vivo middle cerebral artery plaque imaging by high-resolution MRI. Neurology 2006; 67: 327–329. Chaturvedi S, Turan TN, Lynn MJ, et al. for WASID Study Group. Risk factor status and vascular events in patients with symptomatic intracranial stenosis. Neurology 2007; 69: 2063–2068. ´ Arenillas JF, Moro MA, Davalos A. The metabolic syndrome and stroke: potential treatment approaches. Stroke 2007; 38: 2196–2203. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005; 365: 1415–1428.
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65 Bang OY, Kim JW, Lee JH, et al. Association of the metabolic syndrome with intracranial atherosclerotic stroke. Neurology 2005; 65: 296–298. 66 Park JH, Kwon HM, Roh JK. Metabolic syndrome is more associated with intracranial atherosclerosis transextracranial atherosclerosis. Eur J Neurol 2007; 14: 379– 386. 67 Obviagele B, Saver JL, Lynn MJ, Chimowitz M, for the WASID Study Group. Impact of metabolic syndrome on prognosis of symptomatic intracranial atherostenosis. Neurology 2006; 66: 1344–1349. 68 Bang OY, Saver JL, Ovbiagele B, et al. Adiponectin levels in patients with intracranial atherosclerosis. Neurology 2007; 68: 1931–1937. 69 Williams JE, Chimowitz MI, Cotsonis GA, et al. Gender differences in outcomes among patients with symptomatic intracranial arterial stenosis. Stroke 2007; 38: 2055–2062. 70 Thijs VN, Albers GW. Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy. Neurology 2000; 55: 490–497. 71 Libby P, Ridker P, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135–1143. 72 Fassbender K, Bertsch T, Mielke O, et al. Adhesion molecules in cerebrovascular diseases. Evidence for an inflammatory endothelial activation in cerebral large- and small-vessel disease. Stroke 1999; 30: 1647–1690. 73 Arenillas JF, Alvarez-Sab´ın J, Molina C, et al. C-reactive protein predicts further ischemic events in first-ever TIA
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and stroke patients with intracranial large-artery occlusive disease. Stroke 2003; 34: 2463–2470. Ovbiagele B, Lynn MJ, Saver JL, Chimowitz MI, WASID Study Group. Leukocyte count and vascular risk in symptomatic intracranial atherosclerosis. Cerebrovasc Dis 2007; 24: 283–288. Yoo JH, Chung CS, Kang SS. Relation of plasma homocyst(e)ine to cerebral infarction and cerebral atherosclerosis. Stroke 1998; 29: 2478–2483. Sobel BE. Increased plasminogen activator inhibitor-1 and vasculopathy. A reconcilable paradox. Circulation 1999; 99: 2496–2498. Marti H, Risau W. Angiogenesis in ischemic disease. Thromb Haemost 1999; 82: 44–52. ´ Arenillas JF, Alvarez-Sab´ ın J, Montaner J, et al. Angiogenesis in symptomatic intracranial atherosclerosis: Predominance of the inhibitor endostatin is related to a higher extent and risk of recurrence. Stroke 2005; 36: 92–97. ´ Arenillas JF and Alvarez-Sab´ ın J. Basic mechanisms in intracranial large-artery atherosclerosis: Advances and challenges. Cerebrovasc Dis 2005; 20 (Suppl 2): 75–83. Derdeyn CP, Chimowitz MI. Angioplasty and stenting for atherosclerotic intracranial stenosis: rationale for a randomized clinical trial. Neuroimaging Clin N Am 2007; 17: 355–363, viii–ix. Pepys MB, Hirschfield GM, Tennent GA, et al. Targeting C-reactive protein for the treatment of cardiovascular disease. Nature 2006; 440: 1217–1221.
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PART THREE
Diagnostic imaging studies
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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Vascular imaging Edward Feldman, Harry J Cloft, Mai Nguyen-Huynh and Avean McLaughlin
Among the available modalities for evaluation of intracranial stenosis, transcranial Doppler (TCD) is the cheapest and least invasive. However, it is also highly operator-dependent and may not be technically possible on every subject.1 Not all vessels can be insonated, and the posterior circulation can be particularly challenging. Magnetic resonance angiography (MRA) is minimally invasive. It provides a better estimate of degree of stenosis. However, the technology is still not available at all medical facilities and tends to overestimate high-grade stenoses due to turbulent flow.2 Digital subtraction angiography (DSA) is the current gold standard. It provides excellent visualization of intracranial vessels. However, DSA has several important limitations. It is the most expensive and most invasive. It is available only at highly specialized centers. It requires the most expertise and time to perform, and it carries the most risks, making DSA the least desirable as a screening tool.3–6 Given the disadvantages of DSA, many have favored less invasive techniques for evaluation of intracranial vessels. With the advancement over the past decades in machinery and image postprocessing software, computed tomographic angiography (CTA) has emerged as a more popular modality for visualization of many parts of the circulatory system (Fig. 10.1).
Catheter angiography Catheter angiography is the oldest technique for imaging the vascular system in living patients, dating back to 1927.7 Following the introduction of Seldinger’s method of percutaneous catheterization in 1953, the
procedure gained wide acceptance. Since that time, the technique has evolved further through a number of important technical innovations, including advances in subtraction and magnification. DSA gradually has replaced cut film angiography, and has now become the “gold standard” for imaging intracranial vascular pathology.8 Modern DSA offers superb spatial resolution of less than 0.2 mm. Contrast resolution is also superb, with blood vessels appearing quite dark, and all subtracted background appearing nearly white. The superb spatial resolution and contrast are the reasons why DSA remains the gold standard, as no other imaging modality has yet been able to surpass or even match DSA in regard to these basic image quality parameters. Although the image quality is undoubtedly superb, DSA is frequently criticized because it is an invasive procedure. The risks of cerebral angiography have been assessed in a number of prospective studies.3,9 Some of these studies examined complication rates in all patients undergoing cerebral angiography.9,10 whereas others have examined the risk only in patients undergoing angiography for transient ischemic attack (TIA) or ischemic stroke.11 The risk in patients with TIA and ischemic stroke has tended to be higher than in patients with other indications for cerebral angiography. In a meta-analysis of the risk of cerebral angiography in patients with transient ischemic attack or stroke.6 the risk of transient neurological deficit was 3.0% and the risk of permanent neurological deficit was 0.7%. Other risks of DSA include exposure to ionizing radiation, allergy to contrast material, and peripheral vascular complications, but these are all very much less likely to cause clinical consequences.
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Fig 10.1 Magnetic resonance angiography, computed tomographic angiography, and digital subtraction angiography of basilar artery stenosis.
Although there is a risk of permanent neurological deficit with DSA, the risk is low and must be balanced against the risk of an incorrect diagnosis in a patient with a disease that has a substantial risk of ischemic stoke.12,13 Patient care based on an incorrect diagnosis, no matter how caring and well intentioned, is much more likely to fail than care based on the correct diagnosis. The degree of stenosis is thus far the most clinically important parameter when evaluating intracranial atherosclerosis.13 The measurement of cerebrovascular stenosis has been most thoroughly studied and developed for the cervical internal carotid artery.14 A standard measuring technique, which is similar to the method used for the cervical internal carotid artery, has been developed for intracranial stenosis and found to have good interobserver and intraobserver agreements.15 The method defined percent stenosis of an intracranial artery as follows: percent stenosis = [(1 – (Dstenosis /Dnormal ))] × 100, where Dstenosis is the diameter of the artery at the site of the most severe stenosis and Dnormal is the diameter of the proximal normal artery. If the proximal segment was diseased, contingency sites were chosen to measure Dnormal : distal artery (second choice), feeding artery (third choice). This method of measurement was developed for the Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial.12 In addition to degree of stenosis, DSA gives physiologic information about flow contribution from the 128
injected artery. Although usually an advantage, this physiologic effect is sometimes a disadvantage, as slow-flow vessels distal to a stenosis may be poorly filled with contrast material and thus poorly visualized. This phenomenon can make it difficult to get accurate imaging of the distal arteries. In such cases of severe stenosis, CT angiography can be better than DSA, because CT angiography can image dilute contrast pooling in the distal lumen quite reliably.16 It is generally helpful to inject multiple arteries in an effort to show collateral blood flow. For posterior circulation stenosis, both vertebral arteries generally need to be evaluated to accurately display the relevant anatomy and pathology. For those who work in referral centers where complex patients whose symptoms are refractory to medical therapy are referred, angioplasty, stenting, or bypass surgery is sometimes offered.17 These patients will all undergo DSA as part of their pre-intervention evaluation. DSA is also important in documenting the result of the immediate post-intervention result.
CT angiography The earliest CT scanner, developed by Sir Godfrey Hounsfield, was first used for brain imaging in 1972.18 CT uses X-rays to generate cross-sectional, twodimensional images. The earliest scanner acquired images slice by slice, and took hours to complete and
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days to process the images. By the early 1990s, the introduction of helical or spiral CT into clinical practice allowed for continuous volume of contiguous slices, instead of one slice at a time. The new slip-ring technology allowed for larger anatomical sections of the body to be imaged in one breath hold and the study time was shortened significantly. However, the early helical CT scanners were still not fast enough for CTA applications. Limitations included single-row detector technology, X-ray tubes that were unable to handle high heat generated by continuous scanning, and slow processing programs. By the mid-1990s, multislice CT was introduced.19 This technology uses the same basic principles of spiral CT, but allows for acquisition of multiple slices in a much shorter time span. This means CTA can be performed successfully with complete image acquisition during the first pass of intravenous iodinated contrast through an arterial system. However, the huge image datasets from CTA required the purchase of expensive workstations dedicated to post-processing. More recently, faster computers, increased memory, and improved software programs have made CTA technology more affordable. In the USA, most single-detector array spiral CT scanners have been replaced by multirow detector scanners. At many major medical centers, 64-row detector scanners have been in clinical use. CTA is performed via acquisition of images when the vessels are visualized with intravenous iodinated contrast. There are several main types of image postprocessing techniques. The first is multiplanar reformation (MPR), which can create 2-D views in arbitrary planes without loss of information.20 The second type is the maximum intensity projection (MIP). This method shows contrast in blood vessels as well as calcification in vessel wall. Therefore, bone elimination technique is important for processing MIP images. In the presence of dense calcifications or stents, MIP may not be suitable for evaluation of the degree of stenosis. However, thin-slab MIP can be used in conjunction with MPR. The third type is surface rendering, which provides a good 3-D impression of the surface of an object. Finally, volume rendering provides colorful 3-D images, but it lacks features such as accurate measurements, soft tissue, and perivascular processes that can be obtained through planar reconstruction. Clinically, CTA has been used in a wide variety of medical conditions, including evaluation of renal vas-
cular anatomy for potential renal donors21 and evaluation of peripheral arterial bypass grafts.22 In the world of neurovascular imaging, CTA has emerged recently as a popular modality in the evaluation of acute stroke.23,24 CTA has several important advantages, including being minimally invasive, can be performed quickly, is less distorted from motion artifacts than MRA, and depends less on hemodynamic effects than MRA. It is also more widely available in the general community than MRA or DSA. CTA is gaining better acceptance for evaluation of stenosis in the cervical carotid artery with atherosclerotic disease.25–27 Bone subtraction CTA has enhanced visualization of the entire carotid artery system and intracranial vasculature. Therefore, with the correct post-processing techniques it is now possible to use CTA to assess the petrous and cavernous portions of the internal carotid artery. Intracranially, only a small number of studies have examined the accuracy of CTA to detect and quantify degree of arterial stenosis. Fewer studies actually compared CTA directly with the gold standard DSA, but instead used MRA or TCD as a comparison standard. One of the earliest studies examined the use of double-detector technology to demonstrate the normal vascular anatomy, and evaluated the accuracy of CTA MIP images in depicting stenosis compared with DSA as the gold standard.28 CTA was compared with DSA in 112 patients with suspected cerebrovascular disease. The mean interval between the two imaging studies was 5 days. CTA datasets were post-processed with an MIP algorithm followed by bone editing. All images were reviewed independently by two radiologists who were blinded to clinical information. Disagreements were settled by consensus. The degree of stenosis on DSA images was measured using minimal residual diameters and nearby normal vessel diameters with a 10× magnifier. Stenoses were categorized into: normal (0–9%); mild (10–29%); moderate (30–69%); severe (70–99%); and occluded (zero flow seen). The degree of stenosis on CTA images was estimated by visual inspection and then categorized. The authors reported the following findings: (1) all intracranial vessels >0.7 mm in diameter could be visualized reliably by CTA; (2) visibility of small vessels was improved by using source images; (3) the rate of complete agreement in stenosis measurement between CTA and DSA was 70% for MIP images alone and 80% if source images were also used; (4) the majority of wrong assessments were from the petrous portion of 129
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the carotid artery, although occlusions could be identified correctly; and (5) the closest correlation was seen in cases of occlusion (100% sensitivity, 93.4% positive predictive value) and high-grade stenosis (78% sensitivity, 81.8% positive predictive value). In 1999, this study was able to demonstrate that CTA technology at the time was as reliable as MRA in evaluating the intracranial vasculature, except for the petrous portion of the carotid. The same group of investigators examined further the accuracy of CTA in the posterior circulation.29 One hundred and three patients with suspected acute stroke in the posterior circulation underwent CTA and TCD. Of these, 22 patients also underwent DSA. The authors found that CTA was most reliable in evaluating basilar artery lesions, but had more difficulty in identifying stenosis in the vertebral artery. One particular issue was whether the distal segment of the vertebral artery was hypoplastic or stenotic. In addition, artifacts from the skull base added to the problem of assessing the vertebral artery accurately. However, CTA was more sensitive than DSA in its ability to demonstrate retrograde flow in the distal basilar. Performance of CTA in visualizing the intracranial anterior circulation has also been evaluated. CT angiograms of 54 patients were performed with careful exclusion of bone structures and individual reconstruction of each internal carotid artery (ICA).30 Each ICA was divided into four segments: supraclinoid, juxtasellar, presellar, and petrous. Two neuroradiologists independently reviewed routine MIP CTA, routine MIP with targeted CTA, and DSA images for the presence of aneurysm, ectasia, stenosis, or occlusion. The degree of stenosis was not measured. Visual-
ization of each ICA was judged as excellent, good, fair, or poor based on the number of segments that could be seen clearly. Targeted CTA provided better visualization of the ICA: 81% rated as good or excellent compared with 64% for routine MIP. Although visualization was improved significantly with targeted CTA, the overall agreement rates between the two types of CTA and DSA were not statistically different (92% for routine CTA vs 94% for targeted CTA). Both methods of CTA yielded false-positive findings in identifying steno-occlusive disease. Most were felt to be due to post-processing errors. In a small study, 18 patients with suspected intracranial atherosclerosis based on MRA also underwent CTA and DSA.31 Using DSA as the reference standard, the addition of CTA to MRA was found to raise the sensitivity of detecting lesions ≥50% stenosis from 92% to 100%, and raised the specificity from 91% to 99%. However, the authors did not examine the use of CTA alone in detecting these lesions. Combining noninvasive methods for evaluating intracranial vessels may improve sensitivity and specificity of detecting intracranial atherosclerotic disease, but may not be the most feasible or most cost-effective approach. More recently, larger studies compared the accuracy of CTA with DSA in diagnosing intracranial atherosclerotic disease (Fig. 10.2).32,33 Bash et al.32 retrospectively compared images from CTA, DSA, and MRA of 28 patients with suspected intracranial atherosclerosis. Neuroimaging studies were performed within 30 days of each other during the period between 1997 and 2000. CTA stenoses were detected by using 3-D data. Stenosis measurements were carried out on 2-D MPR images with an internal digital
Fig 10.2 Maximum intensity projection image from computed tomographic angiography (CTA) and corresponding frontal view from digital subtraction angiography (DSA) showing a severe stenosis of the left M1 segment. There is excellent correlation between CTA and DSA in the degree of stenosis.
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caliper. MRA and DSA stenosis measurements were made with a handheld digital caliper. MRA measurements were obtained on MIP images. After blinded as well as consensus interpretation of all images by two independent readers, the authors found that CTA had a higher sensitivity (98% vs 70%) and positive predictive value (93% vs 65%) than MRA when compared with DSA as the gold standard. In addition, when CTA and DSA images were analyzed side by side, CTA appeared more sensitive than DSA in detecting vessel patency in cases where slow flow possibly existed in the posterior circulation. The explanation may lie in the differences in image acquisition time for the two modalities. DSA images were obtained during a single intracranial circulation cycle, 5–7 seconds per cycle. CTA images were obtained over approximately 30 seconds using a four-detector helical scanner. This allowed for a larger volume of contrast to circulate intracranially and through a tight stenosis. Another study examined the accuracy of CTA in evaluating intracranial atherosclerotic disease compared with DSA utilized images from more modern CT scanners.33 Forty-one patients with suspected ischemic stroke or TIA with CTA and DSA performed within 30 days of each other between 2000 and 2006 were selected for the study. Two blinded readers independently reviewed all images. Stenosis on CTA was detected using all available reconstructions, including source images, MIP and/or 3-D data. Stenosis measurements were made on MIP images only. All measurements on CTA and DSA were made with handheld digital calipers. Disagreements of greater than 10% were adjudicated by a third reader. The study reported an intraclass correlation of 0.98 between CTA and DSA for all major intracranial arterial segments, with disease or not. Similar to prior studies, CTA was found to have 100% sensitivity and specificity for detecting occlusions. For detection of ≥50% stenosis, CTA had 97.1% sensitivity and 99.5% specificity. The authors also found that in order for CTA to detect all lesions ≥50% stenosis as determined by DSA, the screening cutoff point should be placed at ≥30% for CTA. However, the study did not have an adequate sample size to accurately determine the sensitivity and specificity of CTA for detecting ≥70% stenosis. It is important to determine CTA accuracy for 70–99% stenosis, since patients with this severe intracranial disease may need more aggressive and invasive treatment options than medical therapy. The
Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial,34 discussed in greater detail below, found in a small sample size that the negative predictive value (NPV) of CTA for detecting 70–99% intracranial stenosis was 84%, but that the positive predictive value (PPV) was poor. There is now a growing body of evidence for the use of CTA in evaluation of intracranial circulation. CTA does have some disadvantages. It requires the use of iodinated contrast, which may be an absolute contraindication in some patients. Dense and extensive mural calcification may reduce the accuracy of assessment for stenosis, although future advances in bone subtraction CTA will likely improve this scenario. The smallest arterial size that can be reliably detected by multidetector CTA has been reported to be 0.7 mm compared with 0.4 mm for DSA.35 Although these small intracranial arteries can be visualized by modern CTA, accurate measurement of vascular diameter in these arteries is difficult. Currently, the use of CT angiography is not recommended for diagnosing cerebrovascular abnormalities in the distal circulation such as vasculitis or mycotic aneurysms. CTA is also not as reliable as DSA in the determination of the presence of stenosis in small arteries beyond the first 1 cm of a vessel.35 How well CTA can evaluate restenosis within an intracranial stent is yet to be determined. As the technology develops further, CTA may overcome these current limitations. The growing popularity of CTA has been attributed to recent advances in CTA technology including faster speed, higher spatial resolution, and better postprocessing software. In addition to these technological advances, CTA has relatively lower costs, is more widely available, and appears to be more accurate than other non-invasive neuro-imaging techniques for the screening of intracranial atherosclerotic disease. Compared with DSA, CTA also has a better safety profile, can offer a greater number of viewing angles, and appears to be highly accurate in the evaluation of intracranial stenosis. CTA may be the preferred approach for identifying and following patients with intracranial atherosclerotic disease.
Magnetic resonance angiography MRA was developed in the 1980s36 and has been introduced into clinical practice in the past decade.37 131
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MRA quickly gained popularity as a tool for detecting intracranial (IC) atherosclerosis because it is a lowcost, low-risk procedure that can visualize the lumen. Most information gained about MRA has been from studies conducted in the extracranial vascular and peripheral arteries. There have only been a limited number of studies on the ability of MRA to detect intracranial atherosclerosis. Several MRA techniques are used for detecting intracranial atherosclerosis. The most common38 and extensively studied MRA technique is the 3D timeof-flight (TOF) sequence. The SONIA trial studied 3D-TOF MRA in a prospective, multicentered study.8 SONIA compared the diagnostic accuracy of 3D-TOF MRA against the gold standard, catheter angiography. The SONIA trial measured the PPVs and NPVs of MRA. A PPV measures how often an abnormal or positive result on the test correctly represents the disease, and the NPV is the measure of how often a negative test result correctly represents the absence of disease.39 The SONIA trial found that for a stenosis ≥50–99%, the PPV for MRA was 59% (95% CI: 54 to 65) and NPV was 91% (95% CI: 89 to 93),8 SONIA demonstrated that 3D-TOF MRA has a high NPV, and is therefore a reliable test to exclude disease. The PPV for MRA is low and therefore is not a sufficient test for detecting disease. Angiography should be used as a confirmation for an abnormal test result, especially before treatment. The prevalence of the disease also affects the predictive values and should be considered. If there is a very high prevalence of disease, then the positive predictive value will be greater. However, if the prevalence of the disease is very low in the population, then the positive predictive value will be decreased and more false positives can be expected.39 There is a low prevalence of intracranial atherosclerosis in the USA, where SONIA was performed, and this would relatively decrease the PPV. MRA would have a higher PPV in a population, such as China, which has a greater prevalence of intracranial atherosclerosis.40 There are other MRA techniques used for the detection of intracranial atherosclerosis besides 3D-TOF. One popular technique is the use of contrast agents. This is an appealing technique to lessen some of the traditional problems that occur with MRA. Contrastenhanced (CE) MRA is usually used with the contrast
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agent gadopentetate dimeglumine, with the optimal dosage of 5–10 mL.41 CE MRA appears to lessen the problem of overestimation of the length and degree of stenosis, a common obstacle with 3D-TOF MRA.41 CE MRA is also credited with being able to better visualize small vessels.42 Many studies support the use of CE MRA.38,42 However, these are often small studies without comparison to a gold standard. CE MRA also poses a small risk to the patient because of the use of contrast agents.43 CE MRA is promising, but lacks the needed rigorous study to be routinely adopted for clinical use. Another popular MRA technique is black blood (BB) MRA, which is named after the dark appearance of the blood vessels. BB MRA selectively saturates blood flow43 and has been suggested to be superior to TOF MRA when imaging vessels with irregular flow.44 BB MRA is less sensitive to the motion of breathing, which has been a significant problem in MRA. BB MRA holds promise to overcome some of the shortcomings of TOF MRA and provide better visualization of the vessels, but has only been used in limited studies in the intracranial vasculature and needs further investigation before this technique is adopted in common practice.44,45 Stenting is currently being researched for use in the intracranial arteries. Stenting is a promising and increasingly common treatment for intracranial stenosis. Metallic stents could theoretically pose a risk to the patient if they received an MRA after stent placement because of magnetic interactions.46 However, there are a number of stents on the market that do not have ferromagnetic properties and therefore would not pose a risk to the patient.46 These stents still cause an artifact on MRA that depends on the stent material, orientation, and direction of the magnetic field.46 Bartels et al.46 examined MRA artifacts produced by five low-artifact vascular stents. They determined that the stents produced both susceptibility artifacts and radiofrequency-induced eddy current artifacts, but that there were methods to reduce these artifacts. The authors also noted that the artifacts are dependent on the direction of the main magnetic field. These low-artifact stents, made from materials like nitinol, could be used with MRA, although they did create some difficulty with interpretation. Such artifacts preclude a reliable assessment with MRA of restenosis after stenting.
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Transcranial Doppler ultrasound Transcranial Doppler ultrasound (TCD) is another noninvasive diagnostic test that is commonly used for the diagnosis of intracranial atherosclerosis. The diagnostic accuracy of TCD was also measured in SONIA and compared against catheter angiography8 . TCD preformed similar to 3D-TOF MRA, having a high NPV 83% (95% CI: 79 to 86) and a lower PPV 55% (95% CI: 36 to 74).8 TCD will be discussed in greater detail in Chapter 12. In summary, several excellent noninvasive techniques for imaging the intracranial vasculature for intracranial atherosclerosis exist. As we continue to study and develop these tests, physicians should recognize the role of DSA as the gold standard, and the need for DSA when rigorous confirmation of the diagnosis is desired.
References 1 Demchuk AM, Christou I, Wein TH, et al. Accuracy and criteria for localizing arterial occlusion with transcranial Doppler. J Neuroimaging 2000; 101: 1–12. 2 Korogi Y, Takahashi M, Mabuchi N, et al. Intracranial vascular stenosis and occlusion: diagnostic accuracy of three-dimensional, Fourier transform, time-of-flight MR angiography. Radiology 1994; 1931: 187–93. 3 Dion JE, Gates PC, Fox AJ, et al. Clinical events following neuroangiography: a prospective study. Stroke 1987; 186: 997–1004. 4 Hass WK, Fields WS, North RR, et al. Joint study of extracranial arterial occlusion. II. Arteriography, techniques, sites, and complications. JAMA 1968; 20311: 961–968. 5 Theodotou BC, Whaley R, Mahaley MS. Complications following transfemoral cerebral angiography for cerebral ischemia. Report of 159 angiograms and correlation with surgical risk. Surg Neurol 1987; 282: 90–92. 6 Cloft HJ, Joseph GJ, Dion JE. Risk of cerebral angiography in patients with subarachnoid hemorrhage, cerebral aneurysm, and arteriovenous malformation: a metaanalysis. Stroke 1999 302: 317–320. 7 Moniz E. L’encephalographie arterielle, son impartance dans la localisaton des tumeurs cerebrales. Revue Neurologique 1927; 2: 72–90. 8 Feldmann E, Wilterdink JL, Kosinski A, et al. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) Trial. Neurology 2007; 68: 2099–2106.
9 Heiserman JE, Dean BL, Hodak JA, et al. Neurologic complications of cerebral angiography. AJNR Am J Neuroradiol 1994; 158: 1401–7; discussion 8–11. 10 Dion JE, Gates PC, Fox AJ, et al. Clinical events following neuroangiography: a prospective study. Stroke 1987; 186: 997–1004. 11 Hankey GJ, Jamrozik K, Broadhurst RJ, et al. Long-term risk of first recurrent stroke in the Perth Community Stroke Study. Stroke 1998 Dec; 2912: 2491–2500. 12 Chimowitz M. Warfarin vs. aspirin for symptomatic intracranial disease: Final results. 29th International Stroke Conference; 2004; San Diego. 13 Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352: 1305– 1316. 14 Fox AJ. How to measure caratid stenosis. Radiology 1993; 186: 316–318. 15 Samuels OB, Joseph GJ, Lynn MJ, et al. A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol 2000; 21: 643–646. 16 Bash S, Villablanca JP, Jahan R, et al. Intracranial vascular stenosis and occlusive disease: Evaluation with CT angiography, MR angiography, and conventional angiography. AJNR Am J Neuroradiol 2005; 26: 1012–1021. 17 Marks MP, Marcellus M, Norbash AM, et al. Outcome of angioplasty for atherosclerotic intracranial stenosis. Stroke 305: 1065–1069. 18 Dolmatch BL. The history of CT angiography. Endovascular Today 2005: 23–30. 19 Schoepf UJ, Becker CR, Bruening RD, et al. Multislice CT angiography. Imaging 2001; 13: 357–365. 20 Lell MM, Anders K, Uder M, et al. New techniques in CT angiography. RadioGraphics 2006; 26: S45–S62. 21 Cochran ST, Krasny RM, Danovitch GM. Helical CT angiography for examination of living renal donors. AJR Am J Roentgenol 1997; 168: 1569–1573. 22 Willmann JK, Mayer D, Banyai M, et al. Evaluation of peripheral arterial bypass grafts with multi-detector row CT angiography: comparison with duplex US and digital subtraction angiography. Radiology 2003; 2292: 465–474. 23 Smith WS, Tsao JW, Billings ME, et al. Prognostic significance of angiographically confirmed large vessel intracranial occlusion in patients presenting with acute brain ischemia. Neurocrit Care 2006; 41: 14–17. 24 Wintermark M, Meuli R, Browaeys P, Reichhart M, et al. Comparison of CT perfusion and angiography and MRI in selecting stroke patients for acute treatment. Neurology 2007; 689: 694–697. 25 Phillips CD, Bubash LA. CT angiography and MR angiography in the evaluation of extracranial carotid vascular disease. Radiol Clin North Am 2002; 404: 783–798.
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26 Alvarez-Linera J, Benito-Leon J, Escribano J, et al. Prospective evaluation of carotid artery stenosis: elliptic centric contrast-enhanced MR angiography and spiral CT angiography compared with digital subtraction angiography. AJNR Am J Neuroradiol 2003; 245: 1012–1019. 27 Josephson SA, Bryant SO, Mak HK, et al. Evaluation of carotid stenosis using CT angiography in the initial evaluation of stroke and TIA. Neurology 2004; 633: 457– 460. 28 Skutta B, Furst G, Eilers J, et al. Intracranial stenoocclusive disease: double-detector helical CT angiography versus digital subtraction angiography. AJNR Am J Neuroradiol 1999; 205: 791–799. 29 Graf J, Skutta B, Kuhn FP, Ferbert A. Computed tomographic angiography findings in 103 patients following vascular events in the posterior circulation: potential and clinical relevance. J Neurol 2000; 24710: 760–766. 30 Iwanaga S, Yoshiura T, Shrier DA, Numaguchi Y. Efficacy of targeted CT angiography in evaluation of intracranial internal carotid artery disease. Acad Radiol 2000; 75: 325–334. 31 Hirai T, Korogi Y, Ono K, et al. Prospective evaluation of suspected stenoocclusive disease of the intracranial artery: combined MR angiography and CT angiography compared with digital subtraction angiography. AJNR Am J Neuroradiol 2002; 231: 93–101. 32 Bash S, Villablanca JP, Jahan R, et al. Intracranial vascular stenosis and occlusive disease: evaluation with CT angiography, MR angiography, and digital subtraction angiography. AJNR Am J Neuroradiol 2005; 265: 1012– 1021. 33 Nguyen-Huynh MN, Wintermark M, English J, et al. How accurate is CT angiography in evaluating intracranial atherosclerotic disease. Stroke 2008; 39: 1184–1188. 34 Feldmann E, Wilterdink JL, Kosinski A, et al. The Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) trial. Neurology 2007; 6824: 2099–2106. 35 Villablanca JP, Rodriguez FJ, Stockman T, et al. MDCT angiography for detection and quantification of small intracranial arteries: comparison with conventional
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catheter angiography. AJR Am J Roentgenol 2007; 1882: 593–602. Pipe JG. Limits of Time-of-flight magnetic resonance angiography. Topics Magnetic Resonance Imaging 2001; 123: 163–174. Arlart I, Bongartz G, Marchal G. Magnetic resonance angiography, 2nd edn. New York, NY: Springer, 2003. Pedraza S. Comparison of preperfusion and postperfusion magnetic resonance angiography in acute stroke. Stroke 2004; 35: 2105–2110. Altman DF, Bland JM. Statistics notes: diagnostic tests 2: predictive values. Br Med J 1994; 309: 102. Feldmann E, Daneault N, Kwan E, et al. Chinese-white differences in the distribution of occlusive cerebrovascular disease. Neurology 1990; 4010: 1541–5. Jung HW, Chang KH, Choi DS, Han MH, Han MC. Contrast-enhanced MR angiography for the diagnosis of intracranial vascular disease: optimal dose of gadopentetate dimeglumine. Am J Roentgenol 1995; 1655: 1251– 1255. Yang JJ, Hill MD, Morrish Wfi, et al. Comparison of preand postcontrast 3D time-of-flight MR angiography for the evaluation of distal intracranial branch occlusions in acute ischemic stroke. Am J Roentgenol 2002; 23: 557– 567. Heiserman JE. Magnetic resonance angiography and evaluation of cervical arteries. Topics Magnetic Resonance Imaging 2001; 123: 149–161. Lui K, Margosian P. Multiple contrast fast spin-echo approach to black-blood intracranial MRA: use of complementary and supplementary information. Magnetic Resonance Imaging 2001; 199: 1173–1181. Naganawa S, Zto T, Shimada H, et al. Cerebral black blood MR angiography with the interleaved multi-slab three-dimensional fast spin echo sequence. Radiat Med. 1997; 156: 385–388. Bartels LW, Smits Hfi, Bakker CJ, Viergever MA. MR imaging of vascular stents: effects of susceptibility, flow, and radiofrequency eddy currents. J Vasc Interv Radiol 2001; 12: 365–371.
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Application of magnetic resonance imaging Dong-Wha Kang and Jong S Kim
The essential diagnostic step for intracranial atherosclerosis (ICAS) is vascular imaging such as catheter angiography, computed tomography angiography (CTA), magnetic resonance angiography (MRA), or transcranial Doppler (TCD) (see Chapters 10 and 12). Magnetic resonance imaging (MRI) is primarily a tool for the detection of acute or chronic cerebral infarcts resulting from ICAS. However, recent studies have shown that advanced MRI techniques provide clinicians with a variety of valuable information that vascular imaging cannot. This additional information includes the characterization of vessel walls or clot, the pathogenic mechanism of initial or recurrent strokes, and perfusion status, which can be obtained from various imaging techniques such as high-resolution magnetic resonance imaging (HR-MRI), gradient echo T2∗ -weighted imaging (GRE), and diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI). This chapter discusses the available data on the application of these MRI techniques in the assessment of ICAS.
Imaging the plaque Angiographies such as catheter angiography, MRA, or CTA have been used to diagnose large artery atherosclerosis. However, these methods provide the information on arterial luminal narrowing only, and cannot provide information on the characteristics of atherosclerotic walls. It has been well known that plaque vulnerability is the more important factor predicting myocardial infarction than the degree of
stenosis in patients with coronary artery disease.1 In carotid atherosclerosis, the mechanism of plaque rupture may be similar to that observed in coronary atherosclerosis.2 Although the role of the plaque rupture remains less clear in ICAS, it may initiate thrombus formation leading to artery-to-artery embolism or hemodynamic compromise resulting in clinical strokes.3 There has been a growing body of interest in the role of MRI for imaging the vessel wall or the plaque. Its usefulness in the detection of plaques has been demonstrated in the aortic arch and carotid disease.4,5 Plaque characteristics identified by HR-MRI in the carotid artery have been shown to correlate well with histologic findings. Research on the characteristics of intracranial vessel walls is limited. Klein et al.6 studied the usefulness of HR-MRI in the assessment of the basilar artery (BA) and middle cerebral artery (MCA) atherosclerosis with the use of 1.5 tesla MRI. They studied 24 patients with paramedian pontine infarcts extending to the basal surface. For high-resolution T2 examination, 12 slices were acquired in an axial plane along the short axis of the BA with slice thickness between 2 mm and 3 mm. On 3D time-of-flight (TOF) MRA, nine had normal basilar luminography, eight had irregular lumen, and the remaining seven had moderate-to-severe stenosis or occlusion of the BA. In contrast, definite atherosclerotic plaques were observed on HR-MRI in 18 patients. The atherosclerotic plaque was scored as “possible” in the remaining six patients, and none had normal basilar wall on HR-MRI. Plaque was clearly identified in all patients with high-grade or moderate
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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stenosis, and in seven of eight patients with basilar irregularity and even in five of nine patients with normal basilar lumen on TOF images. In some patients, plaques reduced the luminal diameter up to 50%, but TOF MRA showed normal findings or irregular BA lumen only. The authors also studied six patients with highgrade MCA stenosis using HR-MRI.7 For HR-MRI, 10 sections of T2-weighted images were acquired along the MCA short axis with slice thickness of 2.5 mm, and a post-contrast sequence was obtained 5 minutes after gadolinium injection. HR-MRI showed focal arterial wall thickening consistent with a plaque. In all cases, plaque enhancement was observed after gadolinium injection. Quantitative measurements of atherosclerotic MCA walls showed a significant increase in the wall thickness. Interestingly, the degree of MCA stenosis calculated from surface measurements was greater than the degree of stenosis estimated with diameters measured on MRA images. Since the number of included patients was small in these studies, further larger scale studies are needed to confirm the role of HR-MRI in identifying vessel wall abnormalities in patients with ICAS. Nevertheless, it seems that plaque imaging by HR-MRI has the following potential clinical implications. First, HR-MRI may identify atherosclerotic plaques before the changes are detected by luminography and may provide more sensitive and objective information on the burden of atherosclerosis than angiographic techniques. Plaque volume identified by HR-MRI may also serve as a potential surrogate marker of progression or regression of ICAS. Second, HR-MRI may be useful in evaluating the mechanism of stroke. For instance, a subcortical infarct considered to be due to small vessel occlusion would be recategorized as branch artery occlusion8 secondary to large artery atherosclerosis if HR-MRI were used. A cryptogenic stroke without evidence of arterial or cardiac source of embolism on conventional evaluations may be recategorized as a stroke due to artery-to-artery embolism if proximal atherosclerosis is identified on HR-MRI. Third, HRMRI may help clinicians to identify high-risk patients through demonstration of vulnerable plaques. These patients may have to be more aggressively treated and carefully monitored. Thus, the HR-MRI technique is a potentially promising noninvasive tool that can be used in clinical practice. 136
Imaging the clot The underlying pathophysiological mechanism of arterial occlusion in acute stroke is heterogeneous: the occlusion may be caused by intrinsic atherothrombosis or embolism from either the proximal artery or the diseased heart. Although the resultant clinical syndromes may be similar, differentiating between atherothrombotic and embolic occlusion is important because therapeutic or preventive strategies differ according to the underlying etiology. However, identifying the nature of the occluded thrombus remains challenging to clinicians. In the past years, there have been efforts to image intravascular thrombus with MRI. Analogous to the hyperdense MCA signs on CT,9 early vessel signs on MRI have been described as “hyperintense vessel sign” on fluid attenuation inversion recovery (FLAIR) images 10,11 and as “susceptibility vessel sign” on gradient-echo images (GRE SVS)12–14 in acute ischemic stroke patients. The presence of hyperintense vessels on FLAIR images has been considered to indicate the presence of slow flow or stasis in those vessels. In contrast, the substrate for the GRE SVS is paramagnetic deoxyhemoglobin and causes the loss of signal intensity; the presence of unpaired electrons in deoxyhemoglobin, methemoglobin, and hemosiderin gives them paramagnetic properties, producing an inhomogeneity in magnetic fields. Therefore, GRE SVS may allow us to examine the composition of the thrombus, thereby providing additional information regarding the pathogenesis of arterial occlusion. The characteristics of intraluminal clot are different according to the origin of the thrombus, i.e., the thrombus originated from intrinsic atherosclerosis, which derived from proximal atherosclerotic lesions, and the thrombus developed at cardiac chambers. White thrombi are predominantly composed of platelet aggregates, whereas red thrombi are rich in fibrin and trapped erythrocytes.15,16 White thrombi form in areas of high shear stress such as the arterial system whereas red thrombi form in low-pressure systems such as cardiac chambers or veins. To evaluate the significance of GRE-SVS in acute stroke, Cho et al.17 studied 95 patients with acute ischemic stroke associated with major intracranial artery occlusion who underwent DWI, GRE, and MRA within 24 hours of onset. They tested the hypothesis that GRE SVS may be closely associated with
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Fig 11.1 (A) A 61-year-old female patient with atrial fibrillation presented with right hemiparesis and aphasia. There are acute left MCA infarcts on DWI, a left MCA occlusion on MRA, and SVS in the occluded vessel on GRE (arrow) on acute scans (1 hour after onset). The patient was treated with intravenous tPA. Follow-up MRA shows complete recanalization of the left MCA. (B) A 56-year-old male patient presented with left hemiparesis. There are right striatocapsular infarcts on DWI, and a right MCA occlusion
on MRA, but no GRE SVS on acute scans (2 hours after onset). The patient was also treated with intravenous tPA. Follow-up MRA shows the right MCA is still completely occluded. The patient did not have cardioembolic sources, and was classified as having large artery atherosclerosis. DWI, diffusion-weighted imaging; GRE, gradient echo imaging; MRA, magnetic resonance angiography; MCA, middle cerebral artery; SVS, susceptibility vessel sign; tPA, tissue plasminogen activator.
a cardioembolic stroke. The assumption was based on the fact that the magnetic susceptibility effect of deoxygenated hemoglobin in red thrombi results in hypointense signals on GRE.18,19 The authors found that GRE SVS was indeed more frequently observed in cardioembolic stroke patients (31 out of 40, 78%) than in other stroke subtypes (14 out of 55, 25%). GRE SVS was independently associated with cardioembolic stroke after adjusting other clinical and imaging confounding factors (Fig. 11.1). Unfortunately, the diagnostic sensitivity (78%) and specificity (75%) of GRE SVS is not sufficiently high
for clinical application. The relatively high falsepositive and false-negative results may be explained by heterogeneous clot composition related to the age of the clot or the degree of fibrin organization. For example, in patients with unstable ICAS, platelet-rich clots may be superimposed by a fibrin network with numerous enmeshed red blood cells that may present as GRE SVS.20 Moreover, a recent analysis on embolectomy material obtained by retrieval devices showed that thromboemboli retrieved from the intracranial arteries of patients with acute ischemic stroke had similar histological components, whether derived from 137
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cardiac or arterial sources.21 In this context, GRE SVS can be used only as an adjunctive information in the acute evaluation of the etiology of the arterial occlusion.
Assessing the pathogenesis of infarction The random motion of water molecules affects magnetic resonance intensity differently according to different tissue characteristics. DWI is an MRI technique using this property. DWI can be obtained by the addition of a pair of symmetric, opposing gradient pulses to a standard pulse sequence. DWI is the most sensitive imaging modality to quickly and accurately detect acute ischemic lesions. The evidence linking DWI lesions with ischemic injury is strong. Ischemic brain lesions corresponding to clinical syndromes are detected by DWI with both high sensitivity and specificity.22–24 DWI also showed high accuracy (95%) for the detection of pathologically verified infarction.25 In general, DWI has the following advantages over CT or conventional MRI:26,27 DWI can (1) show hyperacute cerebral ischemic lesions within minutes after stroke onset, (2) show small cortical or brainstem infarcts that may not be detected on T2-weighted imaging, (3) differentiate between new and old infarcts, (4) detect clinically silent infarcts developed after various diagnostic or therapeutic procedures,28,29 (5) show relevant ischemic lesions in approximately half of patients presenting with transient ischemic attack (TIA),30 (6) show acute, multiple infarcts including asymptomatic as well as symptomatic lesions,31,32 a feature that can be used in the assessment of stroke mechanisms, and (7) identify early, sometimes asymptomatic recurrent ischemic lesions. There has been a great deal of effort to assess the stroke mechanism with the use of DWI, and previous studies have shown a close association between lesion patterns on DWI and the underlying mechanism of stroke.31–35 A variety of lesion patterns identified on DWI may provide a clue to understand the pathogenesis of ischemic stroke. For instance, when DWI reveals multiple acute infarcts in multiple vascular territories, embolism from the heart or systemic hypercoagulability may be considered.34,36 With respect to ICAS, it is less likely to observe acute silent infarcts in different cerebral circulations. Instead, DWI often shows small 138
silent cortical lesions in addition to symptomatic subcortical infarct, indicating the occurrence of silent embolism from diseased intracranial arteries in addition to the occlusion of the perforators.32 Possible mechanisms of cerebral infarction in ICAS include thrombosis leading to complete occlusion, artery-to-artery embolism, hemodynamic compromise, local branch occlusion, or a combination of these. Several studies using DWI have identified these mechanisms.37–40 Lee et al.38,39 reported, in two separate studies, clinical and radiological features of atherosclerotic MCA disease by comparison with cardioembolic MCA occlusion and internal carotid artery disease. They found that whereas territorial cortical or superficial perforator infarcts were associated with cardiac embolic disease or internal carotid artery disease, deep perforator infarcts, and internal borderzone infarcts were more common in atherosclerotic MCA disease. They also showed that deep perforator infarcts were more common in mild MCA stenosis, and borderzone infarcts were more common in severe stenosis or occlusion. Wong et al.40 used DWI and transcranial Doppler to study stroke mechanism in 30 acute ischemic stroke patients with MCA stenosis, and found that common stroke mechanisms were the occlusion of a single perforating artery to produce a small subcortical lacuna-like infarct and artery-toartery embolism to produce multiple cerebral infarcts. Lee et al.37 studied 185 acute MCA stroke patients and compared lesion patterns among atherosclerotic MCA disease (n = 63), internal carotid artery disease (n = 38), and cardioembolism (n = 84).37 They found that concomitant perforator and pial infarcts, concomitant perforator, pial and borderzone infarcts, and single small perforator infarcts were identified more frequently in patients with MCA disease than in those with internal carotid artery disease or cardioembolism. Small perforator infarcts were more common in patients with milder stenosis, whereas pial infarcts were more common in patients with severe stenosis or occlusion of MCA. Interestingly, these DWI studies show us a contradictory phenomenon in atherosclerotic MCA disease: clinically, lacunar syndrome is the most common, whereas radiologically, multiple infarcts are the most common, approximately 50%.37,40 Lee et al.37 found that 31 of 63 patients with atherosclerotic MCA disease presented with clinical lacunar syndromes, whereas DWI revealed multiple lesions in 15 of those
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Fig 11.2 (A) Perforating artery infarct + pial infarcts pattern: a 61-year-old man presented with transcortical sensory aphasia and right hemiparesis. (B) Perforating artery infarct + pial infarcts pattern: a 67-year-old woman presented with lacunar syndrome (dysarthria
and left hemiparesis); (C) Perforating artery infarct + pial infarcts + borderzone pattern: a 65-year-old man presented with transcortical mixed aphasia and right hemiparesis. Arrows indicate the site of middle cerebral artery disease.
31. Concomitant, small, cortical infarcts accompanied by symptomatic perforating artery infarcts were frequently noted in patients presenting with clinical lacunar syndrome (Fig. 11.2). Since the concomitant small cortical infarcts might not be detected by CT or conventional MRI, especially in the acute stage, the stroke subtype could be misclassified as small vessel occlusion if DWI were not used. The most common pattern of multiple infarcts in atherosclerotic MCA disease was the combination of perforating artery infarcts and pial or borderzone infarcts. Pial infarcts resulting from MCA disease may be the marker of embolism. Evidence of embolism in cortical branches from the thrombi generated in MCA
disease has been histopathologically documented.3,41 Border-zone infarcts may also be caused by embolism in a setting of hemodynamic compromise. Thus the combination of perforating artery infarcts and pial or borderzone infarcts in atherosclerotic MCA disease suggests that the combination of local branch occlusion and embolism, with or without hemodynamic compromise, is a common mechanism of stroke resulting from MCA disease. The concept of coexisting multiple stroke mechanisms has previously been proposed.42 As postulated by Caplan and Hennerici,42 the combination of embolism and hypoperfusion can lead to impaired clearance of emboli and produce infarcts in borderzone where perfusion is most impaired, 139
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especially in patients undergoing cardiac surgery43 or those with severe internal carotid stenosis.44 The coexistence of borderzone infarcts and territorial infarcts was frequent in those studies. Other important results obtained through these studies show that single perforating artery infarcts are the specific lesion pattern for atherosclerotic MCA disease. The precise pathogenic mechanism of perforating artery infarcts in atherosclerotic MCA disease is not clear, but it may be attributed to the following mechanisms. The atheroma in MCA may occlude the origin of a perforating artery and lead to a lacune-like infarct.8 Alternatively, small embolic particles arising from MCA atherosclerosis may lodge in an adjacent perforating artery.45 However, it is still possible that MCA disease is merely a bystander whereas the lacunar infarcts are caused by concomitant lipohyalinotic disease in the perforating artery. Future advanced imaging techniques to visualize perforating arteries will allow us to specify the stroke mechanism further. Thus, DWI provides us useful information regarding the pathogenic mechanism of infarcts. However, previous studies using DWI have had several limitations. Most importantly, the classification of lesion patterns and the definition of multiple infarcts are not consistent among studies. The time point that DWI is performed is also heterogeneous in these studies. It has been reported that new ischemic lesions frequently develop during the early post-stroke period,46 and lesion patterns on DWI may therefore be influenced by the time when DWI is performed. Although Wong et al.40 observed that the number of microembolic signals on transcranial Doppler predicted the number of acute infarcts detected on DWI in patients with atherosclerotic MCA disease, the link between lesion patterns and the real underlying mechanism has not been solidly established.
Assessing early recurrence of infarction Approximately 30% of strokes in population-based studies are recurrent events, and these recurrent strokes are more likely to be disabling or fatal than first strokes.47 The incidence of recurrent strokes is variable among studies, partly because of the inconsistency in the definition of a recurrent ischemic stroke. Recurrent strokes were variably defined as new strokes (1) pro140
ducing a new stroke syndrome unrelated to previously affected vascular territory or of different subtype from the previous stroke,48,49 (2) occurring after a certain period of time (21 days or 28 days) after the index stroke,50–52 or (3) associated with significantly worsening of the previous stroke scale.53 Considering that DWI can reliably detect small, clinically silent, acute ischemic lesions, serial DWI examinations may identify early recurrent ischemic lesions more sensitively and more objectively than evaluation based on clinical observation or the patient’s report. Clinically silent, early recurrent ischemic lesions (ERILs) on DWI have been found to be much more frequent than clinical recurrence within the first week and up to 1–3 months.46,54,55 Kang et al.46 studied 99 acute ischemic stroke patients who underwent DWI within 6 hours of onset and subsequent MRI within the first week. They found that 34% of the patients had recurrent lesions on DWI, and 15% showed “distant recurrent lesions” occurring outside the initial perfusion defect. Multiple infarcts shown on initial DWI were associated with the more frequent occurrence of ERILs within a week. The authors also studied 80 acute ischemic stroke patients who had initial MRI performed within 48 hours and follow-up MRI at 5 days and at 30 or 90 days after onset.55 Recurrent lesions on 30- or 90-day DWI or FLAIR occurred in 26% of patients, and were more frequently observed on 30-day MRI than 90-day MRI. Early lesion recurrence was an independent predictor of late lesion recurrence. Coutts et al.54 studied 143 patients with minor stroke (National Institutes of Health Stroke Scale <6) or TIA presenting within 12 hours of symptom onset who underwent baseline MRI and 1-month follow-up MRI. Fourteen patients (10%) had MRI evidence of new lesions at 30 days. Patients with multiple lesions at baseline were at an increased risk for new ischemic lesions. Sylaja et al.56 analyzed DWI and apparent diffusion coefficient (ADC) in 137 patients with acute stroke or TIA, and found that patients with multiple DWI lesions of varying ages (DWI-positive lesions with reduced and normalized ADC) were at higher risk of new infarcts on 30-day MRI than those with lesions of the same age. The risk of early recurrent stroke is likely related to the underlying etiologic stroke subtypes. Population-based studies have reported that patients with large artery atherosclerosis had the highest risk of early clinical recurrent stroke.52,57 DWI studies also
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showed that large artery atherosclerosis was the most frequent stroke subtype associated with recurrent ischemic lesions.46,54 These studies, however, were performed in Western countries, in which the prevalence of ICAS is much lower than that of extracranial atherosclerosis, and they did not distinguish between intracranial and extracranial atherosclerosis. Kang et al.58 studied 133 acute ischemic stroke patients with ICAS (n = 55), extracranial atherosclerosis (n = 19), or cardioembolism (n = 59), who underwent acute and follow-up DWI within a week. They found that ERILs were most common in ICAS than in any other stroke subtypes: ERILs were observed in 50.9% of patients with ICAS, 47.4% of those with extracranial atherosclerosis, and 44.1% of those with cardioembolism. ERILs in ICAS had the following characteristics. First, they occurred mostly in the pial area of the same vascular territory as the index stroke. This is consistent with the results of a long-term clinical follow-up study showing that in most patients with ICAS, clinical recurrence occurred at the territory of the referent artery, whereas the pattern of recurrence was unpredictable in patients with extracranial diseases.59 Considering that early recurrences occur more frequently in the same vascular territory as the initial stroke, restricting recurrent stroke to that occurring only in different vascular territory may substantially underestimate the incidence of early recurrence. Second, ERILs in ICAS were more frequently observed in patients with a higher grade of stenosis than in milder stenosis, whereas ERILs in patients with extracranial atherosclerosis were not related to the degree of stenosis. This finding seems to be consistent with the previous notion that the mechanism of stroke is different between ICAS and extracranial atherosclerosis. In ICAS, the progression of stenosis has been shown to be associated with an increased risk of recurrent ischemic stroke,60 associated with a greater risk of artery-to-artery embolization or hemodynamic failure. In contrast, in extracranial atherosclerosis, plaque heterogeneity rather than the degree of stenosis may be more important in pathogenesis.61 However, there is a limitation in generalizing this hypothesis, because the number of patients with extracranial atherosclerosis was small in the study of Kang et al. Third, whereas ERILs in cardioembolism were mostly associated with subsequent recanalization, ERILs in ICAS were not associated with subsequent
recanalization (Fig. 11.3). This result suggests that ERILs in patients with cardioembolism may result from fragmentation of the initial embolus, whereas those in ICAS appear to be caused by actual recurrence of ischemic events. In this regard, recurrent artery-toartery embolism or hemodynamic failure may be the plausible mechanism for ERILs in ICAS. Finally, ERILs in ICAS were more closely associated with clinical recurrence within the first week than in extracranial atherosclerosis or cardioembolism. Patients with stroke resulting from ICAS have been found to be at a high risk of recurrent stroke (more than 20% over 2 years), indicating a need for more aggressive therapies.62 These results suggest that ERILs in ICAS may be a marker of increased risk of clinical recurrence, and that ERILs can be used as a potential surrogate marker of clinical recurrence in clinical trials. A previous study also showed that the recurrence of silent ischemic lesions on MRI up to 90 days after stroke onset predicted subsequent clinical cerebrovascular events.63 However, additional studies are required to determine whether ERILs in ICAS are indeed associated with a higher risk of subsequent clinical events. Thus, DWI studies have shown that silent, early recurrent lesions are more frequent than clinical recurrence. These results broaden our understanding of the mechanism of stroke recurrence. Further prospective studies are needed to establish the clinical significance of silent recurrent lesions identified by DWI. Moreover, it should be explored whether pharmacologic intervention to reduce ERILs also prevents recurrence of clinical events.
Assessing the perfusion status PWI is a set of techniques that creates images depicting hemodynamics at the microvascular level. It shows perfusion abnormalities that are undetected by vascular imaging studies.64 PWI has an advantage over other tools such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) in that it can easily be combined with structural and vascular MRI in a single session. The most common technique to obtain perfusion parameters employs the intravenous bolus injection of a paramagnetic contrast agent. This dynamic susceptibility contrast approach creates large signal changes 141
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Fig 11.3 Patterns of early recurrent ischemic lesions (ERILs) related to recanalization in intracranial atherosclerosis (A) and cardioembolism (B) patients. Follow-up DWI in both showed multiple ERILs in the pial and/or borderzone areas (thin arrows). Follow-up MRA showed persistent middle cerebral artery stenosis in the
patient with intracranial atherosclerosis (A), whereas the artery was recanalized in the cardioembolism patient (B). (From Kang DW, Kwon SU, Yoo SH, et al. Early recurrent ischemic lesions on diffusion-weighted imaging in symptomatic intracranial atherosclerosis. Arch Neurol 2007; 64: 50–54, with permission.)
as the contrast passes through the brain vasculature. This technique generates time–contrast concentration curves, which allow the computation of the regional mean transit time (rMTT), time-to-peak (rTTP), and cerebral blood volume (rCBV) along with regional cerebral blood flow (rCBF). These perfusion parameters may be useful in guiding stroke therapy. The most sensitive MRI measure of abnormal perfusion is the rTTP map, which includes benign oligemic tissue rather than a truly penumbral area. Thus, an abnormal area detected by rTTP and rMTT images is usually greater than that shown in rCBF and rCBV images.
The ischemic penumbra is a region of critically underperfused but still viable tissue surrounding the infarct core. Rapid identification of the penumbra can allow rational therapeutic decisions to be made based on the assessment of pathophysiology in an individual patient. The combined use of DWI and PWI can allow assessment of at-risk or threatened brain tissue in the ischemic penumbra.65 The presence of penumbral tissue is estimated as the difference, or mismatch, between the perfusion defect on PWI and the ischemic core defined by DWI. Rapid evaluation of the presence and extent of the penumbra is likely to be valuable in the selection of patients for acute therapy.
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Fig 11.4 A 64-year old man presented with sensory aphasia and mild right hemiparesis (National Institutes of Health Stroke Scale score = 8), which had developed 12 hours prior to admission. On admission, diffusion-weighted imaging (DWI) (A and B) and perfusion-weighted imaging (C and D) showed large perfusion–diffusion mismatch, and magnetic resonance angiography (MRA) (E) showed complete occlusion of the left middle cerebral artery
(MCA). The next day, the patient deteriorated to global aphasia and right hemiplegia. Follow-up DWI (F and G) showed additional small new infarcts, and MRA (H) and catheter angiography (I) showed persistent MCA occlusion. Intraluminal angioplasty was performed and a stent was successfully used, resulting in complete revascularization of the MCA (J). The patient made a complete recovery.
Little is known about the natural evolution patterns of perfusion and diffusion abnormalities according to stroke subtypes. However, there may be substantial differences in acute ischemic lesion evolution between the thrombotic and embolic occlusion models. In an animal study using DWI and PWI, Henninger et al.66 compared the spatiotemporal evolution of ischemia in rats up to 180 minutes after permanent suture MCA occlusion (sMCAO; n = 8) and embolic MCA occlusion (eMCAO; n = 8). They found that compared with eMCAO animals, the CBF lesion volume was significantly smaller in sMCAO at all time points, and was highly correlated with the infarct size. The presence of PWI–DWI mismatch was shorter and mismatch volumes were smaller in the sMCAO model than in eMCAO animals. The results of the human study are partly consistent with those of the animal study. Kim et al. (unpublished data) studied 90 acute
MCA infarct patients with PWI–DWI mismatch (the rMTT lesion is 20% larger than the DWI lesion): 52 had intrinsic atherosclerotic MCA disease and 38 had cardioembolic MCA occlusion. They found that compared with the cardioembolic occlusion group, the intrinsic atherosclerotic MCA disease group had milder stroke and smaller infarct volume at baseline, and smaller infarct growth during the first 1 week after stroke. Smaller infarct growth within the PWI– DWI mismatch area in intrinsic MCA disease compared with cardioembolism is probably because intrinsic atherosclerotic disease is a more chronic occlusive process allowing for better collaterals or ischemic tolerance, resulting in less infarct growth, whereas cardioembolism is associated with more sudden embolic occlusion and poorly developed collaterals. In contrast, intrinsic atherosclerotic occlusive disease may be vulnerable to hemodynamic changes 143
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because cerebral perfusion largely depends on anterior or posterior leptomeningeal collaterals that are sometimes not sufficient to perfuse the whole MCA territory. PWI and DWI findings may provide a clue to understand the hemodynamic status: the presence of borderzone infarcts with a large PWI–DWI mismatch may indicate impending clinical deterioration. Thus, these MRI findings prompt us to consider urgent stroke therapy such as angioplasty or stenting, particularly in clinically fluctuating or worsening patients (Fig. 11.4).
Summary Advanced MRI techniques provide additional information on ICAS that conventional MRI or angiographic evaluation cannot. HR-MRI can visualize plaques in the vessel wall in normal-looking intracranial arteries on MRA. GRE images are useful in characterizing the nature of the clot and in predicting the origin of thrombi. The lesion patterns on DWI and early recurrence on serial DWI examinations help us to understand the pathogenic mechanism of initial and recurrent ischemic strokes in patients with ICAS. A combined use of DWI and PWI helps us to understand the tissue perfusion status of a particular patient and guides us to appropriate stroke therapy. These MRI techniques are currently available or can easily be added to conventional MRI. Further studies are needed to translate these MRI findings into diagnostic and therapeutic strategies, hopefully to improve the care of stroke patients.
References 1 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657–671. 2 Wasserman BA, Wityk RJ, Trout HH, 3rd, Virmani R. Low-grade carotid stenosis: looking beyond the lumen with MRI. Stroke 2005; 36: 2504–2513. 3 Ogata J, Masuda J, Yutani C, Yamaguchi T. Mechanisms of cerebral artery thrombosis: A histopathological analysis on eight necropsy cases. J Neurol Neurosurg Psychiatry 1994; 57: 17–21. 4 Toussaint JF, LaMuraglia GM, Southern JF, et al. Magnetic resonance images lipid, fibrous, calcified, hemorrhagic, and thrombotic components of human atherosclerosis in vivo. Circulation 1996; 94: 932–938.
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5 Yuan C, Miller ZE, Cai J, Hatsukami T. Carotid atherosclerotic wall imaging by MRI. Neuroimaging Clin N Am 2002; 12: 391–401, vi. 6 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. 7 Klein IF, Lavallee PC, Touboul PJ, Schouman-Claeys E, Amarenco P. In vivo middle cerebral artery plaque imaging by high-resolution MRI. Neurology 2006; 67: 327– 329. 8 Caplan LR. Intracranial branch atheromatous disease: A neglected, understudied, and underused concept. Neurology 1989; 39: 1246–1250. 9 Schuierer G, Huk W. The unilateral hyperdense middle cerebral artery: An early CT-sign of embolism or thrombosis. Neuroradiology 1988; 30: 120–122. 10 Kamran S, Bates V, Bakshi R, Wright P, Kinkel W, Miletich R. Significance of hyperintense vessels on FLAIR MRI in acute stroke. Neurology 2000; 55: 265–269. 11 Toyoda K, Ida M, Fukuda K. Fluid-attenuated inversion recovery intraarterial signal: An early sign of hyperacute cerebral ischemia. AJNR Am J Neuroradiol 2001; 22: 1021–1029. 12 Chalela JA, Haymore JB, Ezzeddine MA, et al. The hypointense MCA sign. Neurology 2002; 58: 1470. 13 Flacke S, Urbach H, Keller E, et al. Middle cerebral artery (MCA) susceptibility sign at susceptibility-based perfusion MR imaging: Clinical importance and comparison with hyperdense MCA sign at CT. Radiology 2000; 215: 476–482. 14 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. 15 Friedman M, Van den Bovenkamp GJ. The pathogenesis of a coronary thrombus. Am J Pathol 1966; 48: 19– 44. 16 Jorgensen L, Torvik A. Ischaemic cerebrovascular diseases in an autopsy series. I. Prevalence, location and predisposing factors in verified thrombo-embolic occlusions, and their significance in the pathogenesis of cerebral infarction. J Neurol Sci 1966; 3: 490–509. 17 Cho KH, Kim JS, Kwon SU, et al. Significance of susceptibility vessel sign on T2∗ -weighted gradient echo imaging for identification of stroke subtypes. Stroke 2005; 36: 2379–2383. 18 Osborn AG. Diagnostic neuroradiology 1994: 154–173. 19 Patel MR, Edelman RR, Warach S. Detection of hyperacute primary intraparenchymal hemorrhage by magnetic resonance imaging. Stroke 1996; 27: 2321–2324.
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20 Brogan GX, Jr. Bench to bedside: Pathophysiology of acute coronary syndromes and implications for therapy. Acad Emerg Med 2002; 9: 1029–1044. 21 Marder VJ, Chute DJ, Starkman S, et al. Analysis of thrombi retrieved from cerebral arteries of patients with acute ischemic stroke. Stroke 2006; 37: 2086–2093. 22 Fiebach JB, Schellinger PD, Jansen O, et al. CT and diffusion-weighted MR imaging in randomized order: Diffusion-weighted imaging results in higher accuracy and lower interrater variability in the diagnosis of hyperacute ischemic stroke. Stroke 2002; 33: 2206– 2210. 23 Lovblad KO, Laubach HJ, Baird AE, et al. Clinical experience with diffusion-weighted MR in patients with acute stroke. AJNR Am J Neuroradiol 1998; 19: 1061–1066. 24 van Everdingen KJ, van der Grond J, Kappelle LJ, et al. Diffusion-weighted magnetic resonance imaging in acute stroke. Stroke 1998; 29: 1783–1790. 25 Kelly PJ, Hedley-Whyte ET, Primavera J, et al. Diffusion MRI in ischemic stroke compared to pathologically verified infarction. Neurology 2001; 56: 914–920. 26 Warach S, Chien D, Li W, et al. Fast magnetic resonance diffusion-weighted imaging of acute human stroke. Neurology 1992; 42: 1717–1723. 27 Warach S, Gaa J, Siewert B, et al. Acute human stroke studied by whole brain echo planar diffusion-weighted magnetic resonance imaging. Ann Neurol 1995; 37: 231– 241. 28 Derdeyn CP. Diffusion-weighted imaging as a surrogate marker for stroke as a complication of cerebrovascular procedures and devices. AJNR Am J Neuroradiol 2001; 22: 1234–1235. 29 Rordorf G, Bellon RJ, Budzik RE, Jr, et al. Silent thromboembolic events associated with the treatment of unruptured cerebral aneurysms by use of guglielmi detachable coils: Prospective study applying diffusion-weighted imaging. AJNR Am J Neuroradiol 2001; 22: 5–10. 30 Kidwell CS, Alger JR, Di Salle F, et al. Diffusion MRI in patients with transient ischemic attacks. Stroke 1999; 30: 1174–1180. 31 Baird AE, Lovblad KO, Schlaug G, Edelman RR, Warach S. Multiple acute stroke syndrome: Marker of embolic disease? Neurology 2000; 54: 674–678. 32 Roh JK, Kang DW, Lee SH, Yoon BW, Chang KH. Significance of acute multiple brain infarction on diffusionweighted imaging. Stroke 2000; 31: 688–694. 33 Bonati LH, Lyrer PA, Wetzel SG, Steck AJ, Engelter ST. Diffusion weighted imaging, apparent diffusion coefficient maps and stroke etiology. J Neurol 2005; 252: 1387–1393. 34 Engelter ST, Wetzel SG, Radue EW, et al. The clinical significance of diffusion-weighted MR imaging in infratentorial strokes. Neurology 2004; 62: 574–580.
35 Kang DW, Chalela JA, Ezzeddine MA, Warach S. Association of ischemic lesion patterns on early diffusionweighted imaging with TOAST stroke subtypes. Arch Neurol 2003; 60: 1730–1734. 36 Cho AH, Kim JS, Jeon SB, et al. Mechanism of multiple infarcts in multiple cerebral circulations on diffusionweighted imaging. J Neurol 2007; 254: 924–930. 37 Lee DK, Kim JS, Kwon SU, et al. Lesion patterns and stroke mechanism in atherosclerotic middle cerebral artery disease: Early diffusion-weighted imaging study. Stroke 2005; 36: 2583–2588. 38 Lee PH, Oh SH, Bang OY, et al. Isolated middle cerebral artery disease: Clinical and neuroradiological features depending on the pathogenesis. J Neurol Neurosurg Psychiatry 2004; 75: 727–732. 39 Lee PH, Oh SH, Bang OY, et al. Infarct patterns in atherosclerotic middle cerebral artery versus internal carotid artery disease. Neurology 2004; 62: 1291–1296. 40 Wong KS, Gao S, Chan YL, et al. Mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: A diffusion-weighted imaging and microemboli monitoring study. Ann Neurol 2002; 52: 74– 81. 41 Masuda J, Ogata J, Yutani C, et al. Artery-to-artery embolism from a thrombus formed in stenotic middle cerebral artery. Report of an autopsy case. Stroke 1987; 18: 680–684. 42 Caplan LR, Hennerici M. Impaired clearance of emboli (washout) is an important link between hypoperfusion, embolism, and ischemic stroke. Arch Neurol 1998; 55: 1475–1482. 43 Wityk RJ, Goldsborough MA, Hillis A, et al. Diffusionand perfusion-weighted brain magnetic resonance imaging in patients with neurologic complications after cardiac surgery. Arch Neurol 2001; 58: 571–576. 44 Kang DW, Chu K, Ko SB, et al. Lesion patterns and mechanism of ischemia in internal carotid artery disease: A diffusion-weighted imaging study. Arch Neurol 2002; 59: 1577–1582. 45 Fisher CM. Capsular infarcts: The underlying vascular lesions. Arch Neurol 1979; 36: 65–73. 46 Kang DW, Latour LL, Chalela JA, et al. Early ischemic lesion recurrence within a week after acute ischemic stroke. Ann Neurol 2003; 54: 66–74. 47 Coull AJ, Rothwell PM. Underestimation of the early risk of recurrent stroke: Evidence of the need for a standard definition. Stroke 2004; 35: 1925–1929. 48 Moroney JT, Bagiella E, Paik MC, et al. Risk factors for early recurrence after ischemic stroke: The role of stroke syndrome and subtype. Stroke 1998; 29: 2118–2124. 49 Sacco RL, Foulkes MA, Mohr JP, et al. Determinants of early recurrence of cerebral infarction. The Stroke Data Bank. Stroke 1989; 20: 983–989.
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50 Burn J, Dennis M, Bamford J, et al. Long-term risk of recurrent stroke after a first-ever stroke. The Oxfordshire Community Stroke Project. Stroke 1994; 25: 333– 337. 51 Hankey GJ, Jamrozik K, Broadhurst RJ, et al. Long-term risk of first recurrent stroke in the Perth community stroke study. Stroke 1998; 29: 2491–2500. 52 Petty GW, Brown RDJ, Whisnant JP, et al. Ischemic stroke subtypes : A population-based study of functional outcome, survival, and recurrence. Stroke 2000; 31: 1062– 1068. 53 Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: A doubleblind randomised study. HAEST study group. Heparin in Acute Embolic Stroke Trial. Lancet 2000; 355: 1205– 1210. 54 Coutts SB, Hill MD, Simon JE, et al. Silent ischemia in minor stroke and TIA patients identified on MR imaging. Neurology 2005; 65: 513–517. 55 Kang DW, Latour LL, Chalela JA, et al. Early and late recurrence of ischemic lesion on MRI: Evidence for a prolonged stroke-prone state? Neurology 2004; 63: 2261– 2265. 56 Sylaja PN, Coutts SB, Subramaniam S, et al. Acute ischemic lesions of varying ages predict risk of ischemic events in stroke/TIA patients. Neurology 2007; 68: 415– 419. 57 Lovett JK, Coull AJ, Rothwell PM. Early risk of recurrence by subtype of ischemic stroke in population-based incidence studies. Neurology 2004; 62: 569–573. 58 Kang DW, Kwon SU, Yoo SH, et al. Early recurrent ischemic lesions on diffusion-weighted imaging in symp-
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tomatic intracranial atherosclerosis. Arch Neurol 2007; 64: 50–54. Shin DH, Lee PH, Bang OY. Mechanisms of recurrence in subtypes of ischemic stroke: A hospital-based follow-up study. Arch Neurol 2005; 62: 1232–1237. Arenillas JF, Molina CA, Montaner J, et al. Progression and clinical recurrence of symptomatic middle cerebral artery stenosis: A long-term follow-up transcranial Doppler ultrasound study. Stroke 2001; 32: 2898–2904. AbuRahma AF, Wulu JT, Jr, Crotty B. Carotid plaque ultrasonic heterogeneity and severity of stenosis. Stroke 2002; 33: 1772–1775. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352: 1305– 1316. Kang DW, Lattimore SU, Latour LL, Warach S. Silent ischemic lesion recurrence on magnetic resonance imaging predicts subsequent clinical vascular events. Arch Neurol 2006; 63: 1730–1733. Staroselskaya IA, Chaves C, Silver B, et al. Relationship between magnetic resonance arterial patency and perfusion-diffusion mismatch in acute ischemic stroke and its potential clinical use. Arch Neurol 2001; 58: 1069–1074. Kidwell CS, Alger JR, Saver JL. Evolving paradigms in neuroimaging of the ischemic penumbra. Stroke 2004; 35: 2662–2665. Henninger N, Sicard KM, Schmidt KF, et al. Comparison of ischemic lesion evolution in embolic versus mechanical middle cerebral artery occlusion in sprague dawley rats using diffusion and perfusion imaging. Stroke 2006; 37: 1283–1287.
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Transcranial Doppler Qing Hao, Ka Sing Lawrence Wong and Andrei V Alexandrov
Among a variety of neuroimaging techniques that investigate intracranial vessels for the presence of an atherosclerotic stenosis, transcranial Doppler (TCD) is the most convenient, cheapest, and non-invasive test.1 In the past several decades, TCD has been brought to acute stroke units, emergency rooms, operating rooms, outpatient clinics, and even to community screening, to reveal stenosis of large arteries, assess the hemodynamic changes, and monitor progression of lesions. This proved to be very helpful in understanding the mechanism of cerebrovascular disease and choosing treatment strategies.2–10 The common applications of TCD include: evaluation of intracranial steno-occlusive disease, detection of vasospasm after spontaneous subarachnoid hemorrhage, vasomotor reactivity testing, brain death, monitoring carotid endarterectomy, thrombolysis, and coronary artery bypass graft operations.11 For patients with intracranial atherosclerotic disease, the main and also the most important role of TCD is to first detect large artery steno-occlusive lesions. Unlike magnetic resonance angiography (MRA), computed tomography angiography (CTA) and digital subtraction angiography (DSA), TCD examination is operator dependent. In order to improve the accuracy of the diagnosis of an arterial stenosis, we must first consistently apply a standard scanning protocol with hand-held transducers and interpret the results using knowledge of anatomy, physiology, and pathology of the vascular and nervous systems. Performance skills
and interpreting methods are two key considerations in TCD examinations. Since TCD offers real-time assessment of cerebral hemodynamics and deploys a 2 MHz frequency able to detect transient high-intensity signals, it is also used to detect microembolic signals (MES) caused by large artery stenosis or monitor MES intra-operatively during carotid interventions and cardiac surgery.12–15 Continuous TCD monitoring may also enhance recanalization during thrombolytic therapy for acute ischemic stroke. This is a newly developed therapeutic application of this technology.16
The physics and principles of transcranial Doppler Physical principles Ultrasound When the vibration frequency of a sound is above 16 000 Hz, it is called ultrasound since it is beyond the range that the human ear can detect. The diagnostic frequency of ultrasound is 1–20 MHz, which has no adverse biological effects according to the current literature for intensities below 700 mW. Doppler effects TCD is based on the Doppler effect, which was named after the famous mathematician Christian Doppler, who in 1842 attempted to explain color shift in light from moving galaxies. The Doppler effect explains
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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a phenomenon where the sound wave from a moving source is perceived as having a higher pitch (due to increased frequency) when the source is approaching the listener and a lower pitch (due to decreased frequency) when the source is moving away. If the sound source is stationary and the reflector is moving, the frequency of reflected sound will still change. The change from the emitted frequency is called Doppler shift, and the faster the velocity of a moving object, the greater the frequency change. If the change in frequency is known, the velocity and the direction of the reflector movement can be calculated. However, measurement of the frequency shift will be most accurate if the reflector moves in a direction parallel to the emission ultrasound. In TCD, it is assumed that all reflectors or vessels are intercepted at a zero-degree angle and this removes the need for angle correction. Furthermore, the assumed zero-degree angle allows TCD to never overestimate the velocity. Continuous wave mode and pulse wave mode Ultrasound is emitted and received by the transducer, which utilizes the piezoelectric effect to convert electrical energy into mechanical ultrasound energy and vice versa. If the transducer has two crystals with one constantly emitting and another receiving the ultrasound waves, it is called continuous wave (CW) Doppler. This form of ultrasound cannot identify the distance from the reflector to the transducer. If a single crystal is used first to emit an ultrasound wave and then receive a return echo at a certain time interval, it is called pulsed wave (PW) mode. Since PW ultrasound can identify the distance from the reflector to the transducer, it can be used for intracranial Doppler examinations as well as structural and functional imaging with ultrasound. Transcranial power motion mode Mark Moehring first introduced transcranial power motion mode (PMD or M-mode) in 2002 and motion mode in general has now become a part of most TCD equipment.17 It can facilitate window location and alignment of the ultrasound beam to view blood flow from multiple vessels simultaneously, thus helping an inexperienced person to find the acoustic window and identify intracranial vessels. PMD is also used for multi-vessel, multi-depth emboli tracking and as a
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guide to more thorough spectral Doppler examination of the intracranial vessels. Transcranial color-coded duplex sonography Although spectral Doppler velocity measurement remains the mainstay of vascular ultrasound examinations, transcranial color-coded duplex sonography (TCCD) has also been developed to help guide Doppler examinations with structural brightnessmodulated (B-mode) and functional color flow imaging of the brain and proximal vasculature. TCCD can identify arteries more accurately, since branches of the circle of Willis are recognized more easily with imaging.18 Previous studies showed that the velocities measured with angle correction on TCCD were significantly greater than those attained with TCD in all vessels.19,20 Owing to the differences in transducers and emitting crystals, TCCD generally tends to fail to detect acoustic windows more often than TCD. This can be corrected by application of intravenous ultrasound contrast agents. Hemodynamic principles21 Flow resistance Similar to the electric current, the blood flow rate (Q) in a vessel is determined by the pressure difference between the beginning and the end of the vessel (P) and the resistance (R): Q = P/R
(12.1)
Under ideal conditions of laminar flow and constant viscosity in a rigid cylindrical tube, the Hagen– Poiseuille law describes further flow dependence on the following: Q = Pr 4 π/8ηl
(12.2)
The flow rate is dependent on the viscosity (η) length (l) and radius of the tube (r ). If equations 12.1 and 12.2 are combined, the flow resistance will be: R = 8ηl/r 4 π
(12.3)
Increased viscosity and decreased vessel radius will lead to high resistance. Flow velocity The arterial flow velocity (v) is proportional to the flow rate (Q) and inversely proportional to the vessel
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cross-sectional area (πr 2 ): v = Q/πr 2
(12.4)
Halving the vessel radius doubles the velocity in the Spencer’s curve, which provides a theoretical basis of why the flow velocity can reflect the severity of the stenosis. Decreasing viscosity will also lead to an increase in velocities. Turbulent flow The Reynolds number summarizes factors that will affect the generation of a turbulent flow instead of laminar flow: flow velocity (v), vessel diameter (r ), and density of the blood (ρ): Re = 2r v(η/ρ)
(12.5)
With smooth vessel walls, turbulent flow will appear if the Reynolds number is between 2000 and 2200. Turbulent flow tends to occur at sites of curvature or expansion of vessels. It can be found distal to a high-grade stenosis, where chaotic motion of blood occurs in the post-stenotic dilation. However, since TCD examination is usually carried out with a large sample volume that covers both stenotic and poststenosis segments, the sound of turbulence can be heard along with maximal velocities at the site of stenosis. Turbulence is not always a sign of a stenosis since other hemodynamic factors can produce this phe-
nomenon, such as anemia, increased cardiac output, and flow collateralization. There are several findings that indicate the presence of turbulence in intracranial vessels. 1 Low-frequency turbulence appears as highintensity/low-frequency signals above and below the baseline, usually seen in systolic and may be accompanied by an audible bruit. 2 High-frequency turbulence appears as spindle-like clusters near the baseline and may be accompanied by a more pronounced audible component. 3 Musical murmurs appear as short arch-like signals aligned above and below the baseline symmetrically and accompanied by sounds that resemble musical tones. These signals are quite often recognized by sonographers as signs of turbulence; however, they do not represent a measurement of turbulence and their significance is not known in grading the severity of an arterial stenosis.
Examination techniques for intracranial arteries In TCD examination, an artery can be identified by the following criteria (Table 12.1).21,22 First, determine the position and the angle of the probe; second, the insonation depth; third, the direction of the flow. The power, sample volume, gain, scale, zero line, and envelope should be adjusted properly to display the spectrum clearly.
Table 12.1 Criteria for identifying arteries in transcranial Doppler Artery
Acoustic window
Insonation depth (mm)
Frequency shift
Pulsatility index
MCA ACA PCA TICA OA Siphon ICA VA BA
Temporal Temporal Temporal Temporal Orbital Orbital Occipital Occipital
30–65 60–75 55–75 60–70 40–50 60–75 40–75 75–120
Positive Negative P1: Positive; P2: Negative Positive Positive Positive or negative Negative Negative
Low (<1.2) Low Low Low High Low Low Low
ACA, anterior carotid artery; BA, basilar artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior cerebral artery; ophthalmic artery, OA; terminal internal carotid artery, TICA; VA, vertebral artery.
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Fig 12.1 Normal MCA and ACA flow detected by TCD.
Since TCD is extremely operator dependent, it is important for sonographers to follow a standard insonation protocol and to obtain sufficient training.21–24
Fig 12.2 Reverse positive flow in ACA due to ipsilateral proximal ICA occlusion.
3 Flow direction: A positive M1 MCA signal means that the blood flow moves towards the probe. A negative signal with the depth less than 50 mm may suggest the M2 segment or transcortical collateral flow in the presence of ipsilateral ICA severe stenosis or occlusion.
Middle cerebral artery (Fig. 12.1) 1 Position and the angle of the probe: Put the probe at the preauricular temporal window, which is above the zygomatic arch and anterior to the ear. The probe should be aimed slightly upward and anterior to intercept M1 and M2 segments of the MCA. 2 Insonation depth: The origin of MCA is located at 60–70 mm; the distal segment can be as shallow as 30 mm. It is better to start from the stem of M1 MCA, which will be at a depth of 50–60 mm, and then follow the signal to the distal M1 and M2 at a depth of 30–50 mm, then MCA–ACA (middle cerebral artery/anterior carotid artery) bifurcation at depths of 60–65 mm, and to the terminal internal carotid artery (ICA) at depth of 65–70 mm. Since M1 MCA is the continuation of the terminal ICA, it is difficult to differentiate these two clearly. Follow the rule “go with the flow.”
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Anterior cerebral artery (Fig. 12.2) 1 Position and the angle of the probe: Continue temporal window examination and visualize bidirectional signals with increasing depth of insonation. 2 Insonation depth: A1 ACA can be detected from a depth of 60–75 mm. 3 Flow direction: The signal is negative. However, in the presence of severe ipsilateral ICA, severe stenosis, or occlusion, the A1 ACA flow can reverse because of anterior cross-filling from the contralateral ICA through the anterior communicating artery (AcomA). Under this condition, the positive signal can be traced from the depth of the MCA to 80 mm (Fig. 12.2). Negative signals can also be present if retrograde filling of the ICA siphon occurs from the same collateral flow.
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Posterior cerebral artery 1 Position and the angle of the probe: Continue with the temporal window insonation and turn the transducer posteriorly and slightly downward if necessary away from the MCA–ACA bifurcation signal. 2 Insonation depth: P1 and P2 PCA (posterior cerebral artery) can be detected from depth of 55–75 mm. P1 PCA will be detected at a deeper depth than P2 PCA. 3 Flow direction: The signal is positive for P1 PCA and proximal P2, negative for more distal aspect of P2. In the presence of posterior circulation stenosis, the posterior communicating artery (PcomA) is negative because the collateral flow is established from the anterior circulation, and vice versa. It can also be bidirectional due to tortuosity of PcomA and adjacent vessels. Ophthalmic artery and siphon internal carotid artery (Fig. 12.3) 1 Position and the angle of the probe: Put the probe gently over the closed eyelid on a more lateral aspect and aim slightly towards the inner corner of the orbit. 2 Insonation depth: OA can be detected from depth of 40–60 mm, and siphon ICA from 60–75 mm.
Fig 12.3 Normal OA and siphon ICA flow detected by TCD.
3 Flow direction: The signal is positive for OA, positive for cavernous segment of the siphon, and negative for its supraclinoid segment. A reversed OA flow with low pulsatility is a sensitive sign for severe stenosis or occlusion in the ipsilateral ICA.25 However, most patients with ICA occlusion do not have reversed OA due to competency of the intracranial collaterals of the circle of Willis. Vertebral artery and basilar artery (Fig. 12.4) 1 Position and the angle of the probel: Have the patient sit or lie laterally with the head slightly tilted forward, put the probe slightly to the right or the left of the midline. 2 Insonation depth: VA can be detected from depths of 40–75 mm, and basilar artery (BA) from 75–120 mm. 3 Flow direction: The signal is negative for VA and BA. Positive signals can originate from the posterior inferior (PICA), anterior inferior (AICA), and superior (SCA) cerebellar arteries. In the presence of a severe stenosis or occlusion in the ipsilateral proximal subclavian artery, VA flow can reverse completely or in systoli showing an alternating signal with high pulsatility towards the probe since the VA now supplies the arm. If the collateral flow comes from the anterior
Fig 12.4 Reversed flow in left VA due to occlusion of the ipsilateral proximal subclavian artery. Black arrow, normal side VA; black arrow; head; BA.
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circulation through BA, the flow of BA will also reverse. This condition is known as the subclavian steal.
Diagnosis for intracranial large artery stenosis Numerous studies have been performed to explore the accuracy and best criteria for diagnosis of intracranial large artery stenosis.26–36 TCD has higher accuracy for detection of stenoses in the MCA and BA than in other vessels since these vessels are less tortuous than other arteries. Current diagnostic criteria focus mainly on the middle cerebral artery >50% stenosis and are mostly based on velocity alone (peak velocity or mean velocity). In clinical practice, interpretation of TCD findings should take multiple parameters into account and be individualized, i.e., not only the velocity values, but also spectrum, waveform patterns, flow pulsatility, presence of collateral flows, conditions of extracranial vessels, systemic conditions, etc. Generally, all these parameters can be divided into direct changes detected at the stenosis, and the indirect changes seen in other vessels.
Diagnostic criteria for MCA Navarro et al.37 systematically reviewed the accuracy of TCD compared with digital subtraction angiography (DSA) for the diagnosis of ≥50% MCA stenosis. In this review, mean flow velocities (MFV) of 80 cm/second and MFV of 100 cm/second were frequently used as the cut-off value. In addition, one study also adopted segmental increase in systolic peak frequency of more than 20%26 ; another study used a prestenotic to stenotic MCA velocity ratio of 1: ≥2 in addition to the MFV threshold.32 This review also showed the overall accuracy of MFV = 100 cm/second was more balanced with sensitivity 91.8%, specificity 92.2%, PPV 88.8%, and NPV 98.4%. Owing to differences in patient populations, scanning protocols, and analyzed parameters, these published data can be used as a guide for development and validation of local diagnostic criteria to be used by a particular laboratory. In addition to the focal velocity increase, the velocity decrease should also be considered seriously. In the condition of severe stenosis or occlusion, the velocity 152
will fall to another side of the Spencer’s curve.38,39 Diffuse intracranial stenosis can also produce a decrease in velocity with high pulsatility.35 To identify these abnormally decreased velocities, it is important to examine the differences between homologous arteries, the differences between anterior and posterior circulation, the waveform pattern, and pulsatility index(PI) values. To diagnose MCA stenosis, the following parameters should be considered.24 1 Focal velocity increase: MFV ≥ 100 cm/second or PSV > 140 cm/second or follow locally validated velocity criteria; if velocity increase appears to be global, i.e., in ACA, PCA, and VA–BA, check systemic hemodynamics (e.g., anemia can produce these findings). Velocity decrease: MFV < 30 cm/second with MCA < ACA or any other intracranial artery: suspicious of MCA subtotal stenosis or near occlusion. Note that diffuse intracranial disease can produce low velocity and PI ≥ 1.2 in multiple vessels. 2 The difference between bilateral MCAs, MCA and ACA, MCA and PCA: a difference >30% should be considered abnormal for high velocity findings. 3 The spectrum pattern: The presence of low frequency turbulence, high frequency turbulence, contour oscillation, musical murmurs suggest significant stenosis (Fig. 12.5). 4 The waveform pattern: The blunted waveform with low pulsatility usually suggests stenosis proximal to the site of insonation; dampened waveform with high pulsatility usually suggest distal obstructions (Fig. 12.6). Diagnostic criteria for other arteries24 There are few reports about the diagnostic criteria for the anterior, posterior cerebral arteries, siphon and terminal internal carotid artery, and the vertebrobasilar artery. One study used MFV ≥ 100 cm/second as abnormal for ACA, MFV ≥ 50 cm/second for PCA, VA and BA,35 one study used PSV ≥ 120 cm/second for ACA and SICA, PSV ≥ 100 cm/second for PCA, VA and BA.6 The multicenter SONIA study showed when diagnosing >50% stenosis with a single velocity threshold, the accuracy is not as reliable (PPV = 55%, NPV = 83%) when using a cut-off value of MFV = 90 cm/second for intracranial ICA, 80 cm/second for VA and BA.40 Besides simplification of diagnostic criteria, these results may be due to tortuosity of these
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A
B
C
D
Fig 12.5 Spectral patterns. (A) normal; (B) low frequency turbulence; (C) high frequency turbulence; (D) musical murmurs.
vessels, which will compromise the accuracy because of the increased insonation angle. Another reason is that anatomical variations are common in ACA and VA, which may further contribute to velocity asymmetry. Therefore, it is important to consider all information. Generally, criteria include:24 1 Focal velocity increase:6,35,40 ACA, MFV ≥ 100 cm/ second or PSV ≥ 120 cm/second; PCA, VA, and BA, MFV ≥ 50 cm/second or PSV ≥ 100 cm/second; siphon, MFV ≥ 90 cm/s or PSV ≥ 120 cm/second. 2 The normal hierarchy of flow velocity is disrupted: MCA ≥ ACA ≥ ICA ≥ PCA ≥ BA ≥ VA. 3 The spectrum pattern: The presence of low frequency turbulence, high frequency turbulence, contour oscillation, and musical murmurs suggest significant stenosis. 4 The waveform pattern: The blunted waveform with low pulsatility usually suggests a steno-occlusive lesion proximal to the site of insonation; dampened wave-
form with high pulsatility usually suggests a distal obstruction. Especially for the A2, distal P2, distal BA, and cervical VA which are difficult to insolate, these indirect findings could be quite useful yet need to be cautiously applied due to suboptimal angle of insonation or hypoplasia that are common with these vessels.
Other applications in intracranial atherosclerosis Microembolic signal detection The detection of arterial emboli using TCD is a wellestablished technique, which had been commonly used in interventional procedures such as cerebral and coronary angiography, carotid angioplasty, carotid endarterectomy and coronary angiography and in patients with carotid and intracranial large artery atherosclerotic stenosis.14 More and more studies have 153
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Fig 12.6 Waveform and velocity changes at a stenosis (upper TCD figure) and post-stenosis (lower TCD figure).
shown that microemboli detection is useful in risk stratification, evaluating the effectiveness of novel therapies, and in perioperative monitoring.14 Characteristics of microembolic signals The large acoustic impedance difference between air, thrombus, platelet aggregates, or atheroma and red blood cells causes a significantly increased ultrasound intensity of reflected echoes relative to the blood flow backgound.12,14 In general, characteristics of microembolic signals include: high-intensity (usually above 3–9 dB or higher), transient (duration, 10– 100 ms), unidirectional, within the flow spectrum appearance accompanied by a characteristic chirping sound (Fig. 12.7).12,14,41
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Mess et al. reported four kinds of artifacts: changes of TCD settings, probe movement, low flow artifact and electrocautery.42 Elimination of artifact can be achieved by standard practices and proper parameter settings. To differentiate true emboli and artifact, it is necessary not only to apply automated artifact rejection software but also review possible MES. In contrary to true emboli, artifacts are usually bidirectional and maximal at low frequencies, appearing simultaneously at two depths.41 True emboli signals may also produce bidirectional signals, yet will have a time delay between two depths of insonation and characteristic chirping sounds. Multi-depths monitoring and synchronous audio recording are encouraged when performing MES detection.
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Fig 12.7 Microemboli detected from MCA.
Regarding the nature of the emboli, there are no definite criteria for differentiating solid and gas emboli.43,44 Regarding the source of emboli, appearances in unilateral artery suggest carotid or MCA origin, while bilateral signals suggests a cardiac origin.45 Gao and Wong15 reported three types of emboli according to the frequencies of these signals displayed on the post-FFT spectrum: focused-frequency signals (FFSs), bottom-frequency signals (BFSs), and multifrequency signals (MFSs). MES from MCA atherosclerotic lesions may have special characteristics of multiple frequency on both post-FFT spectra and pre-FFT time domain signals. Regarding the time course, most emboli can be detected several days after the ischemic event, and the prevalence will decrease over time, but are still present 2 weeks after the onset of symptoms.45–48 Note, that
artery-to-artery MES in the MCA can change flow velocity implying that some of these emboli have sizes sufficient to alter cerebral blood flow. Techniques for microembolic signal detection In 1998, the International Consensus Group on Microembolus Detection published criteria for MES detection. In this consensus statement, 14 parameters will affect detectability of MES and should be reported in a research paper: ultrasound device, transducer type and size, insonated artery, insonation depth, algorithms for signal intensity measurement, scale settings, detection threshold, axial extension of sample volume, fast Fourier transform size, FFT lengths (time), FFT overlap, transmitted ultrasound frequency, high pass filter settings, recording time. Recently, Droste et al. suggested that the use of 1 MHz instead of 2 MHz
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may be useful when evaluating the recordings off-line by an experienced blinded observer.49
Clincal significance of microembolic signals Early studies showed that MES are quite common during interventional procedures and in patients with carotid stenosis, carotid dissection, aortic arch atherosclerosis, and cardiac disorders.50–56 MES are more prevalent in symptomatic patients with severe carotid stenosis51 , and these asymptomatic-at-atime-of-detection emboli can predict the likelihood of stroke recurrence.57,58 Even for patients with asymptomatic significant (≥60%) carotid stenosis, MES can predict the stroke event at 1 year follow-up. If MES are detected from asymptomatic lesions, these patients might also benefit from carotid endarterectomy or stenting.59 A large ongoing multicentre prospective study, Asymptomatic Carotid Emboli Study (ACES) will reveal more about the relationship between MES and carotid stenosis. For intracranial atherosclerosis, Wong et al.60 Nabavi et al.61 and reported MES in acute stroke patients with MCA stenosis. During the last decade, numerous studies have described the association between MES and severity of the MCA stenosis, extension of the ischemic lesions on DWI, recurrent ischemic events, and the effects of therapeutic measures.46,47,62–68 It has been reported that MES were common in large artery stenosis compared with other subtype groups (TOAST stroke classification)56,63,64 and even more common in patients with severe stenoses. In one study, all the patients with peak velocity ≥210 cm/second had MES despite anticoagulation69 ; in another study, 48% patients with severe stenosis on MRA had MES.64 The number of MES can predict the number of acute infarcts on Diffusion-weighted MRI (DWI); artery-toartery emboli tend to cause multiple small cerebral infarct along the borderzone region because of impaired clearance.62,68,70 MES can also predict the recurrence of ischemic events. In a 13.8 month follow-up, the presence of MES was the only predictor of a further ischemic stroke/TIA by Cox regression (adjusted odds ratio, 8.45; 95% CI 1.69–42.22; p = 0.01).64 Iguchi found that MES detected at 48 hours of stroke onset were associated with recurrent ischemic lesions on DWI on day 746 ; in addition, MES presence after day 7 but not 156
within 24 hours of stroke onset could be a predictor of stroke recurrence at 3 months.47 Finally, the number of MES is affected by treatment. One study reported more frequent MES in anticoagulated patients than in patients receiving antiplatelet treatment.63 The relationship between antiplatelet therapy and MES frequency has been investigated in several studies,66,67,71 which showed that the number of MES may serve as a marker for assessing the therapeutic efficacy in preventing TIA and stroke recurrence. However, the quality control of TCD monitoring remains an important issue. Intra-intervention monitoring TCD monitoring during cardiac and vascular interventions can help to guide management strategies and change techniques to avoid complications.72,73 Several studies report lower complication rate with monitoring compared to historic controls.73–75 Numerous microemboli can be detected during intravascular procedures despite the uniform use of distal protection devices, but most of them are asymptomatic.72,76–79 Some studies report early postoperative appearances of MES can predict the perioperative stroke and most of MES are detected within 30 minutes after procedures, but multicenter trial with large sample is required to confirm these findings.13,80 De Borst et al.81 also performed postoperative MES monitoring in addition to intra-intervention monitoring to compare the influence of antiplatelet therapy, which showed no significant difference between the number of postoperative MES among the three groups (Asasantin, Asasantin plus clopidogrel, Asasantin plus Rheomacrodex).
Application of ultrasound in stroke therapy During systemic thrombolysis for acute ischemic stroke, TCD shows hemodynamic changes with timing, speed, and degree of arterial recanalization and reocclusion.82–85 Furthermore, 2 MHz TCD also has a safe therapeutic effect of enhancement of enzymatic thrombolysis with tissue plasminogen activator (TPA):16,86 The CLOTBUST trial (Combined Lysis Of Thrombus in Brain ischemia using transcranial Ultrasound and Systemic TPA) showed a higher recanalization rate in patients who received continuous TCD insonation. Microspheres-potentiated ultrasound-enhanced thrombolysis also can promote
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the ability of sonolysis to induce early arterial recanalization. 14
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81 de Borst GJ, Hilgevoord AA, de Vries JP, et al. Influence of antiplatelet therapy on cerebral micro-emboli after carotid endarterectomy using postoperative transcranial Doppler monitoring. Eur J Vasc Endovasc Surg 2007; 34 (2): 135–142. 82 Saqqur M, Molina CA, Salam A, et al. Clinical deterioration after intravenous recombinant tissue plasminogen activator treatment: a multicenter transcranial Doppler study. Stroke 2007; 38 (1): 69–74. 83 Pagola J, Ribo M, Alvarez-Sabin J, Lange M, Rubiera M, Molina CA. Timing of recanalization after microbubbleenhanced intravenous thrombolysis in basilar artery occlusion. Stroke 2007; 38: 2931–2934.
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84 Saqqur M, Uchino K, Demchuk AM, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke 2007; 38: 948–954. 85 Alexandrov AV, Burgin WS, Demchuk AM, El-Mitwalli A, Grotta JC. Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short-term improvement. Circulation 2001; 103: 2897–2902. 86 Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety. Neurotherapeutics 2007; 4 (3): 420– 427.
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Treatment
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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Antiplatelet therapy Sun U Kwon and Jong S Kim
Intracranial atherosclerosis (ICAS) is prevalent in Asians, black people, and Hispanics. The recurrence rate of stroke in patients with ICAS has been shown to be 7.3–19% annually,1,2 which is comparable with that reported in symptomatic severe carotid stenosis.3 Angioplasty and stenting, or bypass surgery, are occasionally performed in selected patients, but antithrombotic medications remain the mainstay of therapy for ICAS. However, there is no specific recommendation for the medical management of ICAS, because of the paucity of antithrombotic trials focused on the patients with ICAS. In this chapter, we will first present a general view of antiplatelet therapy for ischemic stroke. In the latter part, we will focus on the available data on antiplatelet therapy for patients with ICAS and discuss future directions for better management.
Antiplatelet therapy for stroke: a general view Antiplatelet drugs and their mechanisms Platelet activation and aggregation is a crucial pathogenic event in the development of ischemic heart disease and stroke.4,5 Inhibition of this event is the most popular strategy to prevent these disorders.6,7 The activation and aggregation of platelets depend on the activation state of glycoprotein IIb-IIIa (GpIIbIIIa), a bimolecular membrane complex specific for platelets and megakaryocytes.8–10 GpIIb–IIIa is strictly regulated by a balance of activating signals from ADP, thrombin, and thromboxane A2 (TXA2 ) receptors and inhibitory signals from nitric oxide (NO) and prostacyclin receptors11 (Fig. 13.1). Therefore, the follow-
ing mechanisms can inhibit activation or aggregation of platelets: inhibition of production of TXA2 ; blocking of ADP, thrombin, and TXA2 receptors; or activation of NO and prostacyclin receptors. Many drugs have been developed for these purposes, among which aspirin, clopidogrel, ticlopidine, dipyridamole, and cilostazol have been most popularly used.7,11 Aspirin irreversibly inhibits cyclooxygenase (COX)1 by acetylation of serine-530, which is close to the active site of the COX-1.12 Inhibition of COX-1, which is expressed in platelets or endothelial cells, prevents the conversion of arachidonic acid to various prostaglandin derivatives including TXA2 and prostacyclin. Functions that depend on TXA2 activity are permanently inhibited because anuclear platelets can no longer synthesize the protein.12 In contrast to platelets, cells in the endothelium and the kidney, and leukocytes can replace the non-functioning acetylated COX with newly synthesized protein. Thus, the inhibitory effect of aspirin on the synthesis of prostaglandin in these cells is usually transient. Thienopyridine drugs act on ADP receptors of platelets. There are two types of ADP receptors in platelets, P2Y1 and P2Y12 . These metabotrophic receptors are linked to one or more different G-proteins. The P2Y12 receptor is irreversibly bound by the thienopyridine drugs, clopidogrel and ticlopidine.13 Because this particular subtype of ADP receptor is associated with the amplification of platelet aggregation and secretion,13,14 these drugs irreversibly inhibit ADP-mediated platelet activation. There also are drugs that work primarily on the phosphodiesterase (PDE) system. PDE is a key enzyme for regulating the activation of GpIIb-IIIa in
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Fig 13.1 Mechanisms of current antithrombotic drugs. The principal factor regulating the adhesiveness of platelets is the activation state of GPIIb–IIIa. The affinity status of this receptor is strictly regulated by a balance of activating (+ve; ADP, thrombin, TXA2 (thromboxane A2 )) and inhibitory signals (–ve; prostacyclin, NO (nitric oxide)). A number of these regulatory pathways have been successfully targeted therapeutically, leading to the development of a diverse range of antithrombotic approaches. These include various surface receptor antagonists (ADP P2Y12 receptor: ticlopidine and clopidogrel; GPIIb–IIIa: abciximab,
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tirofiban, and eptifibatide), inhibitors of platelet signalling enzymes (COX: aspirin; cAMP PDE: cilostazol; cGMP PDE: dipyridamole), receptor agonists (prostacyclin: iloprost), and soluble agonist inhibitors (thrombin: heparins, direct thrombin inhibitors, or vitamin K antagonists). AA, arachidonic acid; COX, cyclooxygenase; NO, nitric oxide; PDE, phosphodiesterase; TXA2 , thromboxane A2 . (From Jackson SP, Schoenwaelder SM. Antiplatelet therapy: in search of the magic bullet. Nature Reviews 2003; 2: 775–789, with permission).
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the prostacyclin and NO agonist receptor system (Fig. 13.1). Dipyridamole increases the level of cyclic guanosine monophosphate (GMP) by inhibition of PDE in this pathway. It also indirectly affects the cyclic AMP levels and inhibits cellular uptake and metabolism of adenosine. These mechanisms result in the inhibition of platelet function.15 Cilostazol also exerts its antiplatelet action by increasing cyclic AMP through inhibition of PDE in platelets.16 Antiplatelet agent monotherapy for stroke prevention Aspirin In 1988, based on clinical trials carried out in 1970s and 1980s,17 the Antithrombotic trialists’ Collaboration concluded that aspirin is effective in the secondary prevention of vascular diseases.18 Thereafter, the use of aspirin has been the gold standard of antiplatelet therapy until recently. A meta-analysis of 65 clinical trials showed that aspirin reduced the risk of cardiovascular events by 23% compared with placebo.7 The proportional reduction in vascular events according to the daily dose of aspirin was 19% with 500– 1500 mg, 26% with 160–325 mg, 32% with 75– 150 mg, and 13% with less than 75 mg. The difference was not statistically significant,7 and it seems that an aspirin dose higher than 75 mg provides no additional benefits. However, the efficacy of aspirin is limited by the presence of alternative pathways for platelet activation and is partially offset by inhibition of prostacyclin, a powerful endothelium-derived inhibitor of platelets. Moreover, many reports have described that 5–30% of aspirin users experience suboptimal inhibition of platelet activation with the conventional dose of aspirin. This so-called ‘aspirin resistance’ reduces the efficacy of aspirin on stroke prevention.19–22 The mechanisms for aspirin resistance include poor compliance, poor absorption, and drug interaction.19 In addition, monocytes and macrophages, another major source of TXA2, can regenerate COX-1 enzyme after the exposure of aspirin. In an inflammatory condition, COX expression can be augmented by 10-fold to 20-fold in these nucleated cells. The TXA2 produced by these cells may in turn activate platelets.23 Therefore, a fixed dose of aspirin may not exert constant antiplatelet effects over time. There has been increasing evidence
suggesting that aspirin resistance or variability of the aspirin effect is related to increased risk of vascular events in patients receiving aspirin.22,24 Ticlopidine and clopidogrel Two randomized clinical trials, Ticlopidine–Aspirin Stroke Study (TASS) and the Canadian–American Ticlopidine Study (CATS), showed that ticlopidine is effective in the prevention of recurrent stroke. According to the TASS, ticlopidine was significantly more effective (20% reduction of relative risk) than highdose aspirin (1300 mg per day).25 Ticlopidine showed 23% risk reduction for recurrent ischemic stroke compared with the placebo in CATS.26 However, it was found that ticlopidine produces uncommon, yet serious, adverse effects such as neutropenia and thrombotic thrombocytopenic purpura. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Event (CAPRIE) trial randomized 19 185 patients with recent stroke, recent myocardial infarction, or symptomatic peripheral vascular disease to receive either clopidogrel or aspirin.27 Patients receiving clopidogrel had a slightly lower risk (5.32% annual risk of stroke, myocardial infarction, or vascular death) than those taking aspirin (5.83% annual risk). Because serious adverse effects were rare in patients treated with clopidogrel, clopidogrel has now virtually replaced ticlopidine. However, the issue of clopidogrel insensitivity has recently been raised. Clopidogrel is a prodrug activated by hepatic cytochrome P450(CYP) 3A4, and the extent of platelet inhibition by clopidogrel has a wide interindividual variability according to the CYP3A4 activity.28 The platelet responsiveness to clopidogrel in patients with coronary diseases or stroke had a normal bell-shaped distribution when aggregation was induced by 5 μmol/L ADP.29 The less potent inhibition of platelet aggregation by clopidogrel has been shown to be related to a higher incidence of recurrent cardiovascular events after percutaneous coronary intervention.30,31 Dipyridamole and cilostazol There were clinical trials investigating the efficacy of dipyridamole in the 1980s, and the Cochrane review of 18 studies reported that there was no solid evidence that dipyridamole monotherapy has a significant beneficial effect in reducing vascular death compared with
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placebo.32 The requirement of four daily doses because of its short-lasting effect and frequent headaches due to its vasodilatory effects might have resulted in poor compliance and contributed to the lack of efficacy in the results of these studies. On the other hand, cilostazol, another phosphodiesterase inhibitor, showed a positive effect on the prevention of ischemic stroke in one clinical study. The Cilostazol Stroke Prevention Study (CSPS)33 randomized 1052 stroke patients to receive either cilostazol 200 mg or matching placebo. The result showed that cilostazol reduced the risk of stroke by 42% compared with placebo without significant bleeding complications. However, the number of enrolled subjects in this trial was relatively small, and the proportion of premature termination for various reasons was unacceptably high (43.2% in the cilostazol group and 35.3% in the placebo group). Thus, further studies are required to confirm the efficacy of cilostazol. A recent study from china34 using a relatively small number of patients (n = 720) with ischemic stroke showed a nonsignificant trend favoring cilostazol over aspirin in the prevention of reciment strokes. Cerebral bleeds was significantly less common in patients receiving cilostazol than in those receiving aspirin. Combined use of antiplatelet agents As previously discussed, there are several means of platelet activation and inhibition. Activation of the alternative pathway is one of the important causes of insensitivity or resistance to antiplatelet agents. Thus, the addition of another antiplatelet agent with a different mechanism may block the alternative pathway of platelet activation and would result in more effective inhibition of platelet activation. The combined use of aspirin and clopidogrel has apparent advantages over aspirin monotherapy for the management of acute coronary syndrome, as shown by two large clinical trials. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE)35 trial randomized 12 562 patients with acute coronary syndrome to receive either aspirin alone or aspirin plus clopidogrel. There was a 20% reduction in the occurrence of the composite of cardiovascular death, non-fatal myocardial infarction, or stroke in the combination group. The Clopidogrel for the Reduction of Events During Observation (CREDO)
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trial also revealed the superiority of combination therapy, with a 26.9% reduction of relative risk of death, myocardial infarction, and stroke after percutaneous coronary intervention.36 Although bleeding complications increased in the combination group in both trials, the benefit significantly outweighed the complications. Combination therapy may also be beneficial in the management of stroke patients. The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS)37 evaluated the efficacy of the combination of aspirin and clopidogrel for the prevention of asymptomatic microembolization in patients with symptomatic carotid stenosis. Combination therapy significantly reduced microemboli detected on transcranial Doppler (TCD) and the incidence of clinical events compared with aspirin monotherapy. Subsequently, the European Stroke Prevention Study 2 (ESPS-2)38 examined the efficacy of a fixed combination of low-dose aspirin and slow-release dipyridamole (Aggrenox). A total of 6600 patients with ischemic stroke were randomly assigned to receive aspirin only (25 mg twice per day), modifiedrelease dipyridamole only (Persantin Retard 200 mg twice daily), the combination of both (Aggrenox), or placebo for 2 years. In pairwise comparisons, the stroke risk was reduced by 18% with aspirin only ( p = 0.013), 16% with dipyridamole only ( p = 0.039), 37% with the combination ( p < 0.001) in comparison with placebo. Thus, the combination of aspirin plus dipyridamole seems to be more efficacious in reducing the risk of vascular events than aspirin monotherapy. The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT)39 was another randomized trial that revealed the benefit of the combination of aspirin and dipyridamole. Patients with transient ischemic attacks or minor stroke within 6 months were assigned to the aspirin group (30– 325 mg daily) with (n = 1363) or without (n = 1376) dipyridamole (200 mg twice daily). Primary outcome events, a composite of vascular death, stroke, myocardial infarction, and major bleedings, occurred in 173 (13%) patients in the combination group and in 216 (16%) in the aspirin monotherapy group (hazard ratio, 0.80; 95% CI 0.66–0.98) for 3.5 years. The combination of aspirin and dipyridamole had similar efficacy in the prevention of cardiovascular events (13.1%
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vs. 13.1%) or stroke (9% vs. 8.8%) with clopidogrel monotherapy (dieneretne unpublished result). These studies showed the advantage of using two drugs with different mechanisms in reducing the risk of atherothrombotic events. However, the combined medication has not always been proven to be better than monotherapy and may increase the risk of adverse effects significantly. The Prevention Regimen For Effectively avoiding Second Strokes (PROFESS)40 recruited more than 20 000 patients with ischemic stroke who were assigned into the aspirin plus dipyridamole group or the clopidogrel group. The Management of Atherothrombosis with Clopidogrel in High-risk patients (MATCH)41 study randomized 7599 patients with recent ischemic stroke or transient ischemic attacks to receive either clopidogrel alone or clopidogrel plus aspirin for 18 months. A total of 596 (15.7%) patients reached the primary end-point (a composite of ischemic stroke, myocardial infarction, vascular death, or re-hospitalization for acute ischemia) in the clopidogrel plus aspirin group and 636 (16.7%) in the clopidogrel alone group. The difference was not statistically significant. Moreover, there was a significant increase in major bleedings, which overweighs the slight benefit in reducing vascular events. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) randomly assigned more than 15 000 patients with cardiovascular diseases or multiple risk factors to either the aspirin plus clopidogrel group or the aspirin monotherapy group.42 The rate of the primary efficacy end-point, a composite of myocardial infarction, stroke, or cardiovascular death, was 6.8% with the dual antiplatelet therapy and 7.3% with aspirin monotherapy (relative risk, 0.93; p = 0.22). However, the rate of severe bleeding was significantly higher in the dual-therapy group (1.7%) than in the aspirin monotherapy group (1.3%) (relative risk, 1.25; p = 0.09). Thus, the combination of aspirin and clopidogrel seems to significantly increase the risk of bleeding complications, especially in patients who had strokes. Aside from the increased incidence of side-effects, the increased cost also matters in patients who should receive life-long medication. Thus, the combined use of aspirin and clopidogrel should be applied, with close observation, to a limited number of patients who have a high risk for secondary ischemic events.
Antiplatelet therapy for intracranial atherosclerosis There are several features that should be considered in the management of ICAS. First, as discussed in Chapter 5, the mechanisms of stroke are more diverse in ICAS than in extracranial artery disease. Extracranial ICA disease usually causes ischemic stroke by way of artery-to-artery embolism or hemodynamic insufficiency. These are also important mechanisms of stroke in ICAS,43 but thrombotic occlusion of the stenosed artery44 or occlusion of perforating branches45 due to plaque rupture or local thrombosis are also important mechanisms for ischemic stroke in ICAS. Since the occlusion of the perforating artery can be caused by mild ICAS, mild stenosis may still be important, in contrast to extracranial arterial diseases. Second, as discussed in Chapter 9, intracranial arterial stenosis frequently progresses.46,47 Because intracranial arteries are smaller in diameter than extracranial arteries, the progression of the stenosis may affect cerebral perfusion in the territory of stenotic artery more seriously. Moreover, in patients with multifocal ICAS, hemodynamic disturbances caused by ICAS cannot be compensated for through collateral circulation via the circle of Willis. Previous studies have demonstrated a close relationship between the progression of ICAS and clinical stroke recurrence.46,47 Third, although it is still controversial, the prevalence of diabetes mellitus or metabolic syndrome seems to be higher in patients with ICAS than in other subtypes of stroke.48–50 According to the result from the Primary Prevention Project (PPP) study,51 the efficacy of aspirin in preventing cardiovascular death, stroke, or myocardial infarction was lower in subjects with diabetes mellitus than in those without. Therefore, aspirin monotherapy might not be sufficient in the prevention of stroke in patients with ICAS. On the basis of this line of evidence, we speculate that drugs having actions beyond the simple antiplatelet function, such as inhibition of atherosclerosis progression and suppression of inflammation or smooth muscle proliferation, may have to be considered in the management of symptomatic ICAS. The combined use of drugs with different actions should also be considered seriously in these patients.
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Comparison between antiplatelets and anticoagulants for intracranial atherosclerosis We will briefly describe the use of anticoagulation in ICAS, since this subject will be discussed in detail in Chapter 14. Warfarin has been empirically used for patients with severe occlusive disease in the vertebrobasilar artery and for those with recurrent ischemic stroke despite antiplatelet treatment.17 Retrospective studies have suggested that anticoagulation may be effective in reducing the risk of stroke in patients with ICAS compared with placebo or aspirin.52–54 On the basis of these results, a double-blind randomized controlled trial was performed to compare the efficacy of warfarin and aspirin in patients with symptomatic intracranial artery stenosis, the Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial.3 However, the trial was prematurely terminated because major bleeding complications were significantly higher in the warfarin group than in the aspirin group. Moreover, warfarin was not found to be superior to aspirin in the prevention of primary end-points (stroke and vascular death). Another clinical trial, the Warfarin Aspirin Recurrent Stroke Study (WARSS)55 also failed to reveal the superiority of warfarin therapy over aspirin in noncardioembolic ischemic stroke. Based on these results, oral anticoagulation is nowadays rarely recommended in patients with ICAS. However, the Fraxiparine in Ischemic Stroke (FISS) study results suggested that low molecular weight heparin (LMWH) may be effective in the management of acute ischemic stroke in a country where ICAS is prevalent.56 Unfortunately, larger clinical trials performed afterwards in different ethnic groups failed to reproduce the beneficial effects of LMWH in acute ischemic stroke.57,58 Thus, currently, any type of anticoagulants is not recommended for the management of non-cardiogenic acute ischemic stroke. However, debates still continue whether the positive results of the FISS study represent a simple chance occurrence or illustrate ethnic differences in the underlying pathophysiological mechanism of stroke; FISS was conducted in an area where ICAS is very prevalent. Therefore, the investigators of FISS-tris study assumed that LMWH might be effective in Asian patients with ICAS, and randomly assigned 353 patients with acute ischemic stroke to receive either subcutaneous nadroparin or oral aspirin for 10 days.59 Since FISStris exclusively recruited patients with large artery 168
occlusive disease, 97% of the recruited patients had ICAS (300 had ICAS only and 42 had both intracranial and extracranial diseases). The results were found to be equivocal; although the primary end-point (the proportion of Barthel index ≥85 after 6 months) was not significantly different between the two groups, the LMWH group had better outcomes on the measured modified Rankin score (odds ratio 1.55; 95% CI 1.02– 2.35; the proportion of 0 and 1 on 6 months modified Rankin score). Thus, further larger trials are still required to investigate the possible role of anticoagulation in acute ischemic stroke patients with ICAS.
Antiplatelet therapy for intracranial atherosclerosis Trials of antiplatelets specifically aimed at ICAS have been rare. However, we may gain insight from previous results regarding the choice of antiplatelet agent in patients with ICAS. For instance, ticlopidine might be better than aspirin in preventing secondary stroke due to ICAS; although the location of atherosclerosis was not analyzed in the TASS trial, a subgroup analysis showed that ticlopidine had a more favorable risk–benefit profile for black people than for white people in whom ICAS is quite prevalent.25 However, the African American Antiplatelet Stroke Prevention Study (AAASPS), which compared the efficacy and safety of aspirin (650 mg daily) and ticlopidine (500 mg daily) in black patients, showed that slightly more patients assigned to the ticlopidine group (14.7%; 133 of 902) reached the primary outcome of recurrent stroke, myocardial infarction, or vascular events than those assigned to the aspirin group (12.3%; 112 of 907) (hazard ratio, 1.22; 95% CI, 0.94–1.57).60 Therefore, it seems that monotherapy with thienopyridine drugs is not more beneficial than aspirin. There is at least one trial of antiplatelets specifically focused on ICAS. The Trial of Cilostazol in Symptomatic Intracranial Stenosis (TOSS) is a doubleblind, placebo-controlled study to evaluate the efficacy of the addition of cilostazol to aspirin in the progression of symptomatic ICAS.61 As mentioned previously, the stroke mechanism in ICAS is complex. Aside from artery-to-artery embolism, a focal stenosis of the intracranial artery may predispose to thrombosis in this area, resulting in occlusion of either the main trunk or perforators. Progressive narrowing of
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the stenotic lesions and consequent hemodynamic insufficiency also increase the risk of stroke. Cilostazol has vasodilating and anti-inflammatory effects in addition to its antiplatelet effect, and has been shown to be effective in the symptomatic improvement of intermittent claudication62,63 in the prevention of restenosis after coronary stenting, and in decreasing the progression of carotid intima medial thickness in diabetic patients.64 Moreover, the rate of bleeding complications is low compared with other antiplatelets. A meta-analysis of 13 placebocontrolled, randomized trials with a total of 6165 patients showed that cilostazol reduced the incidence of vascular events by 16% compared with placebo. Patients treated with cilostazol did not have an increased incidence of serious bleeding complications compared with placebo (1.4% vs 1.5%).65 Therefore, TOSS investigators hypothesized that the addition of cilostazol to aspirin could be more beneficial in the management of ICAS by reducing the progression of symptomatic ICAS without increasing the risk of bleeding complications. In this trial, a total of 135 patients with acute symptomatic ICAS were randomly assigned to receive either aspirin 100 mg monotherapy or aspirin plus cilostazol 200 mg. The primary end-point was to assess the progression rate of symptomatic stenosis after 6 months using MRA. The results showed that in the combination therapy group, three (6.7%) symptomatic ICAS patients progressed and 11 (24.4%) regressed. In the aspirin monotherapy group, 15 (28.8%) of symptomatic ICAS patients progressed and eight (15.4%) regressed. The difference was statistically significant ( p = 0.008). The progression rate assessed by TCD showed identical findings. The investigators also examined the status of concomitant asymptomatic intracranial stenosis and found that the combined medication decreased the progression rate of asymptomatic stenosis as well. However, the difference was not statistically significant, probably due to the small number of cases with progressive stenosis. Although dizziness and skin rash developed more often in the combined medication group, serious side-effects such as bleeding complications were not observed in either group. Thus, this result suggested that the combination of aspirin and cilostazol may be significantly better than aspirin monotherapy in reducing the progression of symptomatic ICAS without increasing bleeding complications.
However, TOSS had several limitations: the number of participants was relatively small and there was a high drop-out rate. Moreover, the usage of statin and non-steroidal anti-inflammatory drugs, which can influence the progression of atherosclerosis, was not meticulously controlled. Most importantly, the clinical significance of the progression of stenosis could not be assessed because of the short follow-up period and the small number of patients. Despite these limitations, TOSS is a rare clinical trial demonstrating a positive result using antiplatelet agents in patients with ICAS. Because the progression of stenosis in the intracranial arteries has been shown to be one of the most important markers for the development of clinical events,46,50 the combined use of aspirin and cilostazol seems to be justified in these patients. Despite the TOSS results, there still remain questions regarding the best choice of antiplatelet agents in patients with ICAS. One of the options could be aspirin plus clopidogrel. As previously discussed, artery-to-artery embolism is one of the important stroke mechanisms in patients with ICAS. Studies have shown that asymptomatic microembolic signals detected by TCD are an important predictor of recurrent stroke in the patients with MCA stenosis.36 Gao et al. found that the number of microembolic signals correlated well with the number of acute infarcts detected by diffusion-weighted MRI in patients with ICAS. Since the combination of aspirin and clopidogrel was far more effective in reducing microembolic signals than aspirin monotherapy in the CARESS trial,37 combined medication may improve the outcome of patients with ICAS as well. One of the drawbacks in using the combination of aspirin and clopidogrel is the increased risk of bleeding complications. Overall, in previous clinical trials the rate of major bleeding in patients receiving aspirin and clopidogrel was around 1.2–2.6%. However, the increased bleeding complications in the MATCH trial was due in part to the inclusion of many patients with lacunar infarcts, whereas patients with major vessel atherosclerosis are expected to experience bleeding complications less often. Moreover, as previously mentioned, the annual risk of stroke and recurrence of symptomatic ICAS is fairly high (7.3–19%), which seems to outweigh the risks of bleeding, at least in the early stage of stroke when the risk of recurrent stroke is particularly high. Thus, it seems that the efficacy of the combination therapy with aspirin and clopidogrel 169
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in the early stage of stroke is worth examining in patients with symptomatic ICAS. This was the theoretical basis for another clinical trial, the Trial of Cilostazol in Symptomatic intracranial Stenosis – II (TOSS-2, NCT00130039). The study attempted to compare the efficacy and safety of cilostazol plus aspirin and clopidogrel plus aspirin in the prevention of the progression of symptomatic intracranial stenosis. The TOSS-II is currently ongoing, and 480 patients with acute cerebral infarction caused by ICAS have been recruited and randomized. The patients are supposed to take the study medications with additional low-dose aspirin (75–150 mg daily) for 7 months. The primary end-point is the progression rate of ICAS assessed by MRA. Clinical events and new ischemic lesions in the territory of the symptomatic stenosis will be analyzed as secondary end-points. By the time the results of TOSS II are available, we will have a better understanding of the choice of antiplatelet agents in patients with ICAS. However, considering the large number of antiplatelet agents, either already available or newly introduced, there is no doubt that more studies will be carried out to find out the best medications for patients with ICAS even after the TOSS II results are obtained. Comparison between the best medication and angioplasty and stenting will also be performed in patients with a high risk of recurrence.
References 1 Kern R, Steinke W, Daffertshofer M, et al. Stroke recurrences in patients with symptomatic vs asymptomatic middle cerebral artery disease. Neurology 2005; 65: 859– 864. 2 Mazighi M, Tanasescu R, Ducrocq X, et al. Prospective study of symptomatic atherothrombotic intracranial stenoses: the GESICA study. Neurology 2006; 66: 1187– 1191. 3 Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352: 1305– 1316. 4 Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med 1992; 326: 242– 250.
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5 Falk E, Shah PK, Fuster V. Coronary plaque disruption. Circulation 1995; 92: 657–671. 6 Coull BM, Williams LS, Goldstein LB, et al. Anticoagulants and antiplatelet agents in acute ischemic stroke: report of the Joint Stroke Guideline Development Committee of the American Academy of Neurology and the American Stroke Association (a division of the American Heart Association). Stroke 2002; 33: 1934–1942. 7 Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86. 8 Phillips DR, Charo IF, Scarborough RM. GPIIb-IIIa: the responsive integrin. Cell 1991; 65: 359–362. 9 Du X, Ginsberg MH. Integrin alpha IIb beta 3 and platelet function. Thromb Haemost 1997; 78: 96–100. 10 Plow EF, D’Souza SE, Ginsberg MH. Ligand binding to GPIIb-IIIa: a status report. Semin Thromb Hemost 1992; 18: 324–332. 11 Jackson SP, Schoenwaelder SM. Antiplatelet therapy: in search of the ‘magic bullet’. Nature reviews 2003; 2: 775– 789. 12 Schror K. Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemost 1997; 23: 349–356. 13 Hollopeter G, Jantzen HM, Vincent D et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 2001; 409: 202–207. 14 Fontana P, Dupont A, Gandrille S, et al. Adenosine diphosphate-induced platelet aggregation is associated with P2Y12 gene sequence variations in healthy subjects. Circulation 2003; 108: 989–995. 15 Movsesian MA. Therapeutic potential of cyclic nucleotide phosphodiesterase inhibitors in heart failure. Expert opinion on investigational drugs 2000; 9: 963–973. 16 Umekawa H, Tanaka T, Kimura Y, Hidaka H. Purification of cyclic adenosine monophosphate phosphodiesterase from human platelets using new-inhibitor Sepharose chromatography. Biochem Pharmacol 1984; 33: 3339– 3344. 17 Genton E, Barnett HJ, Fields WS, et al. XIV. Cerebral ischemia: the role of thrombosis and of antithrombotic therapy. Study group on antithrombotic therapy. Stroke 1977; 8: 150–175. 18 Secondary prevention of vascular disease by prolonged antiplatelet treatment. Antiplatelet Trialists’ Collaboration. BMJ 1988; 296: 320–331. 19 Bhatt DL. Aspirin resistance: more than just a laboratory curiosity. J Am Coll Cardiol 2004; 43: 1127–1129. 20 Jilma B. Therapeutic failure or resistance to aspirin. J Am Coll Cardiol 2004; 43: 1332; author reply 1332– 1333.
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21 Pulcinelli FM, Pignatelli P, Celestini A, et al. Inhibition of platelet aggregation by aspirin progressively decreases in long-term treated patients. J Am Coll Cardiol 2004; 43: 979–984. 22 Eikelboom JW, Hirsh J, Weitz JI, et al. Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events. Circulation 2002; 105: 1650–1655. 23 Halushka MK, Halushka PV. Why are some individuals resistant to the cardioprotective effects of aspirin? Could it be thromboxane A2? Circulation 2002; 105: 1620– 1622. 24 Gum PA, Kottke-Marchant K, Welsh PA , et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961–965. 25 Bellavance A. Efficacy of ticlopidine and aspirin for prevention of reversible cerebrovascular ischemic events. The Ticlopidine Aspirin Stroke Study. Stroke1993; 24: 1452– 1457. 26 Gent M, Blakely JA, Easton JD, et al. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989; 1: 1215–1220. 27 A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339. 28 Lau WC, Gurbel PA, Watkins PB, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004; 109: 166–171. 29 Serebruany VL, Steinhubl SR, Berger PB, et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246–251. 30 Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171–3175. 31 Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting: response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908–2913. 32 De Schryver EL, Algra A, van Gijn J. Cochrane review: dipyridamole for preventing major vascular events in patients with vascular disease. Stroke 2003; 34: 2072–2080. 33 Gotoh F, Tohgi H, Hirai S, et al. Cilostazol Stroke Prevention Study: A Placebo-Controlled Double-Blind Trial for Secondary Prevention of Cerebral Infarction. J Stroke Cerebrovasc Dis 2000; 9: 11. 34 Huang Y, Cheng Y, Wu J, et al. Cilostazol as an alternative to aspirin after ischiemic stroke: a randomized, doubleblind, pilot study. Lancet Neurol 2008; 7: 494–499.
35 Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004; 110: 1202–1208. 36 Steinhubl SR, Berger PB, Mann JT, 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288: 2411–2420. 37 Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005; 111: 2233–2240. 38 Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. Journal of the neurological sciences 1996; 143: 1–13. 39 Halkes PH, van Gijn J, Kappelle LJ, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006; 367: 1665–1673. 40 Diener HC, Sacco R, Yusuf S. Rationale, design and baseline data of a randomized, double-blind, controlled trial comparing two antithrombotic regimens (a fixed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: the Prevention Regimen for Effectively Avoiding Second Strokes Trial (PRoFESS). Cerebrovasc Dis 2007; 23: 368–380. 41 Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004; 364: 331–337. 42 Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706– 1717. 43 Gao S, Wong KS, Hansberg T, et al. Microembolic signal predicts recurrent cerebral ischemic events in acute stroke patients with middle cerebral artery stenosis. Stroke 2004; 35: 2832–2836. 44 Lammie GA, Sandercock PA, Dennis MS. Recently occluded intracranial and extracranial carotid arteries. Relevance of the unstable atherosclerotic plaque. Stroke 1999; 30: 1319–1325. 45 Bang OY, Heo JH, Kim JY, et al. Middle cerebral artery stenosis is a major clinical determinant in striatocapsular small, deep infarction. Arch Neurol 2002; 59: 259–263.
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46 Wong KS, Li H, Lam WW, et al. Progression of middle cerebral artery occlusive disease and its relationship with further vascular events after stroke. Stroke 2002; 33: 532–536. 47 Arenillas JF, Molina CA, Montaner J, et al. Progression and clinical recurrence of symptomatic middle cerebral artery stenosis: a long-term follow-up transcranial Doppler ultrasound study. Stroke 2001; 32: 2898– 2904. 48 Lee BC, Roh JK. International experience in stroke registries: Korean Stroke Registry. Am J Prev Med 2006; 31: S243–245. 49 Ovbiagele B, Saver JL, Lynn MJ, Chimowitz M. Impact of metabolic syndrome on prognosis of symptomatic intracranial atherostenosis. Neurology 2006; 66: 1344– 1349. 50 Arenillas JF, Molina CA, Chacon P, et al. High lipoprotein (a), diabetes, and the extent of symptomatic intracranial atherosclerosis. Neurology 2004; 63: 27–32. 51 Sacco M, Pellegrini F, Roncaglioni MC, et al. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. Diabetes Care 2003; 26: 3264–3272. 52 Olsson JE, Brechter C, Backlund H, et al. Anticoagulant vs anti-platelet therapy as prophylactic against cerebral infarction in transient ischemic attacks. Stroke 1980; 11: 4–9. 53 Whisnant JP, Cartlidge NE, Elveback LR. Carotid and vertebral-basilar transient ischemic attacks: effect of anticoagulants, hypertension, and cardiac disorders on survival and stroke occurrence–a population study. Ann Neurol 1978; 3: 107–115. 54 Chimowitz MI, Kokkinos J, Strong J, et al. The WarfarinAspirin Symptomatic Intracranial Disease Study. Neurology 1995; 45: 1488–1493. 55 Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345: 1444– 1451.
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56 Kay R, Wong KS, Yu YL, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995; 333: 1588–1593. 57 Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. JAMA 1998; 279: 1265–1272. 58 Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirincontrolled trial. Lancet 2001; 358: 702–710. 59 Wong KS, Chen C, Ng PW, et al. Low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomised study. Lancet Neurol 2007; 6: 407–413. 60 Gorelick PB, Richardson D, Kelly M, et al. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. JAMA 2003; 289: 2947–2957. 61 Kwon SU, Cho YJ, Koo JS, et al. Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis. Stroke 2005; 36: 782–786. 62 Robless P, Mikhailidis DP, Stansby GP. Cilostazol for peripheral arterial disease. Cochrane database of systematic reviews (Online) 2007: CD003748. 63 Thompson PD, Zimet R, Forbes WP, Zhang P. Metaanalysis of results from eight randomized, placebocontrolled trials on the effect of cilostazol on patients with intermittent claudication. The American journal of cardiology 2002; 90: 1314–1319. 64 Douglas JS, Jr., Holmes DR, Jr., Kereiakes DJ, et al. Coronary stent restenosis in patients treated with cilostazol. Circulation 2005; 112: 2826–2832. 65 Uchiyama S, Goto S, Shinohara Y, et al. Stroke Prevention by Cilostazol in Patients with Cerebrovascular Disease, Peripheral Artery Disease, and Coronary Stenting: A Meta-Analysis of Clinical Trials. Cerebrovasc Dis 2007; 23: 1.
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Anticoagulation Fadi B Nahab and Marc I Chimowitz
Intracranial atherosclerosis is an important cause of stroke, especially in black people, Hispanics, and Asians.1–7 It is responsible for 8–10% of strokes in the USA and is five times more common among black people and Hispanics than white people.3,7 Intracranial atherosclerotic stroke may represent the most common cause of stroke among Asians.5 Anticoagulation is often used for secondary stroke prevention and acute stroke therapy in patients with intracranial stenosis. This chapter discusses the available data on the safety and efficacy of anticoagulation in these two clinical settings.
Anticoagulation for secondary stroke prevention The risk of stroke associated with symptomatic intracranial atherosclerosis has been reported to be as high as 15% in the first year and even higher in patients with severe stenosis.8 Given this high risk of recurrent stroke associated with intracranial atherosclerosis, effective secondary preventive therapies are needed for this disease. The use of anticoagulation to treat occlusive cerebrovascular disease was suggested as early as 1955.9 Over the next three decades, studies suggested that anticoagulation with warfarin may lower the risk of recurrent stroke in patients with carotid or vertebrobasilar territory transient ischemic attack (TIA) or stroke when compared with antiplatelet agents or no treatment.10–14 However, none of these studies were randomized clinical trials.
Since the early 1990s, three multicenter, randomized trials have evaluated the role of anticoagulation in secondary stroke prevention: the Warfarin–Aspirin Recurrent Stroke Study (WARSS),15 the Stroke Prevention in Reversible Ischemia Trial (SPIRIT),16 and the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT).17 WARSS was a double-blind study that compared the effect of warfarin [target international normalized ratio (INR) 1.4– 2.8] and aspirin 325 mg daily on the combined primary end-point of recurrent stroke or death in patients with a prior non-cardioembolic ischemic stroke. Over a 2-year period, there was no significant difference in the primary end-point between patients treated with warfarin vs aspirin (warfarin group 17.8%, aspirin group 16.0%; p = 0.25). SPIRIT compared the effect of anticoagulation (target INR 3.0–4.5) and aspirin 30 mg daily on the composite primary end-point of death from all vascular causes, non-fatal stroke, non-fatal myocardial infarction, or non-fatal major bleeding complication in patients with a history of TIA or non-cardioembolic ischemic stroke. Although randomization and assessment of outcome events were blinded, treatment assignment was open. The trial was stopped after the first interim analysis revealed a significantly higher primary event rate in patients treated with anticoagulation versus aspirin (hazard ratio 2.3; 95% CI 1.6–3.5). Over a mean follow-up of 14 months, there were 53 major bleeding complications in the anticoagulation group compared with only six in the aspirin group. ESPRIT evaluated the effect of anticoagulation (target INR 2.0–3.0), aspirin 30–325 mg daily and
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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aspirin 30–325 mg daily plus dipyridamole 200 mg twice daily, on the combined primary end-point of death from all vascular causes, non-fatal stroke, nonfatal myocardial infarction, or major bleeding complication in patients with a history of TIA or minor stroke of presumed arterial origin. Randomization and assessment of outcome events were blinded but treatment was open. ESPRIT was stopped after the first interim analysis revealed that the combination of aspirin and dipyridamole was more effective than aspirin alone. Over a mean follow-up of 4.6 years, there was no significant difference in the primary end-point between patients treated with anticoagulants and all patients treated with aspirin (hazard ratio 1.02; 95% CI 0.77–1.35). In a post hoc analysis, there was also no significant difference between patients treated with anticoagulants and patients treated with aspirin and dipyridamole (hazard ratio 1.31; 95% CI, 0.98–1.75). Although these studies were multicenter, randomized trials, they did not specifically evaluate the role of anticoagulation in patients with intracranial arterial stenosis. Only a few studies have compared the safety and efficacy of warfarin versus aspirin specifically in patients with intracranial stenosis. The first was a multicenter, retrospective, non-randomized study of patients with symptomatic, angiographically proven intracranial stenosis of 50–99% treated with warfarin or aspirin.18 In this study, patients with extracranial internal carotid artery stenosis ≥50% tandem to an intracranial stenosis, non-atherosclerotic intracranial vasculopathies, a coexistent cardioembolic source, prior disabling stroke, stroke-preventive treatment other than warfarin or aspirin, or lack of follow-up data were excluded. A total of 151 patients were enrolled from seven centers with a median follow-up of 14.7 months (warfarin group) and 19.3 months (aspirin group). Baseline characteristics including vascular risk factors and mean percentage stenosis of the symptomatic artery were similar between the two groups. Kaplan–Meier analysis showed a significantly higher percentage of patients free of stroke, myocardial infarction, or death among patients treated with warfarin ( p = 0.01) and a relative risk of a major vascular event in those treated with warfarin of 0.46 (95% CI 0.23–0.86). Major hemorrhagic complications occurred in three patients on warfarin during 166 patient–years of follow-up and in none of the 174
patients treated with aspirin during 143 patient–years of follow-up. Other retrospective studies have also evaluated the role of anticoagulation in patients with symptomatic intracranial stenosis. Thijs and Albers19 identified 51 patients (32 treated with warfarin and 19 treated with aspirin) that had symptomatic intracranial stenosis and had failed antithrombotic therapy. Patients treated with aspirin were at significantly higher risk of recurrent stroke or TIA after adjusting for age, anterior circulation disease, Caucasian race, and hyperlipidemia (hazard ratio 4.9; 95% CI 1.7–13.9). Qureshi et al.20 retrospectively identified 102 patients with symptomatic vertebrobasilar stenosis. Among those who were treated with anticoagulation or aspirin there was no significant difference in stroke-free survival (hazard ratio 0.63; 95% CI 0.25–1.59). Thus, some but not all of the retrospective studies had suggested that warfarin may be more effective than aspirin for the prevention of stroke in patients with intracranial stenoses. The results of these studies contributed to the fact that at least 50% of stroke neurologists in the USA were using it as their preferred therapy for these patients in 2004.21 However, these studies were all retrospective and limited by small patient numbers, poorly defined inclusion and exclusion criteria, lack of randomization and limited angiographic data.18 Given these limitations, there was a need for a randomized trial to compare the safety and efficacy of warfarin with aspirin in patients with intracranial stenosis.
Warfarin–Aspirin Symptomatic Intracranial Disease trial In 1999, an investigator-initiated NIH-funded, randomized, double-blind, multicenter clinical trial, the Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial, began patient enrollment to compare aspirin 1300 mg daily with warfarin (target INR 2.0– 3.0) in patients with transient ischemic attack or nondisabling stroke caused by an angiographically verified 50–99% stenosis of a major intracranial artery.22 Inclusion criteria included patients ≥40 years of age with a transient ischemic attack or non-disabling stroke (modified Rankin score of ≤3) that occurred within 90 days of randomization and that was attributable to angiographically verified 50–99% stenosis of a
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Probability of Primary End Point
major intracranial artery (internal carotid, middle cerebral, vertebral or basilar artery). Exclusion criteria included tandem 50–99% stenosis of the extracranial carotid artery, non-atherosclerotic stenosis of an intracranial artery, a cardiac source of embolism (e.g., atrial fibrillation), a contraindication to aspirin or warfarin therapy, an indication for heparin administration after randomization, and a coexisting condition that limited survival to less than 5 years. The trial was originally set to recruit a total of 806 patients with mean follow-up of 3 years; however, the safety-monitoring committee recommended stopping enrollment after 569 patients had been enrolled because of concerns about the safety of patients assigned to warfarin. Patients in the trial had high rates of vascular risk factors including 477 (83.8%) with hypertension, 216 (38.0%) with diabetes, 391 (68.7%) with hyperlipidemia, 151 (26.5%) with a history of coronary artery disease, and 138 (24.3%) with a history of ischemic stroke. Baseline characteristics were similar between both treatment groups. During a mean follow-up period of 1.8 years, the primary end-point, defined as ischemic stroke, brain hemorrhage, or death from vascular causes other than stroke, occurred in 22.1% of patients treated with aspirin and 21.8% of patients treated with warfarin (hazard ratio, 1.04; 95% CI, 0.73–1.48; p = 0.83). The Kaplan–Meier curves of the incidence of the primary end-point in both treatment groups are shown in Fig. 14.1. Prespecified secondary end-points
0.4 Aspirin
p = 0.83 0.3 Warfarin 0.2
0.1
0.0 0
1
2
3
4
Years after Randomization No. at Risk Aspirin Warfarin
280 289
192 202
120 130
59 66
18 16
Fig 14.1 Cumulative incidence of the WASID primary end-point after randomization according to treatment assignment. Adapted from Chimowitz MI et al. (2005) with permission.
5
including ischemic stroke in any vascular territory, ischemic stroke in the territory of the stenotic intracranial artery, and a composite of ischemic stroke, death from vascular causes other than stroke, or non-fatal myocardial infarction were not significantly different between the two groups. A major cardiac event (myocardial infarction or sudden death) occurred significantly more frequently in the warfarin group than in the aspirin group (aspirin group 2.9%, warfarin group 7.3%; hazard ratio 0.40; 95% CI 0.18–0.91; p = 0.02). The rate of death in patients treated with warfarin was also significantly higher than patients treated with aspirin (aspirin group 2.4 events per 100 patient–year, warfarin group 5.2 events per 100 patient–year; hazard ratio 0.46; 95% CI 0.23–0.90; p = 0.02). The higher death rate in the warfarin arm was largely attributed to death from non-vascular causes, predominantly cancer. This was not explained by the potential protective ability of aspirin to prevent colon cancer since none of the deaths in the trial were from this disease. Given the overall low number of deaths from non-vascular causes in the study (n = 14) and the fact that previous anticoagulation trials have not shown an increased risk of death from non-vascular causes, the increased risk of death from non-vascular causes in the warfarin arm in WASID was likely the result of chance. Major hemorrhages occurred significantly more in patients treated with warfarin versus aspirin (aspirin group 3.2%, warfarin group 8.3%; hazard ratio 0.39; 95% CI 0.18–0.84; p = 0.01). Major hemorrhages in the patients treated with warfarin were predominantly related to systemic hemorrhages with very few intracerebral hemorrhages in both groups (two in warfarin group and one in aspirin group). Ischemic strokes accounted for the majority of events with 106 patients (19%) having a stroke in any vascular territory. Of these, 77 (73%) occurred in the territory of the stenotic artery. Subgroup analyses revealed that patients with basilar artery stenosis treated with aspirin had a significantly higher risk of the primary end-point than patients treated with warfarin (hazard ratio 2.28; 95% CI, 1.02–5.08; p = 0.044) but there was no significant difference in the time to ischemic stroke in the territory of the symptomatic basilar artery between treatment groups (hazard ratio 1.84; 95% CI 0.67–5.06; p = 0.24). Patients with vertebral artery stenosis treated with aspirin appeared 175
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Table 14.1 Post hoc analysis of on-treatment, INR-specific rates of major hemorrhage, ischemic stroke, and major cardiac events among patients randomly assigned to receive warfarin.* Major Hemorrhage
Major Cardiac Event§
Ischemic Stroke
INR Category†
No. of Patient yr‡
No. of Events
No. of Events per 100 Patient-yr (95% CI)
No. of Events
No. of Events per 100 Patient-yr (95% CI)
No. of Events
No. of Events per 100 Patient-yr (95% CI)
<2.0 2.0–3.0 3.1–4.4 ≤4.5
92.5 256.9 52.6 4.9
1 9 8 6
1.1 (0.03–6.0) 3.5 (1.6–6.6) 15.2 (6.6–30.0) 123.3 (45.3–268.4)
23 13 3 1
24.9 (15.8–37.3) 5.1 (2.7–8.7) 5.7 (1.2–16.7) 20.6 (1.5–114.5)
10 1 3 0
10.8 (5.2–19.9) 0.4 (0.01–2.2) 5.7 (1.2–16.7) 0.(0–61.6)
Adapted from Chimowitz MI et al. (2005) with permission * The analysis did not include follow-up time or events while patients were not receiving study medication. The events not included were 3 of 27 major hemorrhages, 9 of 49 ischemic strokes, and 7 of 21 major cardiac events. INR denotes international normalized ratio, and CI confidence interval. † The categories coincide with the prespecified target INR range (2.0 to 3.0) and critically high INR range (≥4.5).13 ‡ The method assumed a linear interpolation to estimate INRs between consecutive INR tests. For example, if two consecutive INRs obtained a month apart were in the therapeutic range, the method assumed that the INR was in the therapeutic range for the entire month. § A major cardiac event was defined as myocardial infarction or sudden death.
to have a numerically lower risk than patients treated with warfarin though confidence intervals were wide (hazard ratio 0.57; 95% CI 0.24–1.34; p = 0.20). When the symptomatic vessel was classified as anterior circulation versus posterior circulation, there was no difference in the primary end-point or stroke in the territory between the treatment groups (anterior hazard ratio 1.04, 95% CI 0.63–1.72, p = 0.88; posterior hazard ratio 1.04, 95% CI, 0.63–1.73, p = 0.88).23 Altogether, these data suggest that warfarin does not have a clear advantage over aspirin in patients with symptomatic vertebrobasilar stenosis. A post hoc on-treatment analysis of patients assigned to warfarin was performed to determine whether INRs below or above the target range were associated with an increased risk of ischemic or hemorrhagic events. INRs less than 2.0 were associated with a significantly higher risk of ischemic stroke ( p < 0.0001) and major cardiac events ( p = 0.0003), whereas INRs higher than 3.0 were associated with a significantly higher risk of major hemorrhages ( p < 0.0001) (Table 14.1).22 INRs were maintained within the target range 63.1% of the maintenance period, a finding similar to that of other anticoagulation trials and one that exceeds the percentage typically achieved when patients are treated by 176
their personal physicians.24 Based on these post hoc data, Koroshetz25 has suggested that anticoagulation may still have a role in the treatment of intracranial stenosis (e.g., treating recently symptomatic patients with low-molecular-weight heparin followed by a transition to antiplatelet therapy after an asymptomatic period and using anticoagulation with frequent monitoring of INRs in patients who continue to have recurrent ischemic events in the territory of the index vessel despite antiplatelet therapy). Although these hypotheses are interesting, they would need to be tested in prospective studies in order to have therapeutic validity. Overall, the results of WASID show that warfarin is not more effective than aspirin for the prevention of stroke or vascular death in patients with symptomatic intracranial arterial stenosis and is associated with an increased risk of major hemorrhage compared with aspirin. Given these findings, aspirin should be used rather than warfarin for patients with symptomatic intracranial stenosis. The results of WASID appear to have had an impact on clinical practice as a recent survey suggested that more than 70% of neurologists and neurointerventionalists preferred antiplatelet therapy for their patients with symptomatic intracranial stenosis.26
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Anticoagulation for acute ischemic stroke Although the WASID data clearly showed no benefit for long-term warfarin use in patients with symptomatic intracranial arterial stenosis, the role of anticoagulation in the early period after a cerebrovascular event was less clear. The median time from qualifying event to randomization in WASID was 17 days. Patients randomized early (≤17 days) after their qualifying event appeared to have a higher risk of the primary end-point when treated with aspirin (hazard ratio 1.55; 95% CI 0.98–2.44; p = 0.06) whereas patients randomized later (>17 days) after their qualifying event appeared to have a lower risk of the primary end-point with aspirin therapy (hazard ratio 0.58; 95% CI 0.32–1.03; p = 0.06).23 These data suggested that anticoagulation in the early period after a cerebrovascular event may be of benefit. Since 1995, several trials including the Fraxiparine in Ischemic Stroke Study (FISS)27 , the International Stroke Trial (IST),28 FISS-bis,29 the Trial of ORG 10172 in Acute Stroke treatment (TOAST),30 the Heparin Aspirin Ischemic Stroke Trial (HAEST),31 and the Tinzaparin in Acute Ischemic Stroke Trial (TAIST)32 have evaluated the role of anticoagulation with unfractionated, low-molecular-weight heparin or heparinoid for acute ischemic stroke from any cause. Only one study, FISS, had a positive primary outcome favoring low-molecular-weight heparin over placebo and some authors have speculated that the ethnic differences (predominantly Asian stroke patients in FISS) between these trials may have influenced the outcome.33 Given the high incidence of intracranial atherosclerotic disease among Asian stroke patients, it is possible that low-molecular-weight heparin may be specifically beneficial in patients with acute ischemic stroke related to intracranial stenosis. Only one acute stroke anticoagulation study has restricted enrollment to patients with large artery cerebrovascular occlusive disease, most of whom had intracranial occlusive disease. In 2001, an investigatorinitiated, multicenter randomized controlled trial, the Fraxiparine in Ischemic Stroke (FISS-tris) study, began patient enrollment to determine whether a lowmolecular-weight heparin, nadroparin, was superior to aspirin in Asian patients with acute ischemic stroke and evidence of large artery occlusive disease.33 The study was funded by academic institutions in Hong
Kong and Singapore. Patients were randomly assigned to receive nadroparin calcium 3800 anti-factor Xa IU/0.4 mL subcutaneous twice daily or aspirin 160 mg once daily for 10 days. After 10 days, all patients received aspirin 80–300 mg once daily for 6 months. Inclusion and exclusion criteria for patients with large artery occlusive disease are shown in Table 14.2. Patients were included if they were 18–90 years of age, had a clinical diagnosis of acute ischemic stroke, symptoms of stroke were less than 48 hours before receiving first dose of trial medication, and had evidence of motor deficit. Vascular imaging (carotid duplex scan, transcranial Doppler imaging, or magnetic resonance angiography) could be carried out before or after randomization but had to show moderate or severe stenosis (including occlusion) in the extracranial or intracranial internal carotid, extracranial or intracranial vertebral, basilar, middle cerebral, anterior cerebral and posterior cerebral arteries based on previously published criteria.34,35 The primary outcome was defined as the number of patients with a good outcome at 6 months, defined as a Barthel index ≥85. Of 603 patients screened from 2001 to 2004, 353 patients met the inclusion criteria and had evidence of large artery atherosclerotic disease, 173 initially treated with aspirin and 180 initially treated with nadroparin. Thus, 246 patients were excluded from the primary analysis after vascular imaging did not show evidence of large artery atherosclerotic disease and four patients were ineligible or withdrew consent. Intracranial large artery occlusive disease with or without extracranial disease was present in 342 (97%) patients of which only 42 (12%) had combined extracranial and intracranial disease. Baseline characteristics were similar between the two groups with the exception that more patients with diabetes were included in the aspirin group. At 6 months, patients were assessed by a clinician or nurse blinded to the treatment allocation. Analysis of the primary outcome at 6 months revealed that 73% of the nadroparin group and 69% of the aspirin group had a Barthel index ≥85 at 6 months (absolute risk reduction 4%; 95% CI –5 to 13). Analysis of the secondary outcomes showed a significant benefit in the proportion of patients with a modified Rankin scale (mRS) score 0–1 favoring the nadroparin group (nadroparin group 54%, aspirin group 44%; odds ratio 1.55; 95% CI 1.02–2.35). When good outcome was defined as a mRS score 0–2, this benefit 177
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Table 14.2 Inclusion and exclusion criteria for patients enrolled in the FISS-tris study Inclusion criteria Age 18–90 years Clinical diagnosis of acute ischemic stroke Symptoms of stroke less than 48 hours before receiving first dose of trial medication Presence of motor deficit as a result of acute stroke Brain CT scan excluding intracerebral hemorrhage Women of non-childbearing potential or of childbearing potential but with a negative urine pregnancy test Vascular imaging identifying moderate or greater stenosis in the internal carotid, vertebrobasilar, middle cerebral, anterior cerebral and posterior cerebral arteries as confirmed by carotid duplex scan, transcranial Doppler imaging, or magnetic resonance angiography Exclusion criteria Prestroke modified Rankin scale score >1 National Institutes of Health stroke scale score >22 History of intracerebral hemorrhage Known contraindication for the use of low-molecular-weight heparin or aspirin (including hemorrhagic diathesis) Current use of anticoagulation therapy before the onset of stroke Definite indication for anticoagulation Sustained hypertension (systolic >220, diastolic >120 mmHg) before randomization Coexisting systemic diseases such as terminal carcinoma Renal failure (creatinine >200 μmol/L) Cirrhosis Severe dementia or psychosis Brain tumor or other significant non-ischemic brain lesion on brain CT scan Atrial fibrillation on ECG (past or present) Chronic rheumatic heart disease or metallic heart valve Thrombocytopenia (platelet count <100 × 109 /L) Participation in another clinical trial
was no longer significant (nadroparin group 72%, aspirin group 65%; odds ratio 1.39; 95% CI 0.89–2.19). Mean National Institutes of Health stroke scale was also not significantly different between the two groups (nadroparin group 3.8, aspirin group 3.9; p = 0.89). Adverse events in the nadroparin and aspirin groups were not significantly different in the two groups. Mortality after 6 months was 5% in both groups and there was no significant difference in the rates of hemorrhagic transformation of the infarct (symptomatic or asymptomatic) in the two groups (nadroparin group 3%, aspirin group 4%; p = 0.72). Although the primary outcome measure was not significantly different between the two treatment groups, patients treated with nadroparin had a significant benefit when using an mRS score of 0–1 as the measure of a good outcome. The authors of the study speculated that the lack of difference seen in the primary outcome
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may have reflected the relative lack of sensitivity of the Barthel index as a measure of mild stroke given that 71% of patients had a score ≥85 at 6 months.36 On the other hand, using an mRS score of 0–2 as the measure of a good outcome showed no difference between the two groups. Taking into account the results of all the acute stroke anticoagulation studies, there are no convincing data showing the efficacy of anticoagulation for acute stroke but further study in patients with intracranial large artery occlusive disease may be warranted. In summary, although anticoagulation therapy has been suggested for secondary stroke prevention in patients with intracranial atherosclerosis for more than 50 years, the WASID results show that aspirin was as effective as and safer than warfarin in this setting. As such, aspirin should be used instead of warfarin for these patients.
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Currently, there are no data strongly supporting the use of anticoagulation therapy in patients with acute ischemic stroke and intracranial stenosis. The only study to evaluate this showed no benefit of anticoagulation versus aspirin regarding the primary end-point but there was a benefit of anticoagulation based on a secondary end-point. Further studies will be needed to evaluate the role of low-molecular-weight heparin in these patients.
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References 16 1 Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular disease: a review. Stroke 1986; 17: 648– 655. 2 Feldmann E, Daneault N, Kwan E, et al. Chinese-White differences in the distribution of occlusive cerebrovascular disease. Neurology 1990; 40: 1541–1545. 3 Sacco RL, Kargman DE, Gu Q, et al. Race-Ethnicity and determinants of intracranial atherosclerotic cerebral infarction: the Northern Manhattan Study. Stroke 1995; 26: 14–20. 4 Wityk RJ, Lehman D, Klag M, et al. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996; 7: 1974–1980. 5 Wong KS, Huang YN, Gao S, et al. Intracranial stenosis in Chinese patients with acute stroke. Neurology 1998; 50: 812–813. 6 Li H, Wong KS. Racial distribution of intracranial and extracranial atherosclerosis. J Clin Neurosci 2003; 10: 30–34. 7 White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks, and Hispanics: the Northern Manhattan Study. Circulation 2005; 111: 1327–1331. 8 Kasner SE, Chimowitz, MI, Lynn MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113: 555–563. 9 Millikan CH, Siekert RG, Shick RM. Studies in cerebrovascular disease: III. Mayo Clin Proc 1955; 30: 116– 216. 10 Siekert RG, Whisnant JP, Millikan CH. Surgical and anticoagulant therapy of occlusive cerebrovascular disease. Ann Intern Med 1963; 58: 637–641. 11 Baker RN, Broward JA, Fang HC, et al. Anticoagulant therapy in cerebral infarction: report of a national cooperative study. Res Publ Assoc Res Nerv Ment Dis 1966; 41: 287–302. 12 Whisnant JP, Cartlidge NEF, Elveback LR. Carotid and vertebral-basilar transient ischemic attacks: effect of an-
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ticoagulants, hypertension, and cardiac disorders on survival and stroke occurrence—a population study. Ann Neurol 1978; 3: 107–115. Olsson JE, Brechter C, Backlund H, et al. Anticoagulant vs. anti-platelet therapy as prophylaxis against cerebral infarction in transient ischemic attacks. Stroke 1980; 11: 4–9. Buren A, Ygge J. Treatment program and comparison between anticoagulants and platelet aggregation inhibitors after transient ischemic attack. Stroke 1981; 12: 578– 580. Mohr JP, Thompson JLP, Lazar RM, et al. A comparison of Warfarin and Aspirin for the Prevention of Recurrent Ischemic Stroke. N Engl J Med 2001; 345: 1444–1451. SPIRIT Study Group. A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin. The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group. Ann Neurol 1997; 42: 857–865. The ESPRIT Study Group, Algra A. Medium intensity oral anticoagulants versus aspirin after cerebral ischaemia of arterial origin (ESPRIT): a randomized controlled trial. Lancet Neurol 2007; 6: 115–124. Chimowitz MI, Kokkinos J, Strong J, et al. The WarfarinAspirin Symptomatic Intracranial Disease Study. Neurology 1995; 45: 1488–1493. Thijs V, Albers G. Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy. Neurology 2000; 55: 490–498. Qureshi A, Suri M, Ziai W, et al. Stroke-free survival and its determinants in patients with symptomatic vertebrobasilar stenosis: a multicenter study. Neurosurgery 2003; 52: 1033–1040. Chimowitz MI, Williams J, Stern BJ, Cotsonis G, Swanson S, Lynn M, Feldmann E, the WASID Investigators, and the Stroke Section of the AAN. Physician preferences for diagnosis and treatment of symptomatic intracranial arterial stenosis. Neurology 2004; 62 (Suppl 5): A266– A267. Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352: 1305– 1316. Kasner SE, Lynn MJ, Chimowitz MI, et al. Warfarin vs aspirin for symptomatic intracranial stenosis: subgroup analyses from WASID. Neurology 2006; 67: 1275– 1278. Ansell J, Hirsh J, Poller L, et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (Suppl): 204S–233S. Koroshetz, WJ. Warfarin, aspirin, and intracranial vascular disease. N Engl J Med 2005; 352: 1368–1370.
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26 Turan T, Lynn M, Chimowitz M. US survey of stroke neurologists and neurointerventionalists on treatment choices for intracranial stenosis. Cerebrovasc Dis 2007; 23 (Suppl 2): 131. 27 Kay R, Wong KS, Yu YL, et al. Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 1995; 333: 1588–1593. 28 International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. Lancet 1997; 349: 1569–1581. 29 Hommel M, FISS-bis Investigators Group. Fraxiparine in Ischemic Stroke Study (FISS bis). Cerebrovasc Dis 1998; 8 (Suppl 4): 19. 30 Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 1998; 279: 1265–1272. 31 Berge E, Abdelnoor M, Nakstad PH, Sandset PM, on behalf of the HAEST Study Group. Low molecular-weight
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heparin versus aspirin in patients with acute ischaemic stroke and atrial fibrillation: a double-blind randomised study. Lancet. 2000; 355: 1205–1210. Bath PM, Lindenstrom E, Boysen G, et al. Tinzaparin in acute ischaemic stroke (TAIST): a randomised aspirincontrolled trial. Lancet 2001; 358: 702–710. Wong KS, Chen C, Ng PW, et al. Low-molecular-weight heparin compared with aspirin for the treatment of acute ischemic stroke in Asian patients with large artery occlusive disease: a randomised study. Lancet Neurol 2007; 6: 407–413. Wong KS, Li H, Chan YL, et al. Use of transcranial Doppler ultrasound to predict outcome in patients with intracranial large-artery occlusive disease. Stroke 2000; 31: 2641–2647. Wong KS, Lam WW, Liang E, Huang YN, Chan YL, Kay R. Variability of magnetic resonance angiography and computed tomography angiography in grading middle cerebral artery stenosis. Stroke 1996; 27: 1084–1087. Duncan PW, Samsa GP, Weinberger M, et al. Health status of individuals with mild stroke. Stroke 1997; 28: 740– 745.
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Angioplasty and stenting Wei-Jian Jiang, Dae Chul Suh, Yongjun Wang and Thomas W Leung
Ischemic stroke (IS), which constitutes more than 85% of all strokes, is a leading cause of death and adult disability.1 Intracranial atherosclerosis (ICAS) accounts for 8–10% of ischemic strokes in Caucasian populations2,3 and is particularly prevalent in Asian, African, and Hispanic countries.2–5 Treatment for ICAS has been focused on the use of antithrombotic treatments and optimal control of cardiovascular risk factors such as hypertension, hyperglycemia, and hyperlipidemia.6 The symptomatic ICAS portends a high risk of recurrent IS despite medical treatment. In the EC/IC bypass study,7 the ipsilateral IS rate was 7.8 per 100 patient–years in the medically treated patients with middle cerebral artery (MCA) stenosis.8 The Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial revealed a relatively high cumulative risk of recurrent IS in the same vascular territory (12% at 1 year and 15% at 2 years).9 The risk of subsequent stroke in the territory of the stenotic artery is particularly high in patients with stenosis ≥70% or those with recent symptoms.10 Patients with ICAS who failed to respond to antithrombotic therapy had even greater rates of recurrent stroke.11 In these highly risky patients, a more aggressive way of therapy should be considered. Unfortunately, extracranial–intracranial (EC–IC) bypass surgery has not shown definitive benefits in reducing stroke risks in patients with MCA stenosis. Moreover, this invasive therapy is associated with significant morbidity and mortality.7,12,13 Understanding the dismal prognosis of symptomatic ICAS together with the advances in endovascular techniques has prompted the consideration of angioplasty or stenting as a therapeutic option
for intracranial stenosis, which will be reviewed in this chapter.
History of angioplasty and stenting for intracranial stenosis In 1980, Sundt et al.14 first reported successful balloon angioplasty in two patients with refractory basilar artery stenosis. Since then, many case reports and series have described the technical feasibility of balloon angioplasty in ICAS.15–17 However, in these early reports, procedural complications such as intimal dissection, thrombosis, recoiling, and vessel rupture were frequent. In 1999, Connors and Wojak18 advocated slow and submaximal balloon dilatation to reduce vascular complications, which has now been widely accepted by neuro-interventionists.19 Experience from interventional cardiologists also contributed to the development of the technique.20 In 1996, Feldman et al.21 reported the off-label use of a coronary balloon-expandable stent (Palmaz–Schatz) in dilating stenosis at the intracranial segment of the internal carotid artery (ICA). Many case reports and series on intracranial stenting then followed.22–25 However, similar to balloon angioplasty, there remains a high risk of procedure-related complications in balloon-expandable stenting. To reduce the complication rates, Levy et al.26 introduced the staged treatment approach, and de Rochemont et al.27 evaluated the safety and efficacy of undersized stents. Based on location, morphology, and access, Jiang et al.28 proposed the location morphology access (LMA) classification to predict the technical success and outcome
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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of stenting. Factors that are associated with complications were also explored.29,30 A drug-eluting stent was recently tried for patients with intracranial stenosis.31 In 2004, SSYLVIA (Stenting of SYmptomatic atherosclerotic Lesions in the Vertebral or Intracranial Arteries),32 as the first multicenter, non-randomized, prospective study, evaluated the feasibility of the Neurolink intracranial stent system, a balloonexpandable stent system (Guidant, Indianapolis, IN) for intracranial ICA, MCA, and vertebrobasilar stenoses. A retrospective study showed that stenting for ICA stenosis at the petrous and cavernous segment was more effective than angioplasty alone for the initial and late gains in diameter.33 So far, however, no prospective study has compared stenting with balloon angioplasty in the treatment of ICAS. Balloon-expandable stents have certain limitations and potential risks when applied to the intracranial vasculature. First of all, the relatively high profile of the balloon-mounted stent limits its trackability, which is disadvantageous in negotiating tight stenosis. In addition, dislodgement of the stent may occur during advancement in tortuous vessels. Moreover, the high nominal pressure of the balloon-expandable stent may aggravate plaque disruption and lead to vascular trauma. Furthermore, although the uniform postdeployment diameter of the balloon-expandable stent may improve the immediate luminal gain and help reduce the restenosis rate,34 failure of the stent to conform to the natural curvature or tapering of the parent artery may result in over-dilatation or poor stent-towall apposition.35 Recently, based on the results of the European Wingspan pilot study,36,37 the Food and Drug Administration of the USA has approved the Wingspan stent system (Boston Scientific, Fremont, CA) under the Humanitarian Device Exemption for treatment in patients with symptomatic ICAS ≥50% and who are refractory to medical treatment. The Wingspan stent system involves two major steps: submaximal balloon angioplasty (Gateway balloon), and deployment of a selfexpandable stent (Wingspan), which is preloaded in a 3.5F multilumen over-the-wire delivery catheter.37,38 The stent is made of nitinol, and provides at least twice the radial outward strength of the Neuroform III stent (Boston Scientific).35 So far, the long-term outcome of intracranial stenting remains unclear,39–41 and angioplasty or stenting for intracranial stenosis is still considered inves182
tigational at present.6 Randomized studies comparing stenting with medical therapy are needed to define its role in the treatment of ICAS.42
Patient selection based on stroke mechanism Selection of a patient for angioplasty and stenting should be based on a sound understanding of the stroke mechanism involved in each patient. For instance, in many elderly patients, ICAS coexists with small vessel disease or cardiac diseases, in whom ICAS may be a bystander rather than the culprit lesion. Moreover, ICAS may produce stroke by way of a variety of stroke mechanisms: cerebral perfusion failure, artery-to-artery thromboembolism, occlusion of perforator ostium, and local thrombo-occlusion due to plaque rupture, intraplaque hemorrhage, or plaque growth.10,43–49 Thus, proper understanding of stroke mechanisms in an individual patient is important. Progressive ICAS without adequate collateralization would lead to cerebral perfusion failure,49 which is an important predictor of subsequent stroke.48 Hence, ICAS patients with relevant regional hypoperfusion may be those who can benefit most from endovascular revascularization. For patients with unstable plaque that leads to local thrombosis or artery-to-artery thromboembolism, the treatment strategy may have to be primarily focused on plaque stabilization and anti-thrombosis rather than revascularization.49 In patients who have perforator ostial occlusion due to ICAS, stenting not only cannot revascularize the occluded perforators within the stenotic segment, but may even cause further perforator occlusion as a result of the “snow plowing” effect.29 Thus, correlation of the clinical syndrome, infarct topography, cerebral perfusion pattern, and angiographic findings is crucial in deciding the treatment approach based on stroke mechanisms (Fig. 15.1).50
Indication for intracranial angioplasty or stenting Studies have suggested that intracranial stenosis ≥50% with the following characteristics may be considered for angioplasty or stenting: (1) recurrent transient ischemic attacks (TIAs) or IS within
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Fig 15.1 A 55-year-old, right-handed woman was referred to our institute because of recurrent transient ischemic attacks (TIAs) of the left hemiparesis for 2 years despite aspirin treatment. One month previously, she again experienced a similar attack that lasted for 4 hours. T2-weighted magnetic resonance imaging (MRI) showing the infarct in the anterior watershed (A,B), internal watershed (C), and superior watershed area (D). Perfusion CT before stenting revealed a marked decrease in cerebral
blood flow (CBF) (E), a marked increase in cerebral blood volume (CBV) (F) and a marked prolongation in mean transit time (MTT) (G) in the territory of the right MCA. Angiogram before stenting (H) showed severe MCA stenosis that correlates well with the patient’s infarct, perfusion deficit and ischemic symptom. The CBF (I), CBV (J) and MTT (K) in the right MCA territory recovered to nearly normal following successful angioplasty associated with balloon-expandable stenting (L).
180 days; (2) refractoriness to antithrombotic therapy; (3) relevant cerebral hypoperfusion or borderzone infarct in the corresponding territory; and (4) presence of one or more atherosclerotic risk
factors. Contraindications include vasculitis, moyamoya disease, intracranial hemorrhage (ICH) within 6 weeks, platelet count <100 000 international normalized ratio >1.5, bleeding diathesis, or patients
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contraindicated for antithrombotic therapy or contrast medium.14–34,36–41,49–54 Regarding the degree of stenosis, two recent studies deserve attention,10,40 in both of which the degree of stenosis was measured according to the WASID method.54 One is the WASID trial, which revealed that the cumulative probability of lesion-related IS at 1 year was 17% in patients with ≥70% stenosis, whereas it was 7–8% in patients with 50–69% stenosis.10 The other is the study by Jiang et al.,40 which showed no significant differences in the cumulative probability of stroke in the territory of the stenotic artery between the ≥70% stenosis group (7.2% at 1 year and 8.2% at 2 years) and the <70% stenosis group (5.3% at 1 year and 8.3% at 2 years) after elective balloon-expandable stenting. These data indirectly suggest that patients with ≥70% stenosis seem to benefit most from elective stenting. Thus, symptomatic ≥70% intracranial stenosis might be a more reasonable indication for intracranial stenting than ≥50% stenosis.
Endovascular therapy in acute or unstable condition The endovascular procedure is usually performed electively in stable patients as a way of secondary stroke prevention. However, endovascular techniques and stenting can be performed in an emergency situation in conjunction with thrombolytic therapy to achieve early recanalization and to improve the patient’s neurologic deficits. A recent meta-analysis of 53 studies assessing the relationship between recanalization and clinical outcome in 2066 patients with acute ischemic stroke showed that the recanalization rate was 24.1% in the non-treated groups, 46.2% after intravenous thrombolysis, 63.2% after intra-arterial thrombolysis, 67.5% after combined intravenous and intra-arterial thrombolysis, and 83.6% in patients undergoing mechanical thrombolysis.55 Recanalization, whatever method was used, was a factor predicting good clinical outcome. This result suggests that mechanical endovascular intervention may play an important role in the management of stroke in the acute stage. In support of this argument, Choi et al.56 reported that there was an 82% recanalization rate and a 52% good clinical outcome at 6 months following endovas184
cular revascularization through angioplasty and/or stenting of the occluded intracranial artery in conjunction with intravenous and/or intra-arterial thrombolysis in 33 patients with acute stroke. Young age, low initial National Institutes of Health stroke scale (NIHSS) score, and the use of stenting were factors related to good clinical outcome at 6-month follow-up. The endovascular revascularization procedure may also be performed in patients with an unstable clinical course. To compare the efficacy and adverse effects of endovascular procedures between patients with stable and those with unstable clinical presentation, Suh et al.57 categorized the patients as (1) the unstable patient group, patients who had progressive or fluctuating neurological symptoms (NIHSS ≥ 4) within 2 days before revascularization procedure; (2) the stable patient group, patients whose symptoms had resolved, improved, or had been stationary before the revascularization procedure. They found that the adverse event rates after the procedure were greater in the unstable group (25.9%) than in the stable group patients (4.1%). This result suggests that the procedure should not be performed or performed with great caution in patients showing an unstable clinical course. However, since patients with unstable clinical presentation are generally those whose neurologic outcome is expected to be poor, the risk–benefit ratio of the procedure in unstable patients still remains to be determined through further prospective, randomized trials.
Predicting procedural success by angiographic classification In 1998, Mori et al.17 classified intracranial stenosis into three types: type A, short (5 mm or less in length), concentric or moderately eccentric lesions, less than totally occlusive; type B, tubular (5–10 mm in length), extremely eccentric or totally occluded lesions, less than 3 months old; and type C, diffuse (more than 10 mm long), extremely angulated (>90◦ ) lesions with excessive tortuosity of the proximal segment, or totally occluded lesions, and more than 3 months old. They found that the clinical success (residual stenosis <50% after angioplasty without major complications) rate correlated with the classification, and were 92% (11/12), 86% (18/21), and 33% (3/9) for type A, B, and C, respectively. The cumulative risk of ischemic stroke or ipsilateral bypass surgery was 8%,
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Fig 15.2 Access classification. Type I, mild tortuosity with smooth arterial wall, for example, carotid siphon appears “U” shaped, and all turns in the internal carotid artery (ICA) course from distal end of the guiding catheter to the siphon are ≤90◦ (A). Type II, irregular arterial wall or
moderate tortuosity, “U”-shaped siphon, and only one turn >90◦ , or “V”-shaped siphon, and all turns ≤90◦ (B). Type III, severe tortuosity, “U”-shaped siphon, and two or more turns >90◦ , or “V”-shaped siphon, and one turn or more >90◦ (C).
26%, and 87% for type A, B, and C, respectively. At the 1-year follow-up, the restenosis rate was 0%, 33%, and 100% for types A, B, and C, respectively. Mori’s classification is helpful in predicting the likelihood of clinical success when patients undergo intracranial balloon angioplasty. However, the technical success of intracranial stenting appears more related to the condition of vascular access, whereas the risks of complication and restenosis are related to the morphology of the target lesion. Based on this concept, Jiang et al.28 proposed the LMA classification of intracranial stenosis in 2004. The lesion was first classified according to the location: type A, prebifurcation lesion; type B, post-bifurcation lesion; type C, lesion across the non-stenotic ostium of its branch; type D, lesion across the stenotic ostium of its branch; type E, ostium lesion of branch alone; type F, the combinative lesions of prebifurcation and its small branch ostium; and type N, non-bifurcation lesion. Second, the lesion was classified based on its morphology according to Mori’s classification. Lastly, the vascular access
between guide catheter and target lesion was classified into three types (Fig. 15.2). Type I access, smooth arterial wall with mild vascular tortuosity; for example, the carotid siphon appears as a “U” shape and all ICA turns distal to the guide catheter are ≤90◦ . Type II access, irregular arterial wall of moderate tortuosity; for example, a “U” shape carotid siphon with one of the ICA turns >90◦ ; or a “V” shape carotid siphon with all turns ≤90◦ . Type III access, severe vascular tortuosity; for example, a “U” shape carotid siphon with two or more ICA turns >90◦ ; or a “V” shape carotid siphon with at least one ICA turn >90◦ . In a retrospective review of MCA stenting, the technical success rate was 100% (17/17), 100% (18/18), and 85.7% (6/7) for types I, II, and III access, respectively; and perioperative mortality was 2.5% (1/40 patients), and 0% (0/15), 0% (0/23), and 25% (1/4) for types A, B, and C lesions, respectively.28 In this study, however, the difference in profile and trackability of stents (five types of stents were used) might be a problem in accurately evaluating the value of LMA classification. In a recent 185
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study of 46 patients (48 stenoses) who were treated uniformly with one type of balloon-expandable stent (Apollo stent, designed specifically for ICAS by MicroPort Medical, Shanghai, China), severe tortuosity is found to be an independent predictor of stent failure.58 Another recent study on long-term outcome of patients with ICAS after elective stenting revealed that type III access and diabetes were determinants of poor outcome.41
Preoperative assessment and medical treatment For successful outcome, preoperative multidisciplinary evaluation by interventionists, stroke neurologists, and imaging neuro-radiologists is crucial. The evaluation should (1) define the stroke mechanism; (2) correlate the index stroke with the topography of infarction, the stenotic vascular lesion, and perfusion deficit; (3) tabulate the risk and benefit of the procedure; and (4) formulate an individual operative plan and peri-operative medical regimen. Many centers recommend the use of dual antiplatelet agents (commonly aspirin 300 mg plus clopidogrel 75 mg daily) for 3–7 days before the procedure, and to continue to use them for ≥6 months after the procedure.28–30,40,41,58 Probucol (500 mg b.d.), which was shown to reduce restenosis after coronary angioplasty,59,60 may be used as well. Atherosclerotic risk factors should also be controlled stringently.9
Practical issues of intracranial stenting As mentioned before, the concept of submaximal angioplasty with slow balloon inflation has been widely accepted in intracranial angioplasty. Technical success is commonly defined as residual stenosis ≤50% coupled with good anterograde flow. At Tiantan Hospital, China, primary balloon-expandable stenting (without pre-dilatation) for symptomatic intracranial stenoses has been performed since 2001; and stenting with the Wingspan stent system started in January 2007. Readers interested in the evolution of the technique may refer to the pertinent references regarding angioplasty with undersizing of the balloon and slow inflation,18 staged stent placement,26 and angioplasty with undersized stent.27 186
Low-dose nimodipine (Bayer AG, Germany) infusion commencing 2 hours before surgery may be useful in preventing vasospasm during the procedure. Anticoagulation is achieved by heparin given in an intravenous bolus, followed by continuous infusion adjusted by activated clotting time (ACT). The optimal anti-coagulation intensity for intracranial stenting remains uncertain. Two regimens have been tested. In one regimen, heparin was given in a bolus of 3000 units followed by 800 units/hour to maintain an ACT between 250 and 300 seconds. Another regimen involved a lower dose of heparin, in which the bolus and infusion were 2000 units and 500 units/hour, respectively, aiming at an ACT of 160–220 seconds (as used in the PROACT II Study).61 It was found that the rate of ICH was 7.4% (5/68) in the high-dose regimen and 1.0% (1/101) in the low-dose regimen, whereas the thrombotic event rate was 2.9% (2/68) in the highdose regimen and 4.0% (4/101) in the low-dose regimen. Univariate analysis showed that the high-dose regimen was significantly associated with ICH, but did not significantly reduce the target lesion thrombosis.30 Intracranial stenting can be performed either under general or local anesthesia. Apart from the conventional femoral approach, transradial or transbrachial access may be chosen in selected patients. The guide catheter (usually 6F) should perch at the distal cervical segment of the ICA, or the proximal vertebral artery (VA). If the VA accessed is <3.0 mm in diameter, severely tortuous, or the contralateral VA is occluded, the guide catheter should be positioned in the subclavian artery, and an 8F guide catheter should be used for stronger support. The intracranial vasculature is anatomically distinct from the coronary arteries, and, thus, the techniques involved in intracranial angioplasty are different from coronary angioplasty.49,62 First, the cerebral arteries are tortuous and target lesions are located far distally from the guide catheter. A floppy-tipped microwire is often needed for negotiating tortuous access and tight stenosis [such as Transcend 14 EX microwire (Boston Scientific)] before replacement by a stiffer microwire through a microcatheter. Second, perforating branches that supply the basal ganglia and brain stem are often invisible on digital subtraction angiogram (DSA) or roadmap. Injury of perforators may occur during inadvertent microwire manipulation, resulting in a permanent neurological deficit. In practice, any slight deformation of the
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microwire tip may signify direct opposition to a small artery orifice or an atherosclerotic plaque, and should prompt immediate adjustment of the tip orientation and/or partial retrieval of the microwire. Third, cerebral arteries are suspended in cerebrospinal fluid and “anchored” to the brain by small penetrating branches. Any advancement or retrieval of the wire, catheter, balloon, and stent systems may therefore stretch and displace the major cerebral arteries, causing tethering or even avulsion of small penetrating branches. Catastrophic ICH may develop because of avulsion of perforators. Therefore, devices for neuro-intervention should be more flexible and softer than those applied in coronary angioplasty. In cases when coronary stents are used for intracranial disease, gentle manipulation is crucial to avoid any significant displacement of major arteries. Fourth, a functionally less important vessel should be selected for distal access of the microwire. For instance, in M1 MCA angioplasty, the microwire should perch in the inferior division of the MCA, or more preferably, in the temporo-occipital branch as vascular complication arising in this territory is relatively less catastrophic than those of the superior division. By the same token, in basilar artery stenting, it is advisable to place the microwire in the P4 segment of the posterior cerebral artery (PCA) because the prognosis of supratentorial bleeding or distal occlusion of the PCA caused by the microwire tip would be relatively benign compared with infratentorium bleeding or proximal PCA occlusion. Lastly, the wall of the cerebral arteries is thinner than that of the coronary arteries, because of the paucity of vasa vasorum, the absence of external elastic membranes, and the near absence of the adventitia. The thinner tunica media is composed principally of smooth muscle cells. Thus, submaximal angioplasty with extremely slow inflation should be applied in the intracranial vasculature to avoid dissection and rupture. The primary principles of intracranial stenting with balloon-expandable stent at Tiantan hospital are as follows: (1) the microwire and guiding catheter should perch at a site that can stably support the delivery of the stent system; (2) the stent size is selected based on the normal adjacent vessel diameter (on either side of the stenosis, whichever is smaller), the ratio of the stent diameter to the normal adjacent vessel diameter is 0.9–1.0:1.0; (3) after its placement across the stenotic
segment, the stent is released by slow balloon inflation up to 6–8 atm without predilatation (Fig. 15.3). The primary principles of intracranial stenting with the Wingspan stent and the Gateway balloon are as follows: (1) the microwire and guiding catheter should perch at a site that can stably support the delivery of the stent system; (2) stent selection is based on the normal adjacent vessel diameter [fully expanded stent diameter is 0.5–1.0 mm greater than the diameter of the normal adjacent vessel (on either side of the stenosis whichever is larger)] and the length of the stenotic lesion (deployed stent to extend at least 3 mm on either side of the lesion) [the Wingspan stent is available in five diameters (2.5, 3, 3.5, 4, and 4.5 mm) and three lengths (9, 15, 20 mm)]; (3) the dilatation with the Gateway balloon (nominal pressure of 6 atm) is performed before stent placement (the recommended Gateway balloon diameter is 80% or less of the native vessel diameter) on either side of the stenosis whichever is smaller; (4) continuous heparinized saline flush to the Wingspan stent system and Gateway catheter is necessary (Fig. 15.4).
Outcome after angioplasty or stenting Few studies reported the long-term outcome of angioplasty or stenting for intracranial stenosis. Table 15.1 summarizes the results of the three multicenter studies of self-expandable or balloon-expandable stenting (by the Wingspan and the Neurolink stent systems), the two single-center studies of angioplasty with balloonmounted stents (by coronary stents, and Apollo stents (a balloon-mounted stent designed for intracranial vasculature), as well as the results of WASID trial for comparison. Except for the SSYLVIA study, intracranial stenting appears to be effective for symptomatic ICAS when compared with the outcome of patients on medical therapy in the WASID trial. Further randomized trials are needed for confirmation. Peri-operative complications of intracranial stenting remain a prime concern as they may offset the potential benefit of the procedure. Reported vascular complications are diverse, and include ICH, stent thrombosis, perforator stroke, embolic stroke, and vessel dissection. Jiang et al.30 reported 20 complications in 169 patients (11.8%) who underwent balloon-expandable stenting for symptomatic intracranial stenosis. The complications included four 187
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Fig 15.3 A 70-year-old man with symptomatic severe stenosis in the left middle cerebral artery (MCA) (A) underwent elective stenting at our institute. The procedure was performed under local anesthesia. After placing a 6F Envoy guiding catheter (Cordis) into the distal cervical segment of the left internal carotid artery (ICA), a Choice PT microwire (Boston Scientific Scimed) was used to pass through the target lesion, and then left in the M4 segment of the middle cerebral artery (B, arrow). A
2.25 mm × 10 mm BiodivYsio coronary stent (Biocompatibles) was chosen, and placed across the lesion (C). The balloon was inflated slowly (D), and then the stent was released at 7 atm. (E). A good immediate result was obtained after removal of the balloon catheter (F) and after removal of the microwire (G). The patients received an follow up angiograph after 7 months, which revealed good patency in the stenting site (H).
symptomatic ICH, five minor perforator strokes, one embolic stroke, two asymptomatic ICH, six stent thromboses (all treated by intra-arterial thrombolysis without clinical sequelae), one TIA presumably from vasospasm, and one arterial dissection. The perioperative stroke (based on clinical symptom) occurred in 10 patients (5.9%). Compared with coronary stents, angioplasty with stents specifically designed for intracranial vasculature appears to be associated with lower peri-procedural strokes and deaths (Table 15.1).
The rate of peri-procedural stroke was 4.5–6.4% with the Wingspan stent system,37,38 6.6% the with Neurolink stent,32 and 6.5% with the Apollo stent.58 Hyperperfusion and vessel perforation are the two major causes of ICH after intracranial stenting.28,30,63 Currently, aggressive systemic blood pressure control is the best available way to prevent and treat hyperperfusion syndrome.30 Tandem stenting for a single stenosis seems to be an independent risk factor of ICH.30 It appears that in tandem stenting, the stent
188
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Fig 15.4 A 57-year-old female patient with a 70% stenosis in the left middle cerebral artery (MCA) that resulted in the recurrent attacks of weakness and numbness in her left side for 1 month underwent elective stenting at our institute. After putting a 6F Envoy guiding catheter into the distal cervical segment of the left ICA, and a Choice PT microwire in the M3 segment of the MCA (A), a 1.5 × 9 mm Gateway balloon catheter was delivered to lesion site along the microwire (B). The stenosis was reduced to 30% following the balloon dilatation (C). A 2.5 × 15 mm Wingspan stent system was applied in this case. After placing the stent segment of the system across the lesion (D), the stent was released. The angiogram immediately after stenting showed a satisfactory result (residual stenosis of 30% with the smooth vessel wall) (E). Follow-up angiography 8 months later revealed a remolding effect of the Wingspan self-expanding stent. The degree of stenosis had improved further (10% stenosis rate) (F).
struts may perforate the arterial wall when the distal stent is impinged by the proximal stent. In addition, the advancement of the second stent system may catch the deployed stent and thus drag on the major cerebral arteries, leading to avulsion or rupture of the fragile perforators.30 To prevent peri-procedural thrombotic complications, pre-treatment with dual antiplatelet agents, usually aspirin plus clopidogrel, has been recommended.49 Non-compliance with anti-platelet therapy was found to be associated with a higher frequency of stent thrombosis.30 Patients with pre-operative perforator infarct adjacent to the stenotic segment may have a higher rate of perforator stroke after elective stening,29 probably related to displacement of debris by the stent into the ostia of perforators (snow-plowing effect) or coverage of the perforator ostia by the stent struts. Compared with vertebral artery angioplasty, basilar artery stenting is associated with a higher risk of post-stent stroke in relation to its larger number of perforators. The increased risk is also likely to be re-
lated to more distal access of the stent system during basilar artery stenting.64
Treatment for concomitant stenoses Patients with multiple stenoses can be stratified into two groups: (1) multifocal stenoses in different vascular territories (separate lesion group), and (2) tandem stenoses (extracranial or intracranial) in the same vascular territory (ipsilateral lesion group). Each group may require different strategies of revascularization.65 For tandem lesions in the same vascular territory, dilatation of the proximal stenosis should be performed prior to the distal lesion as improvement in the distal run-off after treatment for the proximal lesion may potentially reduce thromboembolic complications in the distal lesion. In cases of multifocal stenoses in different vascular territories, it is optional to perform revascularization in a stepwise fashion or within the same session. Revascularization of multiple stenoses at the 189
Study method
Prospective randomized multicenter trial
Prospective non-randomized multicenter
Prospective non-randomized multicenter
Prospective non-randomized multicenter
Prospective non-randomized single center
Prospective non-randomized single center
First author
WASID investigators
SSYLVIA study
European–Asian Wingspan trial
US Wingspan periprocedural result
ASSIST (Jiang)
Jiang 213 with 220 lesions
46 with 48 lesions
78 with 82 lesions
44
64.3
62.8
Balloon expandable stenting
Apollo stenting
Self-expanding stenting after balloon dilatation
Self-expanding stenting after balloon dilatation 5 (6.4)
2 (4.5)
4 (6.6)
NA
NA
52.8
10 (4.7)
median: 54 3 (6.5)
66.6
66
Neurolink balloon 63.6 expandable stenting
Warfarin
289
61
Aspirin
Therapy
280
No. of cases
2 (0.9)
0
4 (5.1)
1 (2.3)
0
NA
NA
10 (4.7)
3 (6.5)
5 (6.4)
2 (4.5)
4 (6.6)
NA
NA
30-day any stroke/death no. (%)
206
46
NA
42
55
289
280
7 (3.4)
1 (2.2)
NA
1 (2.4)
1.53
2.00
NA
0.5
1.0
1.87
25 (12.1)∗
4 (7.3)
1.80
Mean FU (year) per case
42 (15.0)∗
Ipsilateral No. of FU stroke after cases after 30 days 30 days no. (%)
6.7% at 1 year, 9.8% at 2 years
8.8% at 1 year, 8.8% at 2 years
NA
7.1% at 6 months
13.4% at 1 year
12% at 1 year, 15% at 2 years 11% at 1 year, 13% at 2 years
Cumulative ipsilateral stroke probability including 30-day any stroke/death
August 18, 2008
30-day 30-day Mean age any stroke any death (years) No. (%) No. (%)
Table 15.1 The results of multicenter studies of self-expandable stenting FU, follow up NA, not available.
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same session appears both feasible and cost-effective and may reduce the procedural burden.66 Systemic blood pressure control may become difficult if only one of the high-grade lesions is treated, as hyperperfusion syndrome may develop in the treated vascular territory while the untreated territories remain hypoperfused. The unbalanced cerebral hemodynamics may also accelerate steno-occlusion of the untreated vascular territory.65 Pyun et al.65 recently reported the outcome of simultaneous revascularization in 50 patients having more than one arterial stenoses. They found that the procedural success rate was high (100%) and that periprocedural adverse events were acceptable (10%). The peri-procedural event rate in the ipsilateral lesion group was higher than in the separate lesion group. Major events, including major stroke and death, were more common in patients with unstable than stable clinical presentations. Therefore, multiple concomitant revascularizations appear feasible in supra-aortic arteries, including intracranial vessels. However, multiple concomitant revascularizations should be more carefully performed in the ipsilateral lesion group, especially in patients with unstable clinical presentations. Further studies are required to verify the effect of multiple concomitant revascularizations and to compare the results of a stepwise approach as opposed to simultaneous treatment.
Summary At present, angioplasty or stenting for symptomatic ICAS remains an investigational procedure. Careful patient selection, meticulous peri-procedural care, readily accessible neuro-imaging facilities, and skilful neuro-interventionists are all essential for performing the procedure with an acceptable risk. Patients with recent cerebral ischemic symptoms attributed to an intracranial stenosis ≥70% and associated with perfusion failure may benefit most from this procedure. Diabetes mellitus and excessive tortuosity in vascular access may predict a worse outcome. There are still uncertainties regarding the peri-procedural complications, in-stent restenosis, and long-term clinical outcome. Moreover, randomized studies are not available that confirm the efficacy of stenting/angioplasty in comparison with optimal medical treatment.
Certainly, more studies are needed to elucidate the value of and indication for angioplasty and stenting in patients with ICAS.
References 1 AHA. Heart disease and stroke statistics – 2006 update. Dallas, TX: American Heart Association. 2 Wityk RJ, Lehman D, Klag M, Coresh J, et al. Race and sex differences in the distribution of cerebral atherosclerosis. Stroke 1996; 27: 1974–1980. 3 Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Raceethnicity and determinants of intracranial atherosclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke 1995; 26: 14–20. 4 Caplan LR, Gorelick PB, Hier DB. Race, sex and occlusive cerebrovascular disease: a review. Stroke 1986; 17: 648– 655. 5 Feldmann E, Daneault N, Kwan E, et al. Chinese-white differences in the distribution of occlusive cerebrovascular disease. Neurology 1990; 40: 1541–1545. 6 Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke 2006; 37: 577–617. 7 EC/IC Bypass Study Group. Failure of extracranialintracranial arterial bypass to reduce the risk of ischemic stroke. Results of an international randomized trial. N Engl J Med 1985; 313: 1191–1200. 8 Bogousslavsky J, Barnett HJ, Fox AJ, et al. Atherosclerotic disease of the middle cerebral artery. Stroke 1986; 17: 1112–1120. 9 Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005; 352: 1305– 1316. 10 Kasner SE, Chimowitz MI, Lynn MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113: 555–563. 11 Thijs VN, Albers GW. Symptomatic intracranial atherosclerosis: outcome of patients who fail antithrombotic therapy. Neurology 2000; 55: 490–497. 12 Hopkins LN, Budny JL. Complications of intracranial bypass for vertebrobasilar insufficiency. J Neurosurg 1989; 70: 207–211. 13 Hopkins LN, Budny JL, Castellani D. Extracranialintracranial arterial bypass and basilar artery ligation in
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14
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the treatment of giant basilar artery aneurysms. Neurosurgery 1983; 13: 189–194. Sundt TM, Jr, Smith HC, Campbell JK, Vlietstra RE, Cucchiara RF, Stanson AW. Transluminal angioplasty for basilar artery stenosis. Mayo Clin Proc 1980; 55: 673– 680. Higashida RT, Tsai FY, Halbach VV, et al. Transluminal angioplasty for atherosclerotic disease of the vertebral and basilar arteries. J Neurosurg 1993; 78: 192–198. Yokote H, Terada T, Ryujin K, et al. Percutaneous transluminal angioplasty for intracranial arteriosclerotic lesions. Neuroradiology 1998; 40: 590–596. Mori T, Fukuoka M, Kazita K, Mori K. Follow-up study after intracranial percutaneous transluminal cerebral balloon angioplasty. AJNR Am J Neuroradiol 1998; 19: 1525–1533. Connors JJ, 3rd, Wojak JC. Percutaneous transluminal angioplasty for intracranial atherosclerotic lesions: evolution of technique and short-term results. J Neurosurg 1999; 91: 415–423. Marks MP, Wojak JC, Al-Ali F, et al. Angioplasty for symptomatic intracranial stenosis: clinical outcome. Stroke 2006; 37: 1016–1020. Ecker RD, Levy EI, Sauvageau E, Hanel RA, Hopkins LN. Current concepts in the management of intracranial atherosclerotic disease. Neurosurgery 2006; 59:S210– 218; discussion S213–213. Feldman RL, Trigg L, Gaudier J, Galat J. Use of coronary Palmaz-Schatz stent in the percutaneous treatment of an intracranial carotid artery stenosis. Cathet Cardiovasc Diagn 1996; 38: 316–319. Gomez CR, Misra VK, Liu MW, et al. Elective stenting of symptomatic basilar artery stenosis. Stroke 2000; 31: 95–99. Mori T, Kazita K, Chokyu K, Mima T, Mori K. Shortterm arteriographic and clinical outcome after cerebral angioplasty and stenting for intracranial vertebrobasilar and carotid atherosclerotic occlusive disease. AJNR Am J Neuroradiol 2000; 21: 249–254. Levy EI, Horowitz MB, Koebbe CJ, et al. Transluminal stent-assisted angioplasty of the intracranial vertebrobasilar system for medically refractory, posterior circulation ischemia: early results. Neurosurgery 2001; 48: 1215–1221; discussion 1221–1213. Lylyk P, Cohen JE, Ceratto R, et al. Angioplasty and stent placement in intracranial atherosclerotic stenoses and dissections. AJNR Am J Neuroradiol 2002; 23: 430– 436. Levy EI, Hanel RA, Boulos AS, et al. Comparison of periprocedure complications resulting from direct stent placement compared with those due to conventional and staged stent placement in the basilar artery. J Neurosurg 2003; 99: 653–660.
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27 de Rochemont Rdu M, Turowski B, Buchkremer M, Sitzer M, Zanella FE, Berkefeld J. Recurrent symptomatic highgrade intracranial stenoses: safety and efficacy of undersized stents–initial experience. Radiology 2004; 231: 45– 49. 28 Jiang WJ, Wang YJ, Du B, et al. Stenting of symptomatic M1 stenosis of middle cerebral artery: an initial experience of 40 patients. Stroke 2004; 35: 1375–1380. 29 Jiang WJ, Srivastava T, Gao F, et al. Perforator stroke after elective stenting of symptomatic intracranial stenosis. Neurology 2006; 66: 1868–1872. 30 Jiang WJ, Du B, Leung TW, et al. Symptomatic intracranial stenosis: cerebrovascular complications from elective stent placement. Radiology 2007; 243: 188– 197. 31 Abou-Chebl A, Bashir Q, Yadav JS. Drug-eluting stents for the treatment of intracranial atherosclerosis: initial experience and midterm angiographic follow-up. Stroke 2005; 36:e165–168. 32 Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries (SSYLVIA): study results. Stroke 2004; 35: 1388–1392. 33 Terada T, Tsuura M, Matsumoto H, et al. Endovascular therapy for stenosis of the petrous or cavernous portion of the internal carotid artery: percutaneous transluminal angioplasty compared with stent placement. J Neurosurg 2003; 98: 491–497. 34 Suh DC, Kim JK, Choi JW, et al. Balloon-expandable intracranial stenting of severe symptomatic intracranial stenosis: Outcome analysis of 100 consecutive patients. Am J Neuroradial 2008; 29: 781–785. 35 Hartmann M, Jansen O. Angioplasty and stenting of intracranial stenosis. Curr Opin Neurol 2005; 18: 39– 45. 36 Summary of safety and probable benefit: Wingspan Stent System with Gateway PTA Balloon Catheter. Humanitarian Use Device Designation H050001. Available at http://www.fda.gov/cdrh/pdf5/h050001b.pdf. (accessed April 28, 2006). 37 Bose A, Hartmann M, Henkes H, et al. A novel, selfexpanding, nitinol stent in medically refractory intracranial atherosclerotic stenoses: the Wingspan study. Stroke 2007; 38: 1531–1537. 38 Fiorella D, Levy EI, Turk AS, et al. US multicenter experience with the wingspan stent system for the treatment of intracranial atheromatous disease: periprocedural results. Stroke 2007; 38: 881–887. 39 Yu W, Smith WS, Singh V, et al. Long-term outcome of endovascular stenting for symptomatic basilar artery stenosis. Neurology 2005; 64: 1055–1057. 40 Jiang WJ, Xu XT, Du B, et al. Comparison of elective stenting of severe vs moderate intracranial atherosclerotic stenosis. Neurology 2007; 68: 420–426.
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41 Jiang WJ, Du B, Xu XT et al. Elective stenting of symptomatic intracranial atherosclerosis: long-term outcome and predictors. Stroke 2007; 38: 466–467. 42 Cruz-Flores S, Diamond AL. Angioplasty for intracranial artery stenosis (Cochrane Review). In: The Cochrane Library, 2006. (http://www.mw.interscience.wiley.com/co chran/clsysrev/articles/CD004133/frame.html) 43 Derdeyn CP, Grubb RL, Jr., Powers WJ. Cerebral hemodynamic impairment: methods of measurement and association with stroke risk. Neurology 1999; 53: 251–259. 44 Naritomi H, Sawada T, Kuriyama Y, et al. Effect of chronic middle cerebral artery stenosis on the local cerebral hemodynamics. Stroke 1985; 16: 214–219. 45 Grubb RL, Jr, Derdeyn CP, Fritsch SM, et al. Importance of hemodynamic factors in the prognosis of symptomatic carotid occlusion. JAMA 1998; 280: 1055–1060. 46 Constantinides P. Pathogenesis of cerebral artery thrombosis in man. Arch Pathol 1967; 83: 422–428. 47 Caplan LR. Intracranial branch atheromatous disease: a neglected, understudied, and underused concept. Neurology 1989; 39: 1246–1250. 48 Derdeyn CP, Videen TO, Yundt KD, et al. Variability of cerebral blood volume and oxygen extraction: stages of cerebral haemodynamic impairment revisited. Brain 2002; 125: 595–607. 49 Schumacher HC, Khaw AV, Meyers PM, et al. Intracranial angioplasty and stent placement for cerebral atherosclerosis. J Vasc Interv Radiol 2004; 15:S123–132. 50 Sauvageau E, Ecker RD, Levy EI, et al. Recent advances in endoluminal revascularization for intracranial atherosclerotic disease. Neurol Res 2005; 27 (Suppl 1):S89–94. 51 Kim JK, Ahn JY, Lee BH, et al. Elective stenting for symptomatic middle cerebral artery stenosis presenting as transient ischaemic deficits or stroke attacks: short term arteriographical and clinical outcome. J Neurol Neurosurg Psychiatry 2004; 75: 847–851. 52 Chow MM, Masaryk TJ, Woo HH, et al. Stent-assisted angioplasty of intracranial vertebrobasilar atherosclerosis: midterm analysis of clinical and radiologic predictors of neurological morbidity and mortality. AJNR Am J Neuroradiol 2005; 26: 869–874. 53 Kim DJ, Lee BH, Kim DI, et al. Stent-assisted angioplasty of symptomatic intracranial vertebrobasilar artery stenosis: feasibility and follow-up results. AJNR Am J Neuroradiol 2005; 26: 1381–1388.
54 Samuels OB, Joseph GJ, Lynn MJ, et al. A standardized method for measuring intracranial arterial stenosis. AJNR Am J Neuroradiol 2000; 21: 643–646. 55 Rha J-H, Saver JL. The impact of recanalization on ischemic stroke outcome: a meta-analysis. Stroke 2007; 38: 967–973. 56 Choi WJ, Choi BS, Kim JK, et al. Revascularization of intracranial occlusion: stenting vs. angioplasty. WFITN Proceedings 2007: 124–125. 57 Suh DC, Kim JK, Choi JW, et al. Intracranial stenting of severe symptomatic intracranial stenosis: results of 100 consecutive patients. AJNR Am J Neuroradiol 2008; 29: 781–785. 58 Jiang WJ, Xu XT, Jin M, et al. Apollo stent for symptomatic atherosclerotic intracranial stenosis: study results. AJNR Am J Neuroradiol 2007; 28: 830–834. 59 Tardif JC, Cote G, Lesperance J, et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. N Engl J Med 1997; 337: 365–372. 60 Rodes J, Cote G, Lesperance J, et al. Prevention of restenosis after angioplasty in small coronary arteries with probucol. Circulation 1998; 97: 429–436. 61 Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in acute cerebral thromboembolism. JAMA 1999; 282: 2003–2011. 62 Levy EI, Kim SH, Bendok BR. Interventional neuroradiologic therapy. In: Mohr JP, Choi DW, Weir B, Wolf PA (eds) Stroke: pathophysiology, diagnosis, and management, 4th edn. Churchill Livingstone, Philadelphia 2004; 1475–1520. 63 Abou-Chebl A, Yadav JS, Reginelli JP, et al. Intracranial hemorrhage and hyperperfusion syndrome following carotid artery stenting: risk factors, prevention, and treatment. J Am Coll Cardiol 2004; 43: 1596–1601. 64 Jiang WJ, Xu XT, Du B, et al. Long-term outcome of elective stenting for symptomatic intracranial vertebrobasilar stenosis. Neurology 2007; 68: 856–858. 65 Pyun HW, Suh DC, Kim JK, et al. Concomitant multiple revascularizations in supra-aortic arteries: short-term results in 50 patients. AJNR Am J Neuroradiol 2007; 28: 1895–1901. 66 Henry M, Gopalakrishnan L, Rajagopal S, Rath PC, Henry I, Hugel M. Bilateral carotid angioplasty and stenting. Catheter Cardiovasc Interv 2005; 64: 275–282.
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Surgical therapy Chang Wan Oh and Jeong Eun Kim
Patients with intracranial atherosclerosis are usually treated by medication and occasionally angioplasty/stenting is performed. However, in a subgroup of patients with severe hemodynamic impairment, extracranial–intracranial (EC/IC) bypass surgery may be considered. In addition, in patients with massive infarction due to middle cerebral artery (MCA) occlusion, decompressive craniectomy may lower the mortality rate and improve the long-term quality of life. The benefit of these surgical procedures in patients with intracranial atherosclerosis has long been controversial. In this chapter, surgical therapies for intracranial atherosclerosis are reviewed.
Intracranial revascularization surgery Surgical procedures Revascularization of the ischemic brain distal to intracranial or extracranial steno-occlusive lesions can be achieved through various types of EC/IC bypass surgery using different donor and recipient arteries and conduit vessels.1,2 There are two types of bypass surgery defined by the amount of blood flow through the bypass: a high-flow type and a low-flow type (Fig. 16.1). The high flow-type bypass uses a free venous or arterial graft (saphenous vein or radial artery) to connect the cervical carotid artery to the proximal MCA (M1 or M2 branches in the sylvian fissure). Extracranial internal, external, or common carotid arteries can be used as donor arteries depending on the situation. This type of bypass surgery is usually used in the planned occlusion of the internal carotid artery (ICA) for the treatment of giant aneurysms or skull 194
base tumors. It is less commonly used to treat intracranial atherosclerotic disease because of the high risk of complications, including postoperative massive hemorrhage resulting from hyperperfusion breakthrough. Hemorrhagic complications occur more frequently in patients with a history of previous multiple ischemic symptoms.3 High-flow bypasses also have a relatively low rate of short- and long-term patency, with an occlusion rate of 14% at 1 year; 42% of all graft failures occurring within the first 24 hours after the operation.4 Low-flow bypass usually uses an arterial pedicle, which is a mobilized extracranial artery such as the superficial temporal artery (STA) or occipital artery, and its distal cut end is directly connected to the branches of the MCA without interposition of the vessel graft.1,2,5,6 Compared with the high-flow bypass with vessel graft, this type of direct bypass has fewer complications and better long-term durability, with a patency rate of over 95% at 5 years. The most commonly used recipient artery is the cortical (M4) branch of the MCA, but more proximal branches (M2 or M3) can be used to increase the blood flow through the bypass7 (Fig. 16.2). Double-barrel anastomoses using both frontal and parietal branches of the STA can also be performed to increase flow through the anastomosis8 (Fig. 16.1C,D). The most popular cortical recipient arteries are those from around the temporo-occipital area, especially the angular artery. Prefrontal or anterior temporal cortical branches are also used, although they usually have a smaller diameter than the angular artery. The arteries supplying the eloquent area around the central sulcus are rarely used as the recipient artery because of concerns about potential complications. For posterior circulation revascularization,
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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Fig 16.1 High-flow bypass, using saphenous vein graft (arrow 1), supplies the whole territory of the internal carotid artery (A and B), and double-barrel bypass with two branches of superficial temporal artery (arrow 2) can irrigate the territory of the middle cerebral artery (C and D).
Fig 16.2 Variations in the STA–MCA anastomosis. The recipient artery may be the M2 branch (A, arrow 1), angular artery (B, arrow 2), prefrontal artery (C, arrow 3), or the anterior temporal artery (D, arrow 4). With an appropriate-sized recipient artery (about 1 mm), the single STA–MCA anastomosis can resupply most of the territory of the middle cerebral artery.
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CHAPTER 16
the donor arteries can be connected to the posterior cerebral (PCA), superior cerebellar (SCA), anterior inferior cerebellar (AICA), and posterior inferior cerebellar (PICA) arteries. Bypass surgery for the posterior circulation disorders has a higher risk of complications than that for the anterior circulation diseases.
History of EC/IC bypass surgery The most commonly used bypass surgery in patients with anterior circulation disorders is the STA–MCA anastomosis. In 1967, Yasargil9 and Donaghy10 first applied STA–MCA anastomoses to patients after repeated experimental works using dogs.11 Since then, this procedure has been employed for revascularization of the brain distal to steno-occlusive lesions that are not accessible by the carotid endarterectomy. This procedure improves cerebral perfusion12,13 and according to several reports seems to decrease the occurrence of secondary strokes.13–15 In large series, the technical success rate was reported to be fairly high with the patency rate reaching up to 99%;16 operative morbidity (2–4%) and mortality (1–2.5%) were also acceptable.16,17 The incidence of secondary stroke ipsilateral to the side of successful bypass surgery was reported to be as low as 0.9% per year.17 With the increasing application of this procedure, a group of investigators initiated the International Cooperative Study of Extracranial–Intracranial Arterial Anastomosis (EC/IC Bypass Study) in 1977 to evaluate the efficacy of this surgery in a randomized study. The results of this EC/IC Bypass Study, however, demonstrated that cerebral revascularization using STA–MCA anastomosis provided no benefits over medical treatments18,19 in reducing the subsequent risk of stroke. This study randomized 1377 patients with minor stroke or transient ischemic attack (TIA), including retinal ischemia due to atherosclerotic stenoocclusive disease of the ICA or MCA, with an average follow-up period of 55.8 months. The analysis revealed that a single stroke occurred in 18% in the medication group and 20% in the surgery group. Multiple (two or more) strokes occurred in 10% in the medication group, and in 11% in the surgery group. Thus, bypass surgery was not proven to be beneficial in these patients. Analysis of a subgroup of intracranial lesions also demonstrated similar results; in 268 patients with MCA lesions, the results were not different 196
between the medication and surgery groups. Moreover, after bypass surgery, patients with MCA stenosis experienced worse outcomes than those having vascular lesions in the other areas. This result might have been related to the occlusion of the stenotic lesions after surgery, which was observed on the postoperative angiogram in 14% of these patients.18 The overall surgery-related morbidity and mortality were similar to those of the previous reports.16,17 During the peri-operative period, defined as the period from randomization to 30 days following surgery, 12.2% of the patient had cerebral and retinal ischemic events ranging from trivial to fatal ones. The rate of major stroke morbidity was 4.5%, and the mortality was 1.1%. During surgery and in the following 30 days, however, the major stroke morbidity rate was 3% including 0.6% mortality. The average interval between randomization and EC/IC bypass surgery was 9 days, during which 10 cases of major stroke occurred. Many of them were considered to be related to the preparations for surgery, such as repeated angiography or stress imposed on the patient prior to surgery.18 This result emphasizes the importance of careful peri-operative management in patients at high risk of stroke. The bypass patency rate was as high as 96%, demonstrating the high technical success rate of this procedure, which was compatible with the previous report.16 Several criticisms have been raised against this study result, which include concerns about the internal and external validity.20–27 Two important shortcomings of this trial deserve mention. The first is that a large number of patients, perhaps as many as 3000 based on the data obtained by Sundt,23 were operated on outside the trial, whereas only 663 patients were assigned to surgery within the trial.24 Many of those patients who underwent surgery outside the trial could have been eligible and included in the trial. The omission of those patients might have diluted the efficacy of surgery. However, without detailed information on those patients undergoing surgery outside the trial, further investigation on this question was not possible. The second and more important criticism is that this study enrolled patients based only on clinical symptoms and angiographic findings,19 but without information of the hemodynamic status.20–22 In 1977, when the EC/IC bypass trial was initiated, up-to-date technology for assessing cerebrovascular hemodynamics was not available in most institutes. With the
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advent of cerebral perfusion measurements, it has been shown that only a small proportion of patients with steno-occlusive lesions have decreased blood flow distal to vascular lesions.28 Therefore, the failure of the EC/IC bypass trial might have been related to the inclusion of patients who did not really need cerebral revascularization. Thus, studies should be performed paying more attention to the status of cerebral hemodynamics and the subsequent risk of stroke.22,29
Hemodynamic impairment and the risk of subsequent stroke The Warfarin–Aspirin in Symptomatic Intracranial Disease (WASID) study30,31 has provided a dataset regarding the risk of stroke from intracranial atherosclerotic disease. The risk of stroke increased in proportion to the severity of intracranial stenosis.32 This result correlated well with the findings from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) study,33 which showed an increased risk of stroke in patients with severe stenotic lesions of the extracranial carotid artery. These proportionately increased risks of stroke suggest that the hemodynamic problems associated with the severity of stenosis contribute to an increased risk of stroke. The severity of stenosis alone, however, does not correlate well with the degree of hemodynamic compromise.28 The cerebral vasculature has a high potential for developing collateral channels, including the circle of Willis, ophthalmic artery, and leptomeningeal vessels. Accordingly, the pattern of collateral pathways, especially the development of ophthalmic and leptomeningeal collaterals, is also important in determining hemodynamic impairment.34–36 The pattern of infarction may also suggest the presence of hemodynamic failure. Data from the NASCET study demonstrated that internal borderzone infarction (IBI) occurs in association with a high degree of ICA stenosis.37 The incidence of pure IBI is relatively rare (3.4%) in stroke patients, but the presence of this finding may be strong evidence for hemodynamic failure, along with the lesions occurring in the centrum semiovale.38–40 Although embolism can also result in borderzone infarction, especially in cases with isolated cortical borderzone infarcts,40 this may still be the footprint of hemodynamic impairment occurring during the development of the infarction.
The relationship between cerebral hemodynamic impairment and the risk of subsequent stroke has been investigated by measuring various parameters of cerebral perfusion. Grubb et al.41 categorized cerebral hemodynamic impairment in three stages depending on changes measured by positron emission tomography (PET): from normal (stage 0) to stages 1 and 2 hemodynamic failure with a progressive decrease in cerebral perfusion pressure (CPP). In stage 1, vasodilatation of the arterioles maintains normal cerebral blood flow (CBF) associated with increased cerebral blood volume (CBV). With a further decrease in CPP, autoregulation fails to maintain CBF so that the oxygen extraction fraction (OEF) begins to increase (stage 2) to maintain normal brain oxygen metabolism and function. This stage has been called “misery perfusion.”42 Stage 1 hemodynamic failure can be detected by measurement of increased CBV or CBV/CBF ratio by PET and by computed tomography/magnetic resonance imaging (CT/MRI), quantitatively and qualitatively, respectively. However, these results have been inconsistent regarding their clinical implications.43 Autoregulatory vasodilatation can be evaluated by comparing the CBF before and after a variety of vasodilatory stimuli, such as hypercapnia, intravenous challenge with acetazolamide, or physiological tasks such as hand movements.28,44 If the increase in CBF is impaired following the stimulus compared with the normal condition, the presence of autoregulatory vasodilatory failure is confirmed. This reduced responsiveness to stimuli is also known as reduced cerebrovascular reserve capacity (CVRC). The information on impaired reserve capacity can be obtained by transcranial Doppler ultrasound (TCD), singlephoton emission computed tomography (SPECT), xenon CT, MR, and CT perfusion studies.44 Such qualitative studies provide valuable information on unilateral hemodynamic impairment. However, the relationship between stage 1 hemodynamic failure and the subsequent risk of stroke is inconsistent; although many studies have demonstrated an increased risk of stroke associated with a decreased reserve capacity,45–50 other well-designed studies have failed to show this relationship.51,52 Only PET can accurately detect stage 2 hemodynamic impairment (misery perfusion) by measuring the increase in OEF. A well-designed prospective, blind trial demonstrated that stage 2 hemodynamic 197
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impairment correlated significantly with an increased risk of subsequent stroke.41 This longitudinal cohort study demonstrated that the occurrence of stroke ipsilateral to the occlusive lesion in the stage 2 group was 26.5% in 2 years, whereas it was 5.3% in the patients with normal OEF. The age-adjusted relative risk by stage 2 hemodynamic failure was 7.3 for ipsilateral stroke. Similar results have been reported by another prospective study in patients with symptomatic ICA or MCA occlusive lesions. Over 5 years, the relative risk of ipsilateral stroke was 6.4 for patients with an increased OEF compared with those with normal OEF.53 Based on these results, the presence of misery perfusion has been considered a potential indication for revascularization procedures, including bypass surgery and endovascular intervention. OEF measurement with PET, however, is not widely available in clinical practice. Although a close correlation between OEF and other more commonly available hemodynamic measurements has been reported,54–56 there still remain controversies concerning the validity of these techniques in the prediction of subsequent stroke.
Indications of revascularization based on hemodynamic impairment PET studies have demonstrated that EC/IC bypass can restore the impaired cerebral hemodynamics, including impaired cerebral vasoreactivity and increased OEF.42,57 Iwama et al.58 also showed that STA-MCA
anastomosis improved neurological dysfunction in a subgroup of patients with significantly elevated OEF. They analyzed the results of pre- and postoperative PET studies in 16 patients with stable neurological dysfunction of grades 1–3 on the modified Rankin scale. The EC/IC bypass surgery decreased the average OEF of the affected side, but only six patients showed neurological improvement after surgery. Their preoperative OEF and cerebral metabolic rate of oxygen (CMRO2 ) values were significantly higher than those of the patients without improvement. The improvement in cerebrovascular reserve capacity measured by other imaging methods has also been reported (Fig. 16.3),59,60 and several recent studies have confirmed the efficacy of EC/IC bypass surgery to improve anterior circulation hemodynamic impairment in selected patients.58,61,62 However, the proportion of hemodynamic stroke is relatively small among all stroke patients,63 and impaired cerebral perfusion often improves spontaneously with time.46,64,65 A revascularization procedure, therefore, should be considered carefully for those selected patients with sustained hemodynamic failure following cerebral ischemic events. The hemodynamic parameters should be measured for several weeks following the acute ischemic attack to assess the need for revascularization.58 The potential benefit provided by the EC/IC bypass should always be weighed against the morbidity that might result from the surgery, and patients with major medical problems should be excluded to avoid complications. The evidence also suggests that the best medical treatment
Fig 16.3 Changes in acetazolamide-challenged SPECTs after STA–MCA anastomosis. This patient with occlusion of the left internal carotid artery presented with progressive transient ischemic attacks (TIAs), with concomitant aggravation of the cerebral perfusion. His cerebral perfusion and cerebrovascular reactivity improved after bypass surgery, and TIAs also disappeared. SPECTs were taken 7 weeks (A and B) and 1 week (C and D) before surgery, and 1 week (E and F) and 15 months (G and H) after surgery.
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should always be provided regardless of the need for revascularization procedures. Since the risk of secondary stroke is the highest in the early period following the first attack,31 emergency EC/IC bypass surgery may have to be considered, especially when the patient’s neurologic symptoms fluctuate or progress. The results of the early revascularization procedure have been inconsistent: some showed poor outcome with a high risk of intracranial hemorrhage,14,66 whereas others described favorable results with acceptable complication rates.67–69 It seems that patients with mild to moderate deficits associated with crescendo TIAs or progressing strokes benefit most from early revascularization, whereas those with severe fixed neurological deficits do not. The number of reported cases, however, is too small and further studies are needed to draw a reliable conclusion. There are a few ongoing large bypass surgery trials based on hemodynamic impairment. The Carotid Occlusion Surgery Study (COSS)70 trial uses PET to identify participants in stage 2 hemodynamic failure among patients with symptomatic carotid occlusion. This study started enrolling patients from January 2002 at 28 centers to test the hypothesis that STA– MCA anastomosis can reduce the occurrence of ipsilateral stroke by 40% over 2 years. The target number of patients is 186 for both surgical and medical groups. The Japanese EC/IC bypass Trial (JET)71,72 study enrolled 206 patients (103 each for the medical and surgical groups) from November 1998 to March 2002 at 28 centers in Japan. They used 123 I-IMP SPECT to select participants from patients with TIAs or minor strokes within 3 months before entry. Randomized patients should have ICA or MCA stenoocclusive lesions. In the JET study, patients were included when there was misery perfusion defined by decreased CBF less than 80% of the normal control value and a concomitant decrease in CVRC of less than 10%. They finished an interim analysis of this trial with 196 patients (98 each in the medical and surgical groups) enrolled until January 31, 2002, and reported that, in 2 years, STA–MCA anastomosis had reduced the ipsilateral stroke rate compared with the medically treated patients (3.1% vs 11.2%, p = 0.045).71 However, we still have to wait for the final report that will also include the re-
sults of cognitive function tests performed pre- and postoperatively.71,72
Revascularization surgery for posterior circulation ischemia Stroke patients with intracranial vertebrobasilar stenosis have a relatively poor prognosis, with an annual rate of stroke recurrence or death of 24.2%.73 Similar results were obtained in the subgroup analysis of the WASID study for intracranial posterior circulation disease, which showed an annual rate of ischemic stroke, brain hemorrhage, and non-stroke vascular death of 25% in the aspirin treatment group and 24% in the warfarin treatment group.31 When the risk of stroke was evaluated using quantitative magnetic resonance angiography, patients having low-flow distal to steno-occlusive lesions demonstrated a higher risk of subsequent stroke than those having normal flow.74 Hemodynamic mechanisms may also play a role in the pathogenesis of cerebellar infarction.75 Thus, these patients at increased risk of stroke through hemodynamic impairment may be potential candidates for revascularization procedures. EC/IC bypass of the posterior circulation can be performed by connecting the superficial temporal artery or occipital artery to the PCA or cerebellar arteries (SCA, AICA, or PICA). Free vein or arterial grafts may also be used. Ausman et al.76 reported their experience with 85 cases of EC/IC bypass surgery in the posterior circulation. All the patients had TIAs presumably related to severe bilateral distal vertebral artery or basilar artery diseases. In their series, 69% had complete resolution of symptoms, but the morbidity (13.3%) and mortality (8.4%) rates were high compared with the anterior circulation disease. Recurrence of vertebrobasilar insufficiency was observed in 11.8%, and clinically stable patients showed a better result than unstable patients. A review of the literature by Hopkins and Budny77 also showed significant complications of EC-IC bypass in the posterior circulation. In their review of 86 cases of STA–PCA or -SCA bypass, the patency rate was 79%, the mortality rate 12%, and the complication rate was as high as 55%, with at least 20% of the patients having serious morbidities. A review of 76 cases of occipital artery-to-PICA bypass demonstrated somewhat better results. The
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overall patency rate was 91%, the mortality rate 3%, and the complication rate was 22% with 10% of serious morbidities. The amount of blood flow through this bypass, however, was less satisfactory than that through the STA–PCA or -SCA bypass surgery. These reports suggest that further studies are needed to elucidate the possible benefit of bypass surgery in patients with intracranial diseases in the posterior circulation. At this time, conservative approaches should be taken before considering intracranial bypass surgery in these patients.77
Decompressive craniectomy for massive MCA infarction Intracranial atherosclerosis usually produces subcortical infarction often associated with small, scattered cortical infarcts.78 Thus, in contrast to embolic infarction, massive infarction involving the whole MCA territory is unusual in patients with intrinsic MCA atherosclerosis. However, in occasional patients with
massive MCA territory infarction associated with inadequately developed collateral circulation, decompressive surgery needs to be considered. Massive infarction following occlusion of the MCA leads to a mortality rate as high as 80%, and the survivors also suffer from serious morbidities.79–81 The elevated intracranial pressure induced by the massive edema reduces cerebral perfusion, further increasing the volume of the infarction, and finally leads to brain death by transtentorial herniation. For these patients, Ivamoto et al.82 proposed surgical decompression therapy in 1974. In 1981, Rengachary et al.83 reported three patients who had been successfully treated by hemicraniectomy. In the 1990s, several studies reported that surgical procedure decreased the mortality in these patients, and sometimes improved the final quality of life, especially in young patients with non-dominant hemispheric infarcts.84–88 To provide appropriate reduction of intracranial pressure, a large hemicraniectomy extending to the temporal base is currently recommended, accompanied by durotomy (Fig. 16.4).
Fig 16.4 Hemicraniectomy for massive infarction by the occlusion of the middle cerebral artery. CT scans were taken before surgery (A), immediately after surgery (B), 3 months after surgery (C), and after cranioplasty (D).
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Table 16.1 Summary of results of randomized prospective clinical trials No. of patients
Inclusion Criteria Trials1
Age (years)
DECIMAL DESTINY
18∼55 18∼60
HAMLET
18–60
Pooled analysis
18–60
NIHSS >15 >18 non-dominant; >20 dominant >15 right side; >20 left side >15
Survival at 1 year
mRS ≤ 3 at 1 year
CT infarct volume
MRI infarct volume
Surg.2
Cons.3
Surg.
Cons. Surg.
Cons.
>1/2 >2/3
145 cm3 –
20 17
18 15
75%* 82%*
22% 47%
50% 47%
22% 27%
>2/3
–
14
9
79%*
11%
29%
11%
>1/2
145 cm3
51
42
78%*
29%
43%*
21%
1 Refer
to the text for trial names. Cons. Conservative treatment group; Surg. Surgery group; mRS, modified Rankin score. * Significantly higher than in the conservative treatment group.
There have been five prospective multicenter randomized trials: 1 Hemicraniectomy and Durotomy upon Deterioration from Infarction Related Swelling Trial (HeADDFIRST; the American trial);89 2 Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY; the German trial);90 3 Early Decompressive Craniectomy in Malignant Middle Cerebral Artery Infarction (DECIMAL; the French trial);91 4 Hemicraniectomy after Middle Cerebral Artery Infarction with Life-threatening Edema Trial (HAMLET; the Dutch trial);92 5 Hemicraniectomy for Malignant Middle Cerebral Artery Infarcts (HeMMI; The Philippines trial).93 Data from three of these trials and a pooled analysis of them are currently available89–91,94 (Table 16.1). The HeADDFIRST preliminary report89 demonstrated decreased early mortality in the surgical group compared with the medical group (45.5% vs 26.7%). The final result has not yet been reported. In the DESTINY trial, patients in the surgical group underwent surgery within 36 hours after symptom onset. This study showed that hemicraniectomy improved survival at 1 year compared with conservative management (82% vs 47%). With 32 patients enrolled, this trial failed to demonstrate that hemicraniectomy had any significant benefits in improving the modified Rankin score (mRS: 0–3 vs 4–6) at 6 and 12 months. The trial was terminated early because of the result of the pooled analysis from the three European
trials.90 In the DECIMAL trial, surgery was performed within 30 hours after symptom onset. Patients with an infarct volume more than 145 cm3 from diffusionweighted MR imaging were enrolled. There was a 52.8% absolute reduction in death following hemicraniectomy compared with medical therapy alone ( p < 0.0001). Study results on 38 patients showed that surgery increased the number of patients showing mild to moderate disability (mRS ≤ 3; 25% vs 5.6% at 6 months), which, however, was not statistically significant. This trial was also terminated early following the report of the pooled analysis.91 Before the termination of DESTINY and DECIMAL, DESTINY, DECIMAL, and HAMLET investigators decided to pool their data prospectively. Ninety-three patients were included in this pooled analysis. The surgery group showed a significantly better survival rate than the conservatively treated group (78% vs 29%; 50% reduction in absolute risk). It was also demonstrated that the patients in the decompressive surgery group showed a better clinical outcome than the patients managed conservatively (75% vs 24% with mRS ≤ 4, and 43% vs 21% with mRS ≤ 3). Thus, it was concluded that decompressive surgery undertaken within 48 hours of stroke onset reduces mortality and increases the number of patients having a favorable functional outcome.94
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in symptomatic vertebrobasilar disease. Stroke 2005; 36: 1140–1145. Chaves CJ, Caplan LR, Chung CS, et al. Cerebellar infarcts in the New England Medical Center Posterior Circulation Stroke Registry. Neurology 1994; 44: 1385– 1390. Ausman JI, Diaz FG, Vacca DF, Sadasivan B. Superficial temporal and occipital artery bypass pedicles to superior, anterior inferior, and posterior inferior cerebellar arteries for vertebrobasilar insufficiency. J Neurosurg 1990; 72: 554–558. Hopkins LN, Budny JL. Complications of intracranial bypass for vertebrobasilar insufficiency. J Neurosurg 1989; 70: 207–211. Lee DK, Kim JS, Kwon SU, Kang DW. Lesion patterns and stroke mechanism in atherosclerotic middle cerebral artery disease: early diffusion-weighted MRI study. Stroke 2005; 36: 2583–2588. Berrouschot J, Sterker M, Bettin S, et al. Mortality of space-occupying (malignant) middle cerebral artery infarction under conservative intensive care. Intensive Care Med 1998; 24: 620–623. Hacke W, Schwab S, Horn M, et al. Malignant middle cerebral artery infarction: clinical course and prognostic signs. Arch Neurol 1996; 53: 309– 915. Wijdicks EFM, 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. Ivamoto HS, Numoto M, Donaghy RMP. Surgical decompression for cerebral and cerebellar infarcts. Stroke 1974; 5: 365–369. Rengachary SS, Batnitzky S, Morantz RA, et al. Hemicraniectomy for acute massive cerebral infarction. Neurosurgery 1981; 8: 321–327. Delashaw JB, Broaddus WC, Kassell NF, et al. Treatment of right hemispheric cerebral infarction by hemicraniectomy. Stroke 1990; 21: 874–881. Rieke K, Schwab S, Krieger D, et al. Decompressive surgery in space-occupying hemispheric infarction: Results of an open, prospective trial. Crit Care Med 1995; 23: 1576–1587. Carter BS, Ogilvy CS, Candia GJ, et al. One year outcome after decompressive surgery for massive nondominant hemispheric infarction. Neurosurgery 1997; 40: 1168– 1175. Sakai K, Iwahashi K, Terada K, et al. Outcome after external decompression for massive cerebral infarction. Neurol Med Chir 1998; 38: 131–135. Mori K, Nakao Y, Yamamoto T, Maeda M. Early external decompressive craniectomy with duroplasty
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improves functional recovery in patients with massive hemispheric embolic infarction: timing and indication of decompressive surgery for malignant cerebral infarction. Surg Neurol 2004; 62: 420–429. 89 Frank JI. Hemicraniectomy and durotomy upon deterioration from infarction related swelling trial (HeADDFIRST): first public presentation of the primary study findings (Abstract). Neurology 2003; 60 (Suppl 1): S52.004. ¨ 90 Juttler E, Schwab S, Schmiedaek E, et al. Decompressive surgery for the treatment of malignant infarction of the middle cerebral artery (DESTINY): a randomized, controlled trial. Stroke 2007; 38: 2518–2525. 91 Vahedi K, Vicaut E, Mateo J et al. Sequential-design, multicenter, randomized, controlled trial of early decompres-
sive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial). Stroke 2007; 38: 2506–2517. 92 Hofmeijer J, Amelink GJ, Algra A, et al. Hemicraniectomy after middle cerebral artery infarction with lifethreatening Edema trial (HAMLET). Protocol for a randomised controlled trial of decompressive surgery in space-occupying hemispheric infarction (Abstract). Trials 2006; 7: 29. 93 Kollmar R, Schwab S. Ischaemic stroke: acute management, intensive care, and future perspectives. Br J Anaesth 2007; 99: 95–101. 94 Vahedi K, Hofmeijer J, Juettler E et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomized controlled trials. Lancet Neurol 2007; 6: 215–222.
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Other miscellaneous treatments Christopher Chen, Jinghao Han and KS Lawrence Wong
Treatments for acute stroke due to intracranial atherosclerosis (ICAS) or to prevent recurrence of vascular events in ICAS can be considered under the broad categories suggested by Virchow’s triad: blood flow, endothelial damage, and hypercoagulability. This triad of factors remains a useful concept for understanding the pathogenesis of arterial thrombosis and for designing treatment strategies in patients with stroke. Anticoagulant therapy,1 antithrombotic therapy,2 antiplatelet therapy,3 and revascularization procedures4 are reviewed elsewhere in this book (see Chapters 13–15). The evidence for the effectiveness and safety of other modes of treatment remains limited and will be reviewed in this chapter
Modulation of the vessel wall Statins A recent meta-analysis of 61 prospective observational studies did not show an association of total cholesterol with stroke mortality.5 However, randomized controlled trials of statins in patients with established coronary artery disease, hypertension, diabetes, or at high vascular risk have shown a 17– 21% reduction in relative risk of incident stroke per 1 mmol/L difference in low-density lipoprotein (LDL) cholesterol.6 Moreover, stroke risk reduction with statins has recently been confirmed for the secondary prevention of stroke or transient ischemic attack.7 This paradox may be explained by the heterogeneity of stroke: cholesterol seems to be closely associated 206
with stroke due to large artery atherosclerosis but not to other causes, such as rheumatic heart disease, small artery occlusion, or hemorrhage. Trials of statins demonstrate an effect on the progression of carotid atherosclerosis, and a metaanalysis showed that reduced LDL cholesterol impeded progression of carotid atherosclerosis.8 It has been shown that statins act directly on the vascular endothelium and have anti-inflammatory and plaquestabilizing effects in addition to their ability to lower LDL cholesterol levels. Considering that progression of atherosclerosis and increased inflammatory status are factors related to development of clinical stroke in patients with ICAS (see Chapter 9), statins may be of benefit in patients with ICAS. A recent, randomized double-blinded placebocontrolled trial of simvastain in 227 patients with asymptomatic middle cerebral artery disease diagnosed using magnetic resonance angiography9 showed a non-significant trend towards greater regression of the stenosis in the simvastatin group (–9%) compared with the placebo group (–2%). There was also a trend towards less progression of mean systolic velocity in the simvastatin group (mean 1.7 cm/second) than the placebo group (mean 9.8 cm/second). Further trials of statins in patients with ICAS are warranted given that this might be a group which derives the most benefit from such therapy. Lowering of homocysteine Potential anti-atherogenic therapeutic strategies include lowering homocysteine using folate therapy. This attempt may be effective in the primary
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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prevention of stroke, as shown by a relative risk reduction of stroke by 18% in a meta-analysis of eight randomized trials of folic acid that had stroke reported as one of the end-points.10 Despite the neutral results from several recent trials, it has been suggested that that higher doses of vitamin B12 and new approaches to lowering total homocysteine besides routine vitamin therapy with folate, vitamin B6, and vitamin B12 could reduce the risk of stroke.11 The results are awaited from large global trials of secondary stroke prevention involving countries where folate supplementation is as yet not mandatory.12
Modulation of inflammation A promising approach by raising high-density lipoprotein (HDL) cholesterol, lowering triglycerides, and reducing C-reactive protein (CRP) through niacin has shown an effect on reducing carotid intimal thickness and improving endothelial function in patients with metabolic syndrome.13 Other avenues for therapy include novel targets such as lipoprotein-associated phospholipase (Lp-PLA2), which is a recently described potentially useful plasma biomarker associated with cardiovascular disease.14 Lp-PLA2 is a cardiovascular-specific inflammatory enzyme implicated in the formation of vulnerable, rupture-prone plaque, and new therapeutic approaches through reducing inflammation should also be targets of well-designed clinical trials. Immunomodulation of the inflammatory response through active or passive immunization against mediators involved in atherosclerosis15 or activation of regulatory T cells may also eventually play a role in the treatment of atherosclerosis.16
Modulation of endothelial dysfunction Another interesting target is adiponectin, low levels of which are associated with endothelial dysfunction, an important factor in the pathogenesis of atherosclerosis. Anti-tumor necrosis factor therapy with infliximab has been shown to significantly increase serum adiponectin levels and improve endotheliumdependent vasodilatation in patients with rheumatoid arthritis.17 Another innovative means of improving endothelial function is stem cell therapy, as recent studies have shown that stem cells present in blood and the
vessel wall may repair endothelial cell loss and restore endothelial function.18
Improvement of cerebral blood flow Strategies to improve cerebral blood flow (CBF) can play an important role in stroke management. Improvement of CBF can be accomplished in two broad ways: directly opening arteries or augmenting cerebral blood flow. Thrombolytic therapy is the only widely accepted treatment for acute ischemic stroke but despite recent efforts to utilize magnetic resonance imaging (MRI) criteria to expand the window beyond 3 hours, its use is confined to a few patients. Although balloon angioplasty with or without stenting4 and mechanical clot retrieval19 are available, these approaches are invasive and their clinical benefit remains to be established by large controlled clinical trials. Under such circumstances, the need for a safe, convenient, and effective way of increasing cerebral perfusion by systematic strategies is apparent. Blood pressure and volume management In some patients with arterial occlusive lesions that produce hemodynamic insufficiency, giving medications such as phenylephrine to raise the blood pressure can lead to improved neurological function.20–23 Improvement in function is especially likely when there is an arterial occlusion, and MRI studies show a diffusion–perfusion mismatch indicating the presence of considerable viable brain tissue. Blood volume also affects perfusion pressure and blood flow. Some patients who are not able to eat normally become easily dehydrated and hemoconcentrated. Other factors (i.e., vomiting, eating restrictions because of concern for aspiration, or simply the rush of diagnostic testing occupying patients at mealtimes) contribute to reduced fluid intake during the early hours and days after stroke onset. Blood volume, especially plasma volume, should be kept high. Fluids must often be given intravenously or by nasogastric tube. Albumin has also been used to augment blood volume and may have some neuroprotective effect that is now being tested in trials. Care, however, must be taken to avoid fluid overload and the complications of cardiac failure and brain edema. Careful monitoring of cardiac and brain function should accompany any 207
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therapeutic attempt to augment blood pressure and blood fluid volume. Diastolic counterpulsation Diastolic counterpulsation is known to improve the perfusion of vital organs. Clinically, diastolic counterpulsation has been achieved invasively with intraaortic balloon pump (IABP) or noninvasively by external counterpulsation (ECP). The effects of IABP are based on the intermittent inflation of a balloon in the descending aorta at the beginning of diastole when the heart is at rest and deflation at the end of diastole just before the heart begins to beat. The hemodynamic effects of IABP are a reduction in cardiac afterload and an increase in diastolic blood flow to various organs. ECP operates by applying ECG-triggered diastolic pressure of approximately 250 mmHg to the calves, thighs, and buttocks by means of air-filled cuffs. The diastolic augmentation of the blood flow and the simultaneously decreasing systolic afterload therefore increases blood flow to the heart, brain, and kidneys. As ECP offers a completely noninvasive way of bringing about similar hemodynamic modification, it has become widely used in clinical settings. Clinical applications of external counterpulsation Most clinical trials of ECP have focused on its application in patients with ischemic heart disease. Benefits associated with ECP include reduction of angina and nitrate use, increased exercise tolerance, prolongation of the time to exercise-induced ST-segment depression, and an accompanying resolution of myocardial perfusion defects.24 Based on the findings of multiple clinical studies, ECP received FDA’s approval as an adjunctive treatment for chronic, stable angina by 1995. A course of ECP treatment usually consists of 35 daily 1-hour sessions over a 7-week period. In most clinical and animal studies, 35 hours of treatment appears to be a standard practice.25 A prospective, randomized study recently investigated the impact of ECP on retinal reperfusion in patients with acute central retinal artery occlusion or branch retinal artery occlusion. A significant increase in perfusion as measured by scanning laser Doppler flowmetry was observed immediately after 2 hours of ECP in the ischemic retinal area, whereas there was no significant change in the control group.26 A case report also showed the clinical benefit of ECP for pa208
tients with restless legs syndrome, a syndrome associated with a decrease in vascular flow to the peripheral or central nervous system.27 ECP treatment is relatively safe. Main side-effects include skin abrasion, low back pain, and muscle ache of the lower extremities. However, under certain circumstances, use of ECP therapy is contraindicated or requires precautions: (1) severe aortic insufficiency, aortic dissection, or aneurysm; (2) atrial fibrillation or frequent ventricular premature beats that might interfere with ECP triggering; (3) blood pressure persistently >180/110 mmHg; (4) severe symptomatic peripheral vascular disease; (5) history of deep vein thrombosis or thrombophlebitis; (6) bleeding diathesis and concurrent warfarin use; and (7) presence of active malignancy. Mechanisms of external counterpulsation Despite the clinical benefits of ECP therapy, mechanisms behind are unclear. Possible mechanisms include an increase in blood flow in multiple vascular beds, such as the brain, kidneys, liver, and heart; and also enhancement of the collateral circulation through prexisting channels or by angiogenesis. Role of external counterpulsation in ischemic stroke There is mounting evidence that ECP may enhance cerebral blood flow. A study reported the mean carotid flow velocity integral increased by 22% during ECP, with an average peak carotid diastolic flow velocity of 56 cm/second, which is 75% as high as the systolic wave.28 Werner et al. recorded a 19% increase in flow volume in the carotid artery and a 12% increase in the vertebral artery during the prodecure.29 As ECP may increase brain perfusion, it is plausible to assume that patients with cerebrovascular disease might benefit from this therapy. Physicians in China began treating stroke patients with ECP in the late 1980s and the clinical outcomes were generally promising. After an extensive search of the MEDLINE (1966–2004) database, no paper published in the English literature was found to evaluate the therapeutic effect of ECP for stroke patients. All articles published in the Chinese literature during the past two decades were systematically identified in the Wan Fang and China Academic Journal databases (two major national databases in China) and reviewed to evaluate the therapeutic effect of ECP in cerebrovascular disease. Twenty-two papers were identified. Table 17.1
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lists the studies discussed in this article, together with the study design and other details. Besides its clinical benefit, two studies have shown an enhancement in brain perfusion after ECP treatment.30,31 In another randomized controlled study, the average CBF increased from 45.7 ± 6.0 mL/100 g/minute to 55.6 ± 6.0 mL/100 g/minute in the ECP group, whereas no significant change was found in the control group. Moreover, 72.5% patients in the ECP group, while only 55% patients in the control group, achieved a favorable clinical outcome.32 These studies also noted a significant decrease in hematocrit, fibrinogen level, and plasma viscosity after 12–35 hours of ECP,33−37 which may be related to an improvement in cerebral blood flow. More importantly, these changes in biomarkers were accompanied with a clinical improvement.34,36,37 Niu et al.38 found a similar reduction in plasma endothelin-1 (ET-1) level after ECP treatment in acute stroke patients, as previously seen in angina patients.24 As ET-1-mediated vasoconstriction may further reduce blood flow in the collateral circulation, a significant decrease of plasma ET-1 may contribute to a better outcome. Although the mechanism is largely unclear, the study has also shown a decrease in plasma markers of oxidative stress in patients with cerebrovascular disease.38 Summarizing, ECP may improve neurological outcome by improving brain perfusion,30−32 lowering blood viscosity,33−37 regulating vasomediators as well as oxidative stress.38 Although the results of these studies were encouraging and no serious adverse events were documented, however, most of them were merely observational studies, case series, or studies without appropriate design. Methodological pitfalls include a relatively small sample size; the lack of control group; the variation of treatment duration; and the use of nonstandard outcome measurements. Instead of using standard outcome measurements, such as the National Institute of Health Stroke Scale (NIHSS) and modified Rankin Score (mRS), most studies used the less widely used Chinese Stroke Scale to assess outcome. These shortcomings greatly weaken the reliability of the evidence for a therapeutic effect of ECP on ischemic stroke. Well-designed clinical studies exploring the therapeutic effects of ECP in ischemic stroke are necessary. Of interest and relevance to ICAS is the promising results from a randomized, crossover, assessment-blinded pilot study that showed that ECP
was safe and feasible for stroke patients with large artery disease39 Fifty patients were randomized to either early (ECP weeks 1–7 and no ECP weeks 8–14) or late group (no ECP weeks 1–7 and ECP weeks 8–14). Primary outcomes were an overall change in NIHSS and CBF estimate by color velocity imaging quantification (CVIQ). Secondary outcomes were change in NIHSS, CVIQ, favorable functional outcome (mRS 0– 2), and stroke recurrence at weeks 7 and 14. At the end of week 7, there was a significant change in NIHSS (early 3.5 versus late 1.9; p = 0.042). After adjusting for treatment sequence, ECP was associated with a favorable trend of change in NIHSS of 2.1 versus 1.3 for non-ECP ( p = 0.061). Changes of CVIQ were not significant but tended to increase with ECP. At week 14, a favorable functional outcome was found in 100% of the early group patients compared with 76% in the late group ( p = 0.022). However, randomized controlled trials with larger sample sizes are needed to define the efficacy and safety of ECP in acute stroke management. It is important to identify which subgroups of patients benefit most from ECP treatment as well as the time window for initiating the therapy after symptom onset. Furthermore, it should be appreciated that in a device-related clinical trial, it is impossible to fully blind the patients and personnel applying the treatment, hence the need for a blinded rater, who assesses the patients independently during the follow-up period, as was done in the tissue plasminogen activator (tPA) trials. Finally, more has to be learned about the mechanisms responsible for any clinical benefit. Sphenopalatine ganglion stimulation Another promising means of augmenting cerebral perfusion is stimulation of the sphenopalatine ganglion (SPG). Parasympathetic nerve fibers from the SPG innervate cerebral arteries and stimulation of these postsynaptic projections near the ethmoidal foramen increases CBF,40 presumably by vasodilation mediated by release of nitric oxide.41 Unilateral SPG stimulation has been shown to bilaterally increase CBF in the normal rat brain.42 In a rat permanent middle cerebral artery occlusion model of stroke, SPG stimulation only marginally improved CBF in the ischemic brain, perhaps because of the collateral supply had been exhausted. Nevertheless, SPG stimulation acutely improved penumbral apparent diffusion coefficient (ADC) values and reduced the final infarct 209
210 Study design Dual arm, randomized-controlled Dual arm Non-randomized Dual arm Non-randomized Dual arm, randomized-controlled Case series
Case series
Dual arm, randomized-controlled Case series Dual arm Self-controlled Dual arm, randomized-controlled Assessment-blinded Case series
Study
Zhao GL et al, 1988
Zheng R et al, 1988
Wu ZY, 1990
Zhao GL et al, 1990
Li L et al, 1994
Chen RY et al, 1994
Cheng ZX et al, 1994
Yao WX et al, 1996
Xu JM et al, 1996
Yang SJ et al, 1996
He GP et al, 1996
Intervention 12 hour ECP
12–36 hour ECP
12–24 hour ECP
12 hour ECP
1 hour ECP
1 hour ECP
12 hour ECP + Dextran 40 vs Dextran 40 24–36 hour ECP 1 hour ECP
12 hour ECP
12–72 hour ECP
Participants ECP (n = 24) Non-ECP (n = 24) Stroke (n = 48) ECP (n = 24) Non-ECP (n = 24) Stroke (n = 48) ECP (n = 75) Non-ECP (n = 70) Stroke (n = 145) ECP (n = 22) Non-ECP (n = 22) Stroke (n = 44) CAD (n = 20) Stroke (n = 8) Atherosclerosis (n = 20) CAD (n = 27) Stroke (n = 18) Atherosclerosis (n = 48) ECP (n = 74) Non-ECP (n = 44) Stroke (n = 118) TIA (n = 10) Atherosclerosis (n = 12) Stroke (n = 20) Controls (n = 10) ECP (n = 40) Non-ECP (n = 40) Stroke (n = 80) Stroke (n = 184)
95.1% has favorable clinical outcome*
Favorable clinical outcome*(72.5% vs 55%, p < 0.01); γ-CBF increased by 17.8% in ECP group
t-PA ↑ in both groups D-dimer ↑ in stroke patients No change in PAI in both groups
72.2% had γ-CBF increase
Favorable clinical outcome* (64.1% vs 25%, p < 0.01)
Plasma viscosity ↓ ( p < 0.05)
Plasma viscosity ↓ ( p < 0.05)
Favorable clinical outcome* (94.1% vs 64.7%, p < 0.05); 95.4% had γ-CBF increase in the ECP group
Favorable clinical outcome * (78.7% vs 55.7%, p < 0.01)
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Favorable clinical outcome * (95.8% vs 75%, p < 0.05)
Favorable clinical outcome * (100% vs 75%, p < 0.01)
Outcome measurement
Table 17.1 Chinese studies on the effects of ECP in patients with ischaemic stroke ‘Han JH, Wong KS. Is Counterpulsation a Potential Therapy for Ischemic Strock? Cerebrovasc Dis. 2008; 26: 97–105. (Reproduced with permission from Journal of Cerebrovascular Disease.)
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Dual arm randomized-controlled Dual arm Randomized-controlled Case series Case series Case series
Dual arm randomized-controlled Dual arm Randomized-controlled Assessment-blinded Dual arm Non-randomized, Self-controlled Dual arm Non-randomized Dual arm Randomized-controlled
Meng ZW et al, 2000
Niu JZ et al, 2000
He MZ et al, 2000
Ma XL et al, 2000
Liu XD et al, 2001
Zhang RH et al, 2001
Wu RL et al, 2001
Yao DR et al, 2003
Liu MX et al, 2003
Zhang JL et al, 2003
24 hour ECP+ Dextran 40vs Dextran 40 12 hour ECP + Dextran 40 vs Dextran 40 12–36 hour ECP 10–50 hour ECP defibrase 10 u i.v.for 3 days, followed by 12 hour ECP 12 hour ECP + Dextran 40 vs Dextran 40 72 hour ECP
24 hour ECP +Dextran 40 vs Dextran 40 35 hour ECP
24 hour ECP +Dextran 40 vs Dextran 40
ECP (n = 70) Non-ECP (n = 68) Stroke (n = 138) ECP (n = 20) Non-ECP (n = 22) Stroke (n = 42) Stroke (n = 20) Stroke (n = 241) Stroke (n = 30)
ECP (n = 24) Non-ECP (n = 24) Stroke (n = 48) ECP (n = 30) Non-ECP (n = 30) Atherosclerosis (n = 60) ECP (n = 118) Non-ECP (n = 68) Stroke (n = 186) ECP (n = 60) Non-ECP (n = 63) Stroke (n = 123) ECP (n = 70) Non-ECP (n = 68) Stroke (n = 138)
Favorable clinical outcome * (92.9% vs 73.5%, p < 0.05); Plasma viscosity HCT↓ FIB in ECP group
Favorable clinical outcome (BI) in the ECP group vs control ( p < 0.01)
Favorable clinical outcome * ( 96.0% vs 83.8%, p < 0.05) Plasma viscosity in ECP group
γ−CBF increased by 17.2% in ECP group; no change noted in control group
Favorable clinical outcome* (95.8% vs 75%, p < 0.05)
93.3% has favorable clinical outcome *
97.1% has favorable clinical outcome*
60% has favorable clinical outcome *
SOD↓MDA↓ET-1↓in ECP group
Favorable clinical outcome* (92.9% vs 73.5%, p < 0.05)
Favorable clinical outcome* (95% vs 75%, p < 0.05); Plasma viscosity ↓ in both groups, HCT ↓ FIB ↓ in ECP group
by Chinese Stroke Scale (4th version) Hct, hematocrit; SOD, superoxide dismutase; MDA, malondialdehyde; ET-1, endothelin-1; FIB, fibrinogen; BI, Barthel index.
24–36 hour ECP
ECP (n = 40) Non-ECP (n = 40) Stroke (n = 80)
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∗ Assessed
Dual arm Non-randomized
Du LJ et al, 2000
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size.42 These results may be relevant to clinical stroke due to ICAS and might provide an alternative therapeutic strategy for those ineligible for thrombolysis. Indeed, there are ongoing clinical trials of SPG stimulation in acute stroke and the results are awaited.
Conclusion Statins and other miscellaneous therapies so far reviewed are potentially useful treatment options in patients with ICAS. However, more studies are definitely required to prove their clinical efficacy. In future trials, it is essential to ensure adequate trial designs with appropriate inclusion criteria, sensitive and clinically relevant outcome measures, and global enrollment. Further understanding of the pathophysiology of ICAS will also allow us to develop new therapies and to select the right therapeutic target in a given patient. Although most drugs are developed for targets after the disease has manifested, attention must also be paid to prevent atherosclerosis or to modify the course of the disease.
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6 Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–1278. 7 Amarenco P, Bogousslavsky J, Callahan A, III, et al. Highdose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–559. 8 Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004; 35: 2902–2909. 9 Wong KS, Ng PW, Tsoi TH, Lam W, Rocas Study Group. Statin therapy for patients with asymptomatic middle cerebral artery stenosis: a randomized, double-blind, placebo-controlled study. Neurology 2002; (Suppl 3): A259–A260. 10 Wang X, Qin X, Demirtas H, Li J, et al. Efficacy of folic acid supplementation in stroke prevention: a metaanalysis. Lancet 2007; 369: 1876–1882. 11 Spence JD. Homocysteine-lowering therapy: a role in stroke prevention? Lancet Neurol 2007; 6: 830–838. 12 Ho GY, Eikelboom JW, Hankey GJ, et al. Methylenetetrahydrofolate reductase polymorphisms and homocysteine-lowering effect of vitamin therapy in Singaporean stroke patients. Stroke 2006; 37: 456–460. 13 Thoenes M, Oguchi A, Nagamia S, et al. The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome. Int J Clin Pract 2007; 61: 1942–1948. 14 Carlquist JF, Muhlestein JB, Anderson JL. Lipoproteinassociated phospholipase A2: a new biomarker for cardiovascular risk assessment and potential therapeutic target. Expert Rev Mol Diagn 2007; 7: 511–517. 15 Chyu KY, Nilsson J, Shah PK. Active and passive immunization for atherosclerosis. Curr Opin Mol Ther 2007; 9: 176–182. 16 Kuiper J, van Puijvelde GH, van Wanrooij EJ, et al. Immunomodulation of the inflammatory response in atherosclerosis. Curr Opin Lipidol 2007; 18: 521–526. 17 Komai N, Morita Y, Sakuta T, et al. Anti-tumor necrosis factor therapy increases serum adiponectin levels with the improvement of endothelial dysfunction in patients with rheumatoid arthritis. Mod Rheumatol 2007; 17: 385– 390. 18 Adams B, Xiao Q, Xu Q. Stem cell therapy for vascular disease. Trends Cardiovasc Med 2007; 17: 246–251. 19 Smith WS, Sung G, Starkman S, et al. Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke 2005; 36: 1432–1438. 20 Rordorf G, Cramer SC, Efird JT, et al. Pharmacological elevation of blood pressure in acute stroke. Clinical effects and safety. Stroke 1997; 28: 2133–2138.
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21 Hillis AE, Ulatowski JA, Barker PB, et al. A pilot randomized trial of induced blood pressure elevation: effects on function and focal perfusion in acute and subacute stroke. Cerebrovasc Dis 2003; 16 (3): 236–246. 22 Chalela JA, Dunn B, Todd JW, Warach S. Induced hypertension improves cerebral blood flow in acute ischemic stroke. Neurology 2005; 64: 1979. 23 Hillis AE, Kane A, Tuffiash E, et al. Reperfusion of specific brain regions by raising blood pressure restores selective language functions in subacute stroke. Brain Lang 2001; 79: 495–510. 24 Bonetti PO, Holmes DR, Jr, Lerman A, Barsness GW. Enhanced external counterpulsation for ischemic heart disease: what’s behind the curtain? J Am Coll Cardiol 2003; 41: 1918–1925. 25 Arora RR, Chou TM, Jain D, et al. The multicenter study of enhanced external counterpulsation (MUST-EECP): effect of EECP on exercise-induced myocardial ischemia and anginal episodes. J Am Coll Cardiol 1999; 33: 1833– 1840. 26 Werner D, Michalk F, Harazny J, et al. Accelerated reperfusion of poorly perfused retinal areas in central retinal artery occlusion and branch retinal artery occlusion after a short treatment with enhanced external counterpulsation. Retina 2004; 24: 541–547. 27 Rajaram SS, Shanahan J, Ash C, et al. Enhanced external counter pulsation (EECP) as a novel treatment for restless legs syndrome (RLS): a preliminary test of the vascular neurologic hypothesis for RLS. Sleep Med 2005; 6 (2): 101–106. 28 Applebaum RM, Kasliwal R, Tunick PA, et al. Sequential external counterpulsation increases cerebral and renal blood flow. Am Heart J 1997; 133: 611–615. 29 Werner D, Schneider M, Weise M, et al. Pneumatic external counterpulsation: a new noninvasive method to improve organ perfusion. Am J Cardiol 1999; 84: 950–958. 30 Wu RL, Shi SR, Ge HF, et al. [Effect of external counterpulsation on focal cerebral blood flow]. Nao Yu Shen Jing Ji Bing Za Zhi 2001; 9: 284–286. 31 Yao WX, Chang GJ, Xu ZQ, et al. [Evaluation of brain perfusion by SPECT after external counterpulsation in patients with ischemic stroke]. He Ji Shu 1996; 19: 677– 678.
32 Yang SJ, Gu DX, Li F, et al. [Assessment of cerebral blood ˜ flow by TCD and |A-CBF in patients with ischemic stroke after external counterpulsation]. Xian Dai Yi Xue Yi Qi Yu Ying Yong 1996; 8: 16–18. 33 Chen RY, Xu FL. [Change in blood viscosity after external counterpulsation in patients with cardiovascular and cerebrovascular disease]. Wei Xun Huan Xue Za Zhi 1993; 5: 50–51. 34 Du LJ, Zhang LJ, Hu Y. [Clinical improvement in ischemic stroke patients after external counterpulsation]. Yi Xue Li Lun Yu Shi Jian 2000; 13: 740–741. 35 Li L, Wei XD, Yang HY. [Effect of external counterpulsation on platelet aggregation and blood viscosity]. Wei Xun Huan Za Zhi 1994; 5: 32–33. 36 Yao DR. [External counterpulsation in patients with chronic ischemic stroke]. Si Shuan Yi Xue 2003; 24: 590– 591. 37 Zhang JL, Jiang LW, Li XZ. [Effect of external counterpulsation on cerebral hemodynamics among patients with ischemic stroke]. Xin Xue Guan Kang Fu Yi Xue Za Zhi 2003; 12: 242–243. 38 Niu JZ, Qu HX, Zhu WB. [Changes in plasma ET, MDA and SOD level in patients with acute ischemic stroke after external counterpulsation]. Shan Dong Yi Yao 2000; 40: 11–12. 39 Han JH, Leung TW, Lam WW, et al. Preliminary Findings of External Counterpulsation for Ischemic Stroke Patient with Large Artery Occlusive Disease. Stroke 2008; 1340– 1343. 40 Suzuki N, Hardebo JE, Kahrstrom J, Owman C. Selective electrical stimulation of postganglionic cerebrovascular parasympathetic nerve fibers originating from the sphenopalatine ganglion enhances cortical blood flow in the rat. J Cereb Blood Flow Metab 1990; 10: 383– 391. 41 Toda N, Tanaka T, Ayajiki K, Okamura T. Cerebral vasodilatation induced by stimulation of the pterygopalatine ganglion and greater petrosal nerve in anesthetized monkeys. Neuroscience 2000; 96: 393–398. 42 Henninger N, Fisher M. Stimulating circle of Willis nerve fibers preserves the diffusion-perfusion mismatch in experimental stroke. Stroke 2007; 38: 2779– 2786.
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PART FIVE
Uncommon causes of intracranial arterial disease
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Immunologic and vasoconstrictive disorders Min Lou and Louis R. Caplan
There are numerous etiologies of intracranial vascular disease other than atherosclerosis. This chapter describes various causes related to immunologic and/or vasoconstrictive disorders.
Isolated central nervous system angiitis Isolated angiitis of the central nervous system (CNS) was defined in 1959 as an idiopathic vasculitis restricted to small leptomeningeal and parenchymal arteries and veins, without apparent systemic involvement.1 It is now regarded as an immunological, non-specific T cell-mediated inflammatory reaction rather than a specific entity.2 It is a rare condition with an estimated incidence of less than 1:2 000 000.3 Symptoms may develop acutely within a few weeks, or evolve over a period of months to years. Any age can be affected (mean age, approximately 49 years) and there is a male predominance (approximately 2 to 1).4 Diffuse or multifocal encephalopathy associated with cognitive and behavioral changes, high CSF protein, and, occasionally, seizures are the main clinical presentation. Owing to the protean, yet nonspecific clinical manifestations, it is often difficult to make, a diagnosis. Nevertheless, establishing the correct diagnosis is important because treatment with prednisone and immunosuppressant agents may allow full recovery, whereas it is nearly always fatal when untreated.5–7 The major differential diagnostic consideration is reversible cerebral vasoconstriction, a condition that is many times more common than isolated angiitis.
Stroke in patients with isolated central nervous system angiitis Isolated CNS angiitis is a rare cause of stroke, even in young patients.8 Although angiitis can produce brain infarction, the lesions are usually small and do not present as clinical strokes. All types of strokes have been observed in isolated CNS angiitis, including cerebral infarcts, transient ischemic attacks (TIAs), intracerebral hemorrhage (ICH), or subarachnoid hemorrhage (SAH). A multi-infarct state has also been reported.9–11 Intracranial bleedings might be more prevalent than ischemic strokes, but the incidence of specific stroke subtypes has not been systematically studied. The intracranial bleedings may result from vessel wall weakening due to transmural inflammation.12,13 Stroke presents as the initial manifestation of isolated CNS angiitis in only a minority of patients. Rarely, SAH can be the initial presentation.14,15
Intracranial arterial disease in isolated central nervous system angiitis Intracranial vessels of any size are involved in isolated CNS angiitis; however, there is a predilection for small arteries and arterioles.16,17 Angiography may show sausage-like multiple segmental intracranial arterial narrowing. This finding is not specific for isolated CNS angiitis since similar lesions can be observed in patients with a history of drug abuse or those having reversible vasoconstriction syndromes. Moreover, conventional angiography has a rather low sensitivity
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in showing arterial abnormalities; it is normal in up to 50% of the cases, or shows abnormalities only after repeated tests.18 In autopsy series, isolated CNS angiitis typically, but not invariably, involves small arterioles and venules less than 300 μm in diameter,19 which is below the resolution of conventional digital subtraction angiography.20,21 Definitive diagnosis depends on brain/leptomeningeal biopsy findings, which include a segmental, necrotizing granulomatous vasculitis affecting mostly the leptomeningeal, cortical, and spinal vessels.22 The intima and adventitia of arteries are infiltrated with lymphocytes, giant cells, and granulomas, with preservation of the media. Granulomas can extend into the adjacent brain parenchyma. In some patients, granulomatous changes are shown predominantly in the veins. Including leptomeninges in the biopsy material is crucial since leptomeningeal involvement is a prominent pathological feature.23,24 Biopsy of the nondominant hemisphere, especially the tip of the temporal lobe is recommended, and tissues that contain longitudinally oriented surface vessels should be chosen.
Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic inflammatory connective tissue disorder characterized by multisystem autoimmunity. It was initially described as a skin disorder, with recognition of the systemic, multi-organ involvement by Kaposi in 1872. The clinical picture of SLE can be complex, with an array of different possible presentations. The American College of Rheumatology (ACR) has established diagnostic criteria, which includes documentation of four of 11 potential abnormalities.25
Stroke in patients with systemic lupus erythematosus Multiple cerebral infarcts were described in the autopsy findings of SLE patients with Libman–Sacks endocarditis in 1947, and SLE presenting with stroke was reported in 1963.26 Widespread recognition of stroke as a complication of SLE began in the early 1980s.27–30 Strokes are reported to be present in 2.6– 20% of SLE patients.30–36 and tests for SLE have been 218
included in the evaluation of stroke in the young patients. However, series selected from hospital admission data might overestimate the frequency of stroke, as the subjects may represent those with severe symptoms. The long-term risk of stroke in patients with SLE has not yet been determined but the rate of recurrent stroke is better documented; over 50% of SLE patients who have had a stroke may have recurrent infarcts if preventative treatment is not instituted.37,38 Brain imaging of SLE patients shows a wide spectrum of stroke lesions in various locations, including cortical and/or white matter, the basal ganglia, and the brain stem. MRI often demonstrates discrete focal lesions in SLE patients, even in the absence of a clinical history of stroke,39 which are consistent with autopsy findings showing microinfarcts and microhemorrhages in the brain.40 Asymptomatic microinfarcts are more often recognized nowadays because of the high sensitivity of MRI.41 Occlusions of large arteries resulting in major strokes also occur in lupus patients.42 Intracranial arterial disease in systemic lupus erythematosus Angiography in patients with SLE who have antiphospholipid antibodies may show intracranial arterial abnormalities including mainstem or branch occlusions of pial or basal arteries.43 Luminal narrowing caused by concentric intimal hyperplasia and fibrous occlusions have also been noted in small leptomeningeal arteries.44,45 In lupus patients, cortical and cortical–subcortical infarcts are most often caused by abnormalities of coagulation and cardiac-origin embolism. In one study reporting angiographic findings in patients with antiphospholipid antibodies, about 50% of patients who underwent cerebral angiography had intracranial lesions, and about half of these had branch occlusions, suggesting an embolic origin.46 On echocardiography, as many as 75% of SLE patients have cardiac abnormalities, 37.5% with valvular lesions.47 Abnormalities of the mitral valve and infective endocarditis are frequently encountered.48 Libman–Sacks endocarditis is also common, which is a verrucous endocarditis with deposition of hyalinized blood and platelet thrombus not covered by endothelium. All these cardiac lesions can produce emboli, which appear to be the most common cause of stroke in SLE patients.49
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SLE patients often have a hypercoagulable state characterized by the presence of lupus anticoagulants and anticardiolipin antibodies.50 Both endogenous anticoagulants may contribute to the thrombogenic tendency, along with low functional levels of antithrombin III.51 Immune complex-induced endothelial dysfunction and fibrinolytic defects have also been reported in patients with SLE, with decreased endogenous t-PA activity and inhibition of plasminogen activation.52,53 Atherosclerosis in lupus patients is more frequent than can be explained by the presence of conventional vascular risk factors.54 Steroids, which are frequently administered to lupus patients, are associated with the development of an atherogenic lipid profile.55 Low-density lipoprotein (LDL)-containing immune complexes and the combination of increased triglycerides with anticardiolipin antibodies in these patients also have increased atherogenic potential.56 Hypertension from renal involvement or corticosteroid therapy, and corticosteroid-induced central obesity and hyperglycemia probably all promote atherosclerosis. Premature or accelerated atherosclerosis is an important cause of death in SLE patients.57,58 Cerebral vasculitis has been reported as the etiology of stroke in a series of patients on the basis of indirect evidence, such as concomitant vasculitis in the skin or kidney, and an angiographic diagnosis of vasculitis, which has low specificity. However, most of them did not have neuropathological confirmation. There are a few case reports in the literature of what appears to be a true vasculitis,58 but the most common pathology is a vasculopathy, with perivascular inflammatory infiltrates, perivascular hemorrhages, and proliferation of blood vessels, including vascular occlusion with multiple channels of recanalization.59,61 Vasculitis is often diagnosed in SLE patients showing widespread multifocal hyperintensity in the white matter on T2weighted magnetic resonance imaging (MRI). However, biopsy in such patients has usually demonstrated multifocal ischemic lesions with an unusually large amount of white matter edema rather than vasculitis. A necropsy study found scant evidence of inflammation of brain arteries in these patients.62 Cytokine abnormalities in patients with SLE could contribute to unusually severe white matter damage.63,64 In patients who have inflammatory changes within brain tissue and intracranial vessels, concomitant infection rather than primary inflammatory vasculitis
may have to be considered, such as basilar meningitis from aspergillus.63 In some reports, the mechanism of vasculopathy in CNS involvement of SLE is attributed to intravascular activation of complement that leads to adhesion between neutrophils, platelets, and endothelium, resulting in leukothrombosis in the microvasculature (Shwartzman phenomenon).65,66 Therefore, without biopsy proof, the diagnosis of cerebral vasculitis should be made very cautiously.
Polyarteritis nodosa Polyarteritis nodosa (PAN) is a focal, segmental, necrotizing vasculitis of small and medium-sized arteries, characterized by skin, muscle, kidney, gastrointestinal tract, and peripheral nervous system involvement.67 Kussmaul and Maier68 first described the disease condition in 1866. They used the term “periarteritis nodosa”, which has evolved over time into the more pathologically correct term “polyarteritis nodosa”. The disease affects every organ except the lung and spleen. Approximately 30% of patients have hepatitis B surface antigenemia.69,70 PAN affects middle-aged patients (average age 40–60 years) with the annual incidence of approximately 6.3 per 100 000 habitants.69 Stroke in patients with polyarteritis nodosa Neurological symptoms and signs are a major feature of PAN, the most common one being mononeuritis multiplex. Peripheral nervous system involvement is usually a part of the initial presentation or appears within a few months of the initial diagnosis. On the other hand, symptoms related to CNS involvement typically occur 2–3 years after the onset of the disease. Stroke occurs in 11–14 % of PAN patients, usually as a delayed complication.71 Spinal cord ischemia was also reported.72 On rare occasions, stroke may present as an initial manifestation of PAN.73 In the series by Ford and Siekert,74 stroke was found in 19% of PAN patients. Ischemic, ischemic and hemorrhagic, or hemorrhagic strokes each occurred in almost a third of these patients. Multiple, deep, small ischemic or petechial hemorrhagic infarcts involving the basal ganglia, internal capsule, or the thalamus were common. Clinical evidence for brainstem stroke was found in half of the patients. A study of 53 patients with PAN found that 219
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cerebrovascular disease was the cause of death in five cases, with a mean latency of 2 years after the onset of vasculitis.75 Intracranial arterial disease in polyarteritis nodosa In PAN patients, small branches of the major cerebral arteries are most commonly affected.76 Infiltration of polymorphonuclear leukocytes and monocytes is followed by intimal proliferation, fibrinoid necrosis, and thrombosis of arteries. In some cases, marked loss of the muscular coatings of small intracranial arteries is observed, with replacement by collagenous tissue, resulting in severe luminal narrowing.77 Reports of the cerebral angiographic findings in PAN have shown either alternating segments of narrowing and widening of small and medium-sized intracranial arteries or occlusion of small arteries.78–80 Occasionally, arteries as large as the middle cerebral artery (MCA) or anterior cerebral artery (ACA) are involved.81 Intracranial arterial dissection has been reported in a patient with PAN, but it is unclear whether this was causally related to the underlying arteriopathy.82 Multiple, small, penetrating artery occlusions are found at the subcortical or pontine level in PAN. Small, deep infarcts are the most frequent (73%) stroke pattern associated with PAN. In the study of Reichhart et al.83 more than half of the patients (55%) developed lacunar syndrome such as pure motor or sensorimotor strokes, or ataxic hemiparesis, which correlated with small infarcts occurring in the internal capsule, striatum, centrum semiovale, and corona radiata. Pontine lacunes (27%) and leukoaraiosis (18%) were also observed. This preponderance of lacunar stroke may be partially explained by associated hypertension, seen in 40% to more than half of patients.84 However, the short time interval between disease onset and subsequent cerebrovascular complications suggests that hypertension may not have played a major role in the development of strokes in these patients. The effect of corticosteroids may be one of the potential mechanisms of intracranial arterial disease in PAN. A study described five strokes that developed while patients received corticosteroid therapy.85 In another study, patients were described who had developed lacunar strokes 8 hours to 3 weeks after the beginning of corticosteroid therapy.83 The strokes occurring soon after corticosteroid initiation may be explained by a corticosteroid-induced net increase in 220
platelet thromboxane A2 (TXA2) production. In one study, medium-sized cerebral arteries in PAN patients were found to contain deposits of platelet fragments by immunochemistry analysis.86 Finally, a hypercoagulable state may be another cause of intracranial arterial occlusion in PAN patients. Multiple and recurrent strokes associated with antiphospholipid antibodies have been reported in patients with PAN.87,88 Livedo reticularis was also observed in patients with PAN and stroke,84 but the events were only weakly correlated with positive anticardiolipin antibodies. A direct immunological mechanism of anticardiolipin antibodies against the brain parenchyma,89 or the role of anti-endothelial cell antibodies, present in 28% of patients with active PAN without stroke and in 35 % of patients with Sneddon syndrome,90 has yet to be evaluated.
Takayasu’s arteritis Takayasu’s arteritis is an idiopathic granulomatous vasculitis that affects the aortic arch and main branches.91 Although certain genetic predisposition, chronic inflammation, and immunologic process have been considered,92 the etiology still remains elusive. Most patients present between the ages of 11 and 30 years with systemic symptoms such as fever, malaise, weight loss, night sweats, and arthralgia. These symptoms wax and wane, and symptoms and signs of vascular involvement follow, including diminished or absent pulse and blood pressure, cardiac murmurs, bruits, claudication of extremities, angina, hypertension, and congestive heart failure. Pathologically, lymphoplasmacytic inflammation affects primarily the tuna media causing destruction of the elastic lamina. As the disease process continues, fibrous thickening and loss of compliance of the vessel walls develop, and narrowing and occlusion of the vessel due to superimposed thrombosis may ensue. Approximately 10–15% of patients with Takayasu’s arteritis present with ischemic stroke or TIAs.93,94 Hemodynamic insufficiency and embolism from the stenosed extracranial arteries, aorta, or diseased heart are the main mechanisms of stroke in these patients. In addition, severe hypertension associated with renal artery involvement may produce either accelerated atherosclerosis or hypertensive intracerebral hemorrhages.
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Takayasu’s arteritis is essentially an extracranial arterial disease. However, there is at least one case report that has described autopsy findings of intracranial arteritis in a patient with Takayasu’s arteritis.95 More recently, Klos et al.96 described two patients who showed angiographic evidence of extensive intracranial arterial involvement, including the intracranial ICA, distal basilar artery (BA), and distal branches of the MCA, ACA, and posterior cerebral arteries (PCA). Thus, Takayasu’s arteritis may be considered one of the rare causes of intracranial arterial diseases.
Recreational drug use Drug abuse is a major social and medical problem and has become a significant cause of stroke, especially in young adults. One epidemiological case–control study reported an estimated relative risk of stroke of 6.5 in recreational drug users.97 In another study of 422 cases of ischemic stroke in subjects aged 15–44 years, 4.7% had drug abuse as the probable cause of stroke.98 Intracranial hemorrhage caused by drugs is most often the result of cocaine and amphetamine use,99 whereas ischemic strokes are usually related to cocaine and heroin use.100 Infection, such as hepatitis, AIDS, endocarditis, and fungal infections are common complications in patients with drug addiction, and could contribute to ischemic stroke.101,102 Drugs injected intravenously are often adulterated with other substances that induce an immunological response. Antiphospholipid antibodies and other immunological abnormalities are often found in these patients, which could promote the development of vascular inflammation and hypercoagulability. Cocaine Cocaine can be snorted or injected as cocaine hydrochloride, or may be smoked as “crack cocaine,” a free-base alkaloidal form of cocaine.103,104 Cocaine use has become the most common cause of drugrelated strokes. Both infarction and hemorrhage (SAH and ICH) are associated with the use of cocaine. The strokes usually begin shortly after cocaine exposure, irrespective of the portal of entry (snorted, inhaled, or injected). The use of crack cocaine is associated with a particularly high frequency of brain infarcts.105 Patients may present with TIAs or cerebral infarcts. Infarcts are sometimes multiple and carry a
high risk of hemorrhagic transformation when the subject is hypertensive.106 Infarction may occur in neonates whose mothers used cocaine shortly before delivery. Cocaine-related hemorrhages are related to a higher incidence of aneurysms and vascular malformations than hemorrhages associated with amphetamine use.107 Cocaine also increases the likelihood of vasospasm after aneurysm rupture.108 ICH after cocaine use is also associated with a sudden increase in arterial blood pressure. The exact mechanisms of cocaine-related brain ischemia remain uncertain. Vasoconstriction or spasm by inhibition of re-uptake of norepinephrine at sympathetic nerve endings, increased platelet aggregation, and apparent vasculitis are posited as potential mechanisms. Arterial constrictions, predominantly MCAs and PCAs (focal and diffuse) were found on magnetic resonance angiography (MRA) studies taken 20 minutes after intravenous cocaine administration in healthy subjects who had used cocaine previously.109 Myocarditis, myocardial infarction, and arrhythmia found in patients with cocaine abuse may produce cardioembolic strokes.110 Amphetamine and related agents Amphetamine was introduced into clinical medicine in the 1930s and has been used to treat behavioral disorders in children, narcolepsy, depression, and obesity. Routes of amphetamine administration are intravenous, oral, or inhalation. Methamphetamine, a substance chemically related to amphetamine, is more potent, longer lasting, and more harmful to the central nervous system. Street methamphetamine is referred to by many names, such as “speed,” “meth,” and “chalk.” Methamphetamine hydrochloride, clear chunky crystals resembling ice that can be inhaled by smoking, is referred to as “ice,” “crystal,” “glass,” or “tina.”111 The most common stroke subtype after amphetamine use is ICH, usually beginning shortly after amphetamine exposure. Severe headache develops within minutes of drug use, when the blood pressure is elevated in most patients. Computerized tomography (CT) shows either ICH or SAH. These patients have a relatively lower frequency of harboring aneurysms and vascular malformations than those with brain hemorrhages associated with cocaine use.99,107 221
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Ischemic stroke has also been described following amphetamine abuse. In experimental animals and humans who take amphetamines orally or intravenously, angiography shows segmental changes in intracerebral vessels with prominent beading. Necrotizing angiitis has been demonstrated pathologically.112,113 Thus, the lesions resemble arteriopathy shown in patients with polyarteritis nodosa. In rhesus monkeys, intravenous methamphetamine produces microhemorrhages, thrombosis, infarction, poor vascular filling, and fragmentation of small arterioles and capillary beds.114 Epidemiological studies have shown that methamphetamine use is a risk factor for hemorrhagic or ischemic stroke.115 However, in patients who take multiple drugs, immunological abnormalities are common and it is sometimes difficult to assess whether the vascular symptoms are attributed to amphetamine use. Although amphetamine-induced cerebral vasculitis may be the cause of ischemic stroke,116 the segmental vascular changes in some of the patients may be due to reversible vasoconstriction, since amphetamine is a potent vasoconstrictor. Ischemic and hemorrhagic stroke were also described in users of the decongestant and appetite suppressant phenylpropanolamine (PPA). These reports have raised concerns in using PPA as an ingredient of cough and cold drugs, which was permitted in many countries. A case–control study found that appetite suppressants containing PPA significantly increased the risk of hemorrhagic stroke in women.117,118 There seems to be a dose–response relationship between the duration of PPA exposure and hemorrhagic stroke.118 Heroin Both ischemic and hemorrhagic strokes may develop following intravenous heroin use, but infarction is much more common than hemorrhage.100 Stroke frequently follows the reintroduction of intravenous heroin after a period of abstention.119,120 Focal neurologic deficits may directly follow the injection of heroin but are more often delayed by 6–24 hours. Brain embolism from cardiac lesions also occurs in heroin addicts. Brain imaging usually shows unilateral infarctions in the territories of the MCA or PCA.100,121 Some reports have emphasized the role of heroin in causing borderzone infarction.122,123 Angiographic findings in 222
some of these patients appear to be consistent with either large vessel or small vessel arteritis, but pathological confirmation has been made rarely.124 There is no consensus about the etiology of stroke in heroin addicts. Infectious endocarditis is a major risk among parenteral users, and embolism is the presumed cause of stroke in these patients. Hypersensitivity reactions of the cerebral vessels to heroin were observed in patients who were re-exposed to the drug after a period of abstinence;125 heroin addition is associated with a variety of serologic and systemic abnormalities, including eosinophilia, elevated immune globulins and gamma globulins, Coombs-positive hemolysis, and lymph-node hypertrophy, which may be associated with vascular complications. Illicitly available heroin is often adulterated with a host of fillers and foreign substances. Thus, immune complex deposition or other hyperimmune mechanisms may underlie stroke in patients who are exposed chronically to various antigens.126 Finally, hemorrhagic strokes may be caused by rupture of either a septic “mycotic” aneurysm or non-aneurysmal infectious vasculitis.
Vasoconstriction Vasoconstriction of intracranial arteries has been associated with diverse conditions, including pregnancy, vasoconstrictive drug use, and headaches.127–130 In 1988, Call et al.131 described four patients who presented with acute headache, with or without focal neurologic deficits and seizures, and called this syndrome “reversible cerebral arterial segmental vasoconstriction”. Thereafter, the term “Call’s syndrome” or “Call–Fleming syndrome” has been used.132–135 Noticing the similarity of clinical, laboratory, and angiographic features, Calabrese et al.136 proposed the term “reversible cerebral vasoconstriction syndromes (RCVS).” This was defined as a group of disorders characterized by prolonged but reversible vasoconstriction of the cerebral arteries, usually associated with acute-onset, severe, recurrent headaches, with or without additional neurologic signs and symptoms. Symptoms often start with a severe, suddenonset “thunderclap headache.” The syndrome most often affects young women, especially during the puerperium, but can occur at any age. Some patients have been reported to develop this syndrome after carotid endarterectomy.137
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Stroke in patients with vasoconstriction Ischemia in brain regions perfused by an artery that is severely constricted can develop neurologic symptoms and signs, and prolonged vasoconstriction can lead to infarction. Some patients have shown infarct progression within the hypoperfused regions, indicating that ischemic stroke results from severe cerebral hypoperfusion.138 Intracranial hemorrhage, including cortical SAH, can also occur and explain neurologic dysfunction. Hemorrhage is most likely related to ischemia–reperfusion injury and leakage or rupture of cortical surface vessels in the setting of abrupt hypertension and impaired autoregulation. In a recent prospective series of 67 patients, hemorrhages were found to be early complications, occurring within the first week, whereas ischemic events, including TIAs and cerebral infarction occurred later, mainly during the second week.139 Small areas of infarction, hemorrhage, or brain edema can be found on brain CT and MRI in patients with vasoconstriction, the most frequent finding being bi-hemispheric infarcts in the parieto-occipital lobes and “borderzone” arterial territories. Ischemic lesions are often crescentic or horseshoe-shaped; however, with severe ischemia the cortex becomes affected and lesions appear wedge shaped. Fluid-attenuated inversion recovery (FLAIR) imaging often shows dotshaped or linear hyperintensities along the cortical surfaces, which may reflect slow flow within dilated vessels. Perfusion imaging may show areas of hypoperfusion distal to the affected artery. Some patients develop brain hemorrhage, including parenchymal hemorrhages and small “non-aneurysmal” SAH overlying the cortical surface.140–143 Cortical SAH, a frequent complication of RCVS (22%), consisted of small localized bleeding at the surface of the brain.139 However, up to one-third of patients with RCVS show no abnormality on brain imaging despite multifocal cerebral arterial narrowing on angiograms.142 Vasoconstriction involves many large, mediumsized, and small cerebral arteries. It was suggested that the vasoconstriction starts distally and progresses towards medium-sized and larger arteries.139 The most frequently involved intracranial vessel are mediumsized cerebral arteries, including the middle and anterior cerebral arteries and the intracranial vertebral, basilar, posterior cerebral, superior cerebellar, anterior inferior cerebellar, and posterior inferior cerebellar
arteries. Angiography typically shows diffuse, multifocal, segmental vascular narrowing, with focal regions of vasodilatation, like “sausage string” or “string and bead.”144 Repeated angiography after a few weeks or months usually demonstrates the normalization of cerebral arteries. Transcranial Doppler (TCD) shows high flow velocities in many intracranial arteries, and can be used as a useful diagnostic tool in assessing the reversal of vasoconstriction.145 A transient abnormality in the control of cerebral vascular tone appears to be the main cause of RCVS. Many patients who develop RCVS have a history of migraine. The relationship between migraine and reversible cerebral vasoconstriction may imply that there is a genetic susceptibility of intracranial vessels in migraineurs to develop vascular constriction after an appropriate vasoactive stimulus. Chemical factors, such as circulating catecholamines, serotonin, endothelin1, calcium, nitric oxide, and prostaglandins, may be involved in the pathophysiology of vascular constriction associated with sympathomimetic or serotonergic drugs, hypercalcemia, intravenous immunoglobulin, carotid endarterectomy, neurosurgical trauma, uncontrolled hypertension, and tumors.141–149 The frequent occurrence in women soon after menarche, and during the puerperium and menopause suggests a hormonal effect. Vasospasm after SAH should be differentiated from RCVS, because initial misdiagnosis and subsequent rebleeding of SAH may yield catastrophic results. SAH is most commonly due to rupture of an intracranial aneurysm, accounting for 85% of cases. Both SAH and RCVS present with thunderclap headaches and vascular narrowing in the intracranial arteries. However, the flow velocity is usually higher in patients with vasospasm after SAH than in patients with RCVS.150 This might partially explain the lower incidence of ischemic stroke in RCVS than in SAH patients. Another difference is that cerebral hypoperfusion caused by increased intracranial pressure is common in SAH patients, which might lead to hemodynamic aberration, but this is not the case in most of RCVS patients.151 The angiographic appearance and the temporal course of the vasospasm after SAH may also be different from RCVS. The vasospasm secondary to aneurismal rupture usually correlates with the location and amount of bleeding and is not multifocal, and most often occurs between 7 and 14 days after the onset of SAH.152 223
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It is also important to distinguish stroke caused by RCVS from other disorders with similar clinical features, such as fibromuscular dysplasia, inflammatory vasculitis, and primary angiitis of the CNS, because consideration of these conditions may expose patients to the risks of brain biopsy or to the adverse effects of long-term immunosuppressive therapy. Stroke from RCVS often carries a better prognosis, with spontaneous clinical improvement and resolution of angiographic abnormalities after a few weeks. Complete or near-complete reversibility of vasoconstriction, invariably within 3 months, is the most definitive evidence for the diagnosis. Once RCVS is considered as the cause of stroke, identifying the precipitating secondary cofactor is important, such as stopping the use of vasoactive drugs. Calcium channel blockers (verapamil, nimodipine, and nicardipine) and corticosteroids have been thought to be effective in reversing vasoconstriction in anecdotal observational reports.
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˜ Gil J. Case report. An88 de la Fuente Fernandez R, Grana ticardiolipin antibodies and polyarteritis nodosa. Lupus 1994; 3: 523–524. 89 Frances C, Le Tonqueze BS, Salohzin KV, et al. Prevalence of anto-endothelial cell antibodies in patients with Sneddon’s syndrome. J Am Acad Dermatol 1995; 33: 64–68. 90 Arend WP, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Takayasu’s arteritis. Arthritis Rheum 1990; 33: 1129–1134. 91 Shinohara Y. Takayasu disease. In: Bogousslavsky J, Caplan L (eds) Uncommon causes of stroke. Cambridge, UK: Cambridge University Press, 2001, 37–42. 92 Takano K, Sadoshima S, Ibayashi S, et al. Altered cerebral hemodynamics and metabolism in Takayasu’s arteritis with neurological deficits. Stroke 1993; 24: 1501– 1506. 93 Kerr GS, Hallahan CW, Girando J, et al. Takayasu’s arteritis. Ann Intern Med 1994; 120: 919–929. 94 Molnar P, Hegedus K. Direct involvement of intracerebral arteries in Takayasu’s arteritis. Acta Neuropathol 1984; 63: 83–86. 95 Klos K, Flemming KD, Petty GW, Luthra HS. Takayasu’s arteritis with arteriographic evidence of intracranial vessel involvement. Neurology 2003; 60: 1550– 1551. 96 Kaku DA, Lowenstein DH. Emergence of recreational drug abuse as a major risk factor for stroke in young adults. Ann Intern Med 1990; 113: 821–827. 97 Sloan MA, Kittner SJ, Rigamonti D, Price TR. Occurrence of stroke associated with use/abuse of drugs. Neurology 1991; 41: 1358–1364. 98 Caplan LR. Drugs. In: CS Kase, LR Caplan (eds) Intracerebral hemorrhage. Boston, MA: ButterworthHeinemann, 1994; pp. 201–220. 99 Brust JC, Richter RW. Stroke associated with addiction to heroin. J Neurol Neurosurg Psychiatry 1976; 39: 194–199. 100 Walsh TJ, Hier DB, Caplan LR. Fungal infection of the central nervous system: comparative analysis of the risk factors and clinical signs in 57 patients. Neurology 1985; 35: 1654–1657. 101 Walsh TJ, Hier DB, Caplan LR. Aspergillosis of the central nervous system: clinicopathological analysis of 17 patients. Ann Neurol 1985; 18: 574–582. 102 Daras M, Tuchman AJ, Marks S. Central nervous system infarction related to cocaine abuse. Stroke 1991; 22: 1320–1325. 103 Levine SR, Washington JM, Jefferson MF, et al. “Crack” cocaine-associated stroke. Neurology 1987; 37: 1849– 1853. 104 Levine SR, Brust JC, Futrell N, et al. A comparative study of the cerebrovascular complications of cocaine-
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alkaloidal versus hydrochloride. Neurology 1991; 41: 1173–1177. Green RM, Kelly KM, Gabrielsen T, Levine SR, Vanderzant C. Multiple cerebral hemorrhages after smoking “crack” cocaine. Stroke 1990; 21: 957–962. Nolte KB, Brass LM, Fletterick CF. Intracranial hemorrhage associated with cocaine abuse: a prospective study. Neurology 1996; 46: 1291–1296. Conway JE, Tamargo RJ. Cocaine use is an independent risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 2001; 32: 2338– 2343. Kaufman MJ, Levin JM, Ross MH, et al. Cocaineinduced cerebral vasoconstriction detected in humans with magnetic resonance angiography. JAMA 1998; 279: 376–380. Isner JM, Estes NA 3rd, Thompson PD, et al. Acute cardiac events temporally related to cocaine. N Engl J Med 1986; 315: 1438–1443. Schifano F, Corkery JM, Cuffolo G. Smokable (“ice”, “crystal meth”) and non smokable amphetamine-type stimulants: clinical pharmacological and epidemiological issues, with special reference to the UK. Ann Ist Super Sanita. 2007; 43: 110–115. Rumbaugh CL, Bergeron RT, Scanlan RL, et al. Cerebral vascular changes secondary to amphetamine abuse in the experimental animal. Radiology 1971; 101: 345–51. Rumbaugh CL, Bergeron RT, Fang HC, McCormick R. Cerebral angiographic changes in the drug abuse patient. Radiology 1971; 101: 335–344. Rumbaugh CL, Fang HC, Higgins RE, et al. Cerebral microvascular injury in experimental drug abuse. Invest Radiol 1976; 11: 282–294. Petitti DB, Sidney S, Queensberry C, Bernstein A. Stroke and cocaine or amphetamine use. Epidemiology 1998; 9: 596–600. Citron BP, Halpern M, McCarron M, et al. Necrotizing angiitis associated with drug abuse. N Engl J Med 1970; 283: 1003–1011. Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000; 343: 1826–1832. Yoon BW, Bae HJ, Hong KS, et al. Phenylpropanolamine contained in cold remedies and risk of hemorrhagic stroke. Neurology 2007; 68: 146–19. Woods B, Strewler G. Hemiparesis occurring six hours after intravenous heroin injection. Neurology 1972; 22: 863–866. Caplan LR, Hier DB, Banks G. Current concepts in cerebrovascular disease-stroke: stroke and drug abuse. Stroke 1982; 13: 869–872. King J, Richards M, Tress B. Cerebral arteritis associated with heroin abuse. Med J Aust 1978; 2: 444– 445.
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121 Jensen R, Olsen TS, Winther BB. Severe non-occlusive ischemic stroke in young heroin addicts. Acta Neurol Scand 1990; 81: 354–357. 122 Niehaus L, Meyer BU. Bilateral borderzone brain infarctions in association with heroin abuse. J Neurol Sci 1998; 160: 180–182. 123 Brust JC. Clinical, radiological, and pathological aspects of cerebrovascular disease associated with drug abuse, Stroke 1993; 24: 129–133. 124 Kelly MA, Gorelick PB, Mirza D. The role of drugs in the etiology of stroke. Clin Neuropharmacol 1992; 15: 249–275. 125 Caplan LR, Hier DB, Banks G. Current concepts of cerebrovascular disease -stroke: stroke and drug abuse, Stroke 1982; 13: 869–872. 126 Fisher CM. Late-life migraine accompaniments–further experience. Stroke 1986; 17: 1033–1042. 127 Mourand I, Ducrocq X, Lacour JC, et al. Acute reversible cerebral arteritis associated with parenteral ephedrine use. Cerebrovasc Dis 1999; 9: 355–357. 128 Raroque HG, Jr., Tesfa G, Purdy P. Postpartum cerebral angiopathy. Is there a role for sympathomimetic drugs? Stroke 1993; 24: 2108–2110. 129 Zunker P, Golombeck K, Brossmann J, et al. Postpartum cerebral angiopathy: repetitive TCD, MRI, MRA, and EEG examinations. Neurol Res 2002; 24: 570–572. 130 Call GK, Fleming MC, Sealfon S, et al. Reversible cerebral segmental vasoconstriction. Stroke 1988; 19: 1159– 1170. 131 Martin-Araguz A, Fernandez-Armayor V, MorenoMartinez JM, et al. [Segmental arteriographic anomalies in migranous cerebral infarct]. Rev Neurol 1997; 25: 225–229. 132 Modi M, Modi G. Case reports: postpartum cerebral angiopathy in a patient with chronic migraine with aura. Headache 2000; 40: 677–681. 133 Noskin O, Jafarimojarrad E, Libman RB, Nelson JL. Diffuse cerebral vasoconstriction (Call-Fleming syndrome) and stroke associated with antidepressants. Neurology 2006; 67: 159–160. 134 Nowak DA, Rodiek SO, Henneken S, et al. Reversible segmental cerebral vasoconstriction (Call-Fleming syndrome): are calcium channel inhibitors a potential treatment option? Cephalalgia 2003; 23: 218–222. 135 Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med 2007; 146: 34–44. 136 Lopez-Valdes E, Chang H-M, Pessin MS, Caplan LR. Cerebral vasoconstriction after carotid surgery. Neurology 1997; 49: 303–304. 137 Rosenbloom MH, Singhal AB. CT angiography and diffusion-perfusion MR Imaging in a patient with
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ipsilateral reversible cerebral vasoconstriction after carotid endarterectomy. AJNR Am J Neuroradiol 2007; 28: 920–922. Ducros A, Boukobza M, Porcher R, et al. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome: A prospective series of 67 patients. 2007; 130: 3091–3101. Doss-Esper CE, Singhal AB, Smith MS, Henderson GV. Reversible posterior leukoencephalopathy, cerebral vasoconstriction, and strokes after intravenous immune globulin therapy in guillain-barre syndrome. J Neuroimaging 2005; 15: 188–192. Singhal AB. Cerebral vasoconstriction syndromes. Top Stroke Rehabil 2004; 11: 1–6. Singhal AB, Topcuoglu MA, Caviness VS, Koroshetz WJ. Call-Fleming syndrome versus isolated cerebral vasculitis: MRI Lesion Patterns. Stroke 2003; 34: 264. Ursell MR, Marras CL, Farb R, et al. Recurrent intracranial hemorrhage due to postpartum cerebral angiopathy: implications for management. Stroke 1998; 29: 1995–1998. Singhal AB, Bernstein RA. Postpartum angiopathy and other cerebral vasoconstriction syndromes. Neurocrit Care 2005; 3: 91–97. Bogousslavsky J, Despland PA, Regli F, Dubuis PY. Postpartum cerebral angiopathy: reversible vasoconstriction assessed by transcranial Doppler ultrasounds. Eur Neurol 1989; 29: 102–105. Singhal AB, Caviness VS, Begleiter AF, Mark EJ, Rordorf G, Koroshetz WJ. Cerebral vasoconstriction and stroke after use of serotonergic drugs. Neurology 2002; 58: 130–133. Nighoghossian N, Trouillas P, Loire R, et al. Catecholamine syndrome, carcinoid lung tumor and stroke. Eur Neurol 1994; 34: 288–289. Yarnell PR, Caplan LR. Basilar artery narrowing and hyperparathyroidism: illustrative case. Stroke 1986; 17: 1022–1024. Dagher HN, Shum MK, Campellone JV. Delayed intracranial vasospasm following carotid endarterectomy. Cerebrovasc Dis 2005; 20: 205–206. Aaslid R, Huber P, Nornes H. A transcranial Doppler method in the evaluation of cerebrovascular spasm. Neuroradiology 1986; 28: 11–16. Chen SP, Fuh JL, Lirng JF, et al. Recurrent primary thunderclap headache and benign CNS angiopathy: spectra of the same disorder? Neurology 2006; 67: 2164– 2169. Weidauer S, Lanfermann H, Raabe A, et al. Impairment of cerebral perfusion and infarct patterns attributable to vasospasm after aneurysmal subarachnoid hemorrhage: a prospective MRI and DSA study. Stroke 2007; 38: 1831–1836.
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Arterial dissection, CNS infection and other miscellaneous diseases Jiann-Shing Jeng and Jong S Kim
Arterial dissection is one of the most important nonatherosclerotic intracranial arterial diseases. Although less common, central nervous system (CNS) infection should also be considered a cause of intracranial arterial disease, especially in endemic areas. These conditions and other miscellaneous disorders are described in this chapter. Moyamoya disease, another important cause of non-atherosclerotic intracranial arterial disease, will be described separately in Chapter 20.
Intracranial arterial dissection Epidemiology of cervicocerebral artery dissections Cervicocerebral artery dissections account for 1–2% of all ischemic strokes1–3 ; however, they are one of the major causes of stroke in young and middle-aged patients.4 In these patients, arterial dissections account for 10–25% of ischemic strokes.5,6 According to population-based studies, the incidence of spontaneous arterial dissection was 1.7–3.0/100 000 in the carotid arteries and 1.0–1.5/100 000 in the vertebral arteries (VAs).1,7,8 However, the prevalence of cervicocerebral artery dissections is likely to be underestimated since patients may present with non-specific symptoms, or do not show clear evidence of dissections on imaging studies. The prevalence is higher in men than in women,9,10 and the women are younger and more often have migraine and multiple dissections.9 Intimal fibroelastic abnormalities related to sex hormones,11 the different incidence of hypertension, and different neck muscle strength and dynamic stabilization during head acceleration12 may explain the gender difference.9
Comparison with extracranial dissections It has been shown that intracranial dissection is less frequent than extracranial dissection. In a retrospective analysis of 263 patients with spontaneous cervicocerebral artery dissections at the Mayo Clinic between 1970 and 1991, 33 (12.5%) had intracranial dissections.3 Another study showed that among 67 patients with cervicocerebral artery dissections, nine (13.4%) had intracranial dissections.13 In a study including a series of 169 patients with 195 VA dissections, 21 dissections (11%) occurred intracranially.9 However, the frequency of intracranial dissections might have been underestimated because diagnosis of intracranial dissection is more difficult than diagnosis of the extracranial counterpart. It is also likely that many intracranial dissections are not correctly recognized as dissections. It seems that patients with intracranial dissections are generally younger than those with extracranial dissections, usually presenting symptoms in their second to fourth decades. In a review of 54 patients with middle cerebral artery (MCA) dissections, the mean age was 22.5 years.14 In a study of 103 patients with intracranial dissections, the average age was 44.8 years in patients with non-subarachnoid hemorrhage (SAH), and 50.9 years for those having SAH. The percentage of men was 68% for non-SAH patients and 50% for SAH patients.10 In another study of 49 patients with dissecting aneurysms of the intracranial carotid circulation, the mean age was 45 years in patients with ischemic stroke and 54 years in patients with SAH: the percentage of men was 47% in the former group, and 31% in the latter group.15 These data
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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suggest that ischemic symptoms are associated with a young age and male sex. In addition, patients with intracranial dissections in the carotid artery territory appear to be younger than those having vertebrobasilar artery territory dissection.10,16 Anterior circulation was more frequently involved among children with intracranial dissections.17 SAH is more common in patients with intracranial dissections than in those with extracranial dissections. Pathology Cervicocerebral artery dissections can result from either a primary intimal tear with secondary dissection into the media layer or a primary intramedial hemorrhage. An intimal tear will let circulating blood enter the wall of the arteries and form an intramural hematoma (false lumen). The intramural hematoma is located within the medial layer or near the intimal or adventitial layer. A subintimal dissection leads to luminal stenosis and obstruction, resulting in an ischemic event. A subadventitial dissection may cause aneurysmal formation (dissecting aneurysm) and SAH when it ruptures. A primary intramedial hemorrhage without communication between the true and false lumens may be identified pathologically, which may also disrupt the arterial wall.4,18 In contrast to the extracranial cervical arteries, the intracranial arteries lack external elastic lamina and have only a thin adventitial layer. Therefore, intracranial dissections more readily lead to the development of subadventitial dissections or dissecting aneurysm formation, and subsequent SAH.19,20 SAH was reported in 20% of intracranial carotid artery dissections16 and in more than half of intracranial VA dissections.21 Pathological studies have shown that subadventitial dissections are more frequent in the VA than in the MCA.22,23 This could explain the relatively high frequency of SAH in intracranial VA dissections compared with dissections occurring in the intracranial internal carotid artery (ICA) or MCA. Etiology Dissection can be etiologically categorized as traumatic and spontaneous (non-traumatic). In patients with spontaneous dissections, however, minor trauma may still play a causative role. Inherent conditions predisposing to spontaneous arterial dissections include 230
fibromuscular dysplasia, cystic medial necrosis, α1 antitrypsin deficiency, Ehlers–Danlos syndrome type IV, Marfan syndrome, autosomal dominant polycystic kidney disease, tuberous sclerosis, migraine, recent infection, and hyperhomocysteinemia.3,24 Fibromuscular dysplasia has been reported in 15–20% of patients with cervicocerebral dissections and in half of those with bilateral carotid artery dissections.25 In one study, ultrastructural morphological aberrations of dermal connective tissue were found in more than half of patients with spontaneous cervical artery dissections.26 However, a search for genes known to carry the mutations responsible for connective tissue disorders, such as Ehlers–Danlos syndrome, failed to find an evident correlation with cervicocerebral dissections.27 A recent line of evidence illustrates that trauma, even a minor one, is an important cause of extracranial dissections, but its role is less clear in intracranial dissections.3,20 In a review of MCA dissections, preceding trauma was found in 26% of cases.14 The exact mechanism of a blunt head injury causing MCA dissection is not clear. Some authors have suggested that the impact of the MCA against the sphenoid ridge causes an intimal tear, which results in dissection.28
Clinical manifestations Dissection in anterior circulation In the anterior circulation, dissections most often occur in the supraclinoid ICA or the proximal MCA. Dissection occurring in the extracranial ICA dissections may extend intracranially. In a review of 54 cases with 59 events of MCA dissections, most cases presented with cerebral infarction (91%), whereas SAH was uncommon (9%).14 Most patients showed vascular luminal stenosis (87%) (Fig. 19.1), and a small number of patients showed aneurysmal dilatation (11%) or double lumen (2%). Hemiparesis was the most frequent presenting symptom (92%), followed by headache (61%) and a change in consciousness (44%). Fluctuation of neurological symptoms during the acute phase is more often found in isolated MCA dissections than in intracranial ICA dissections with extension to the MCA (17% vs 3%). Preceding trauma was more often found in isolated MCA dissections than intracranial ICA–MCA dissections (35% vs 19%). In contrast, congenital vessel wall defects were found more often
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Fig 19.1 A left carotid angiogram shows a tapering stenosis from the distal left internal carotid artery to the proximal middle cerebral artery (arrow) in a 45-year-old female patient with left striatocapsular infarct.
in intracranial ICA–MCA dissections than in isolated MCA dissections (26% vs 4%).14 Dissection may account for the majority of fusiform aneurysms arising from the MCA. In a review of 102 cases of spontaneous fusiform MCA aneurysms, the mean age was 38 years, and the male–female ratio was 1.4:1.0.22 Most MCA aneurysms originated proximal to the MCA genu (M1 segment, 69%) and presented with ischemic symptoms or were found incidentally (80%). Day et al.22 explained how the MCA dissections eventually evolve to develop fusiform aneurysms, as illustrated in Fig. 19.2. Dissections involving the anterior cerebral artery (ACA) or intrapetrous ICA are rare occurrences. In a study of 18 patients with non-traumatic ACA dissections, five had SAH, nine had ischemia, and four patients had both.29 The lesion sites of ACA dissections were mainly at the A2 portion for patients with ischemia and at the A1 portion for those having SAH. For intrapetrous ICA dissection, ischemic stroke was noted in three of eight patients.30 Dissection in posterior circulation Intracranial arterial dissections in the posterior circulation present either as SAH or ischemia and most frequently involve the VA near the origin of the posterior inferior cerebellar artery (PICA), often extending into the basilar artery (BA) (Fig. 19.3). In a study on 31 cases with intracranial vertebrobasilar artery dissections, 55% had headache, 48%
had infarction involving the brainstem or cerebellum, and 10% presented with SAH.31 Caplan32 summarized the clinical manifestations of intracranial VA dissections as four overlapping syndromes: (1) brainstem infarcts due to subintimal dissection extending to the BA, often affecting younger patients; (2) SAH due to subadventitial or transmural dissections; (3) aneurysms leading to a mass effect on brainstem and cranial nerves; and (4) chronic dissections due to connective tissue defects, usually involving bilateral VA, producing repeated transient ischemic attacks (TIAs) or minor strokes. BA dissections present with more variable clinical presentations and carry a worse prognosis than VA dissections. In a review of 38 cases with BA dissections, brainstem ischemia occurred in 27, SAH in five, and both in six patients. Thirty patients (79%) died.33 In another study on 10 patients with BA dissections, five presented with impaired consciousness: four due to SAH and one due to mass effect on the brainstem, and the remaining five patients had brainstem ischemia.34 Dissections occurring in the posterior cerebral artery (PCA) are rare.35 In a review of 40 patients with PCA dissections, 15 had ischemia, 15 had SAH, and six had an aneurysmal mass effect. Precipitating factors were found in nearly half of the cases, including trauma, migraine, substance abuse, and the postpartum status.36 Isolated dissections of the PICA without involvement of the VA are rare and present with either SAH or ischemic symptoms37,38 (Fig. 19.4). One report suggested that dissections occurring in the proximal PICA tend to produce ischemic symptoms, whereas those in the distal portion tend to cause SAH.39 Dissection occurring in the superior cerebellar artery seems to produce SAH more often than infarction.40 However, dissections occurring in the PICA or superior cerebellar artery presenting with ischemic symptoms may have been underdiagnosed, since cerebral angiography is often omitted in these patients.
Treatment and outcome The choice of medical treatment of intracranial dissections is not well established. Anticoagulants are not routinely used because of the potential risk of SAH. The Cervical Artery Dissection in Ischemic Stroke 231
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A
B
Fig 19.3 A vertebral angiogram shows a fusiform aneurysmal dilatation of the distal right vertebral arteries (VA) (A) and irregular narrowing of the distal VA with extension to the basilar artery (B).
Patients (CADISO) Study Group advised to use (1) antiplatelet agents if the National Institutes of Health Stroke Scale score is ≥15 or if there are accompanying intracranial dissections, local compression syndromes without ischemic events, or concomitant diseases with increased risk of bleeding; and (2) anticoagulants if the patients have (pseudo)occlusion of the dissected artery, high-intensity transient signals in transcranial ultrasound studies despite (dual) antiplatelet agents, multiple ischemic events occurring in the same vascular territory, or evidence of free-floating thrombus.41
The recanalization rate of initially occluded or stenosed arteries due to intracranial dissections ranges from 50% to 72%, which appears to be lower than that reported in extracranial dissections (62– 90%).10,42 Thus, prolonged antithrombotic therapy seems to be necessary in this condition. Recently, a non-randomized study showed that anticoagulant therapy was safe in patients with intracranial dissections without inducing SAH.10 At 3 months, 64 of 81 non-SAH patients (79%) had a good outcome (modified Rankin scale ≤2), and only one patient died of cerebral infarction. However, there has been no
←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Fig 19.2 Drawings showing the origins and stages of evolution of middle cerebral artery (MCA) dissections. Arrows indicate the direction of blood flow. (A) Arterial dissection, due to congenital or acquired causes, with intramural hemorrhage between the intima and media, producing a demonstrable focal narrowing of the peripheral MCA branch. (B) Extension of bleeding (arrows) into the subarachnoid space, common but rarely clinically significant, especially when arising from the M1 segment. (C) Rupture into the true lumen, with a potential for distal
embolization. (D) Further expansion of the intramural clot leading to vessel occlusion. (E) Recanalization or expansion of lumen, creating focal fusiform dilation of the MCA segment affected. (F) Progressive enlargement of dissection both laterally and longitudinally. (G) Serpentine channel forms as the disease extends longitudinally and incorporates vessel curves, combined with varying degrees of intraluminal thrombosis (by Day et al., 2003, with permission).
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Fig 19.4 A 48-year-old woman without vascular risk factor suddenly developed neck pain, headache, dizziness and gait ataxia. Diffusion weighted MRI shows a cerebellar infarction in the right posterior inferior artery territory. Angiogram shows fusiform aneurismal dilations of the right posterior inferior cerebellar artery caused by dissection (arrow).
randomized trial that compares anticoagulants vs antiplatelet agents vs conservative management. Surgical or endovascular treatment is considered for patients with symptomatic dissecting aneurysms, especially those with hemorrhagic manifestations or with recurrent ischemic symptoms despite adequate antithrombotic therapy. Surgical treatment includes direct clip ligation, trapping, or wrapping of the parent artery, with or without a combined bypass procedure.4 Selection of the treatment modality depends on the characteristics and locations of the dissecting aneurysms and the skill of surgeons. Endovascular treatment is usually achieved by occluding the parent artery at or near the dissection site. Balloons or coils are usually used. Recently, stenting has been used for endoaneurysmal coiling to preserve the parent artery.43 In one study of surgical and endovascular treatment in 49 cases of symptomatic posterior circulation fusiform aneurysms, a favorable outcome (Glasgow outcome scale 4 or 5) was achieved in 59%, with a more favorable outcome shown in PCA aneurysms than in aneurysms at other sites.44 The prognosis of intracranial dissections is poorer than that of extracranial dissections. Bassetti et al.16 reviewed 59 cases of intracranial dissections in the literature, and reported that the case fatality rate was 72%, and permanent neurological sequelae were noted in half of the survivors. In another report studying the outcome of MCA dissections, the mortality was 54%, and 13% remained dependent.14 Fullerton 234
et al.17 reviewed 118 young patients with cervicocerebral dissections and showed that 60% of anterior cerebral circulation dissections and 21% of posterior circulation dissections were intracranial. One-quarter of the patients with cervicocerebral dissections died, and one-third of the survivors had neurological deficits. Recently, however, with the advent of non-invasive neuroimaging techniques, more cases of mild intracranial dissections are being detected. In a recent study by Metso et al.,10 79% of non-SAH patients had a favorable outcome. Intracranial VA dissections presenting with SAH have poorer outcomes.45 In a study of 24 patients with intracranial VA dissections with SAH who were treated conservatively, 16 (67%) died and 14 (58%) had rebleeding episodes.46 During the mean followup period of 4.8 years, 48% of 52 patients with vertebrobasilar non-saccular intracranial aneurysms showed enlargement of aneurysms, with an increase in diameter of 1.3 mm per year.47 The mortality was significantly higher (5.7 times) in patients with growing aneurysms than in those with stable ones.
Infectious diseases of central nervous system Bacterial infection Autopsy,48,49 clinical,48,50,51 and angiographic studies,52–54 have revealed the involvement of cerebral
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vessels in bacterial meningitis. The vascular events typically occur within the first 2 weeks of disease and are most commonly seen with Streptococcus pneumonia infections in adults and Haemophilus influenza infections in children. Vascular involvement is attributed to endothelial or smooth muscle damage by direct invasion of organisms or generation of cytokines and immune complexes in the course of extensive inflammation. Hypercoagulation, vasospasm, thrombus formation, and hemodynamic insufficiency play additional roles in the development of cerebral ischemia. The vascular event is usually a sentinel event; however, it may be a persistent one producing recurrent ischemic events,55,56 suggesting a role of the ongoing immunologic process in this condition. Vascular involvement after bacterial meningitis is one of the most feared complications. According to Pfister et al.,51,57 various complications developed in 43 out of 86 adult patients with bacterial meningitis. The major complications involving the CNS included cerebrovascular involvement in 13 patients (15%), brain swelling in 12 patients (14%), and hydrocephalus in 10 patients (12%). The cerebrovascular complications constituted 37% of all the CNS-related complications. Cerebral angiography performed in 27 patients showed abnormalities in 13 patients, which included narrowing and irregularities of the intracranial large arteries, narrowing, obstruction or ecstatic changes of distal MCAs, focal abnormal parenchymal blush, suggesting small vessel involvement, and thrombosis of the superior sagittal sinus or cortical veins. The prognosis in the patients with cerebrovascular complications was unfavorable; six patients died, one entered a vegetative state, four remained disabled, and only two recovered completely. In patients with bacterial meningitis, the involvement of intracranial arteries may be used as a prognostic indicator. Ries et al.58 prospectively investigated the changes of intracranial cerebral blood flow velocities in 22 patients with bacterial meningitis by means of transcranial Doppler (TCD). Elevated blood flow velocity in the MCA was documented in 18 patients. Seven patients with markedly increased systolic peak velocities (>210 cm/second) had low Glasgow Coma Scales on admission, focal cerebral ischemic deficits, and seizures. Serial examinations performed in 11 patients showed that in most cases elevated blood flow
velocity reached its peak between day 3 and day 6 after the onset of symptoms. Thus, bacterial meningitis is one of the causes of intracranial vascular diseases, and the presence of this complication influences the patient’s prognosis adversely. The vascular involvement assessed by TCD could potentially be used to identify high-risk patients who may benefit from adjuvant therapeutic interventions.59 Although treatment with steroids is often used in patients with meningitis complicated by cerebrovascular disease, whether this improves or prevents ischemic symptoms remains unclear. Tuberculosis It has been shown that 6–47% of patients with tuberculous meningitis develop cerebral infarction.60–62 The agent may involve small, medium, or large arteries or veins, characterized pathologically by mononuclear infiltrates, caseating necrosis, and fibrinoid changes. Vasculitis involving vessels in the base of the brain is one of the most characteristic histopathologic features of tuberculous meningitis. Vascular involvement can be silent or manifest either as sudden focal neurologic deficits or diffuse symptoms such as obtunded mentality, delirium, or cognitive dysfunction. In a study of 25 young patients with tuberculous meningitis with cerebral infarction, a majority (23 patients) had an anterior circulation involvement. The territories involved were lenticulostriate in 16, MCA in three, and multiple in three patients. A majority (23 patients) had concomitant hydrocephalus. The outcomes were poor, and none recovered completely.61 Other studies have also revealed preferential involvement of the anterior circulation territory over posterior circulation in patients with tuberculous meningitis.60,61 In a study from Hong Kong,63 5 out of 12 patients (42%) with cerebral infarction associated with tuberculosis had large artery territory infarction only, whereas the remaining seven (58%) patients had lacunar infarction with or without coexisting large artery territory infarction. Thus, it seems that intracranial artery involvement is frequent in tuberculous meningitis often associated with subcortical infarcts with or without territorial ischemia.64 Once patients have vascular involvement, the outcome is poor and full recovery is rare.61,63 235
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Viral infection Herpes zoster Herpes zoster infection is caused by varicella zoster virus, a DNA virus of the herpes family. The skin vesicles characteristically appear at the peripheral nerve or root dermatome. The virus often affects cerebral vessels. Pathologically, necrotizing granulomatous angiitis of small and medium-sized cerebral arteries are characteristic.65–67 Viral particles are detected in the outer walls or within the media of affected vessels.68,69 The most plausible mechanism for vascular involvement is intraneuronal migration of the virus from the trigeminal ganglion to the cerebral arteries;70 the distribution of vascular lesions (MCA, ACA, and BA) matches the density of trigeminal innervation at the circle of Willis.71,72 Neurologic symptoms such as hemiparesis typically develop 1 week to months (usually 2–6 weeks) after involvement of the skin. The symptoms are usually focal but diffuse symptoms such as stupor, somnolence, and confusion are accompanied in approximately half the patients.71 The infarcts are either subcortical or cortical, and angiographic studies show irregular, beaded, or segmental narrowing or occlusion of the ipsilateral MCA, intracranial ICA, or ACA.73 The PCA or BA can be involved, albeit uncommonly, and deep-seated infarcts in the thalamus, brainstem, and spinal cord may be shown.74 In immunocompromised patients, the infarcts are often bilateral.75,76 CSF studies reveal abnormal findings in 70% of patients.70 The prognosis is poor in patients with a vascular complication, with mortality ranging from 20% to 28%.67,71 Varicella virus-related stroke occurring in children may have been underestimated because of delayed onset of neurological symptoms from the initial infection and the failure to obtain a history of varicella.72 Lanthier et al.77 studied 23 children who developed ischemic stroke or TIAs 4 to 47 weeks after varicella infection. Angiography showed vascular stenosis in 19 children. Subsequent regression of stenosis occurred in 17 children, and further regression was shown in 11 of them during the follow up of as long as 48 months. However, another study showed that 6 out of 24 children developed recurrent TIAs during the median follow-up period of 27 months.78 Arterial stenosis improved in 11 children, although it progressed in seven patients. The progression of stenosis was closely associated with recurrent symptoms. Thus, although post236
varicella cerebral arteriopathy in children usually follows a monophasic course with gradual regression, the vascular lesion may progress in certain patients, which may be related to the continuing immunologic process. Human immunodeficiency virus Vascular complications are common in patients affected with human immuondeficiency virus (HIV). However, autopsy findings of cerebrovascular disease were generally not correlated with clinical stroke before death.79 After a review of the literature, Pinto et al.80 reported that only 1.3% of HIV-infected patients had a clinically overt stroke syndrome. Unlike zoster virus infection, the cause of vascular involvement in HIV infection is complex, especially in adult patients. Cerebral infarcts are generally caused by non-bacterial thrombotic endocarditis or concomitant opportunistic CNS infection, whereas intracerebral hemorrhages are usually associated with thrombocytopenia, primary CNS lymphoma, and metastatic Kaposi’s sarcoma.79 In a recent review of 82 patients with stroke (77 with ischemic stroke and five with intracerebral hemorrhage), the mechanism of ischemic stroke was large artery atherosclerosis in 12%, cardiac embolism in 18%, small vessel occlusion in 18%, other determined etiology in 23%, and undetermined in 29%. Vasculitis was considered responsible for the stroke in 10 patients (13%). Protein S deficiency was noted in 45% and anticardiolipin antibodies were present in 29% of the patients tested.80 Thus, the mechanisms of stroke in HIV-infected patients are diverse, and it seems that only a minority have intracranial vasculitis, usually in association with a concomitant opportunistic infection such as syphilis, varicella zoster, tuberculosis, or cryptococcal meningitis.80 Thus, the direct role of HIV on the development of cerebrovascular disease remains uncertain. Nevertheless, changes in the vasomotor reactivity81 and progression of intima–media thickness of the ICA82 have been reported in adult patients with HIV infection. Moreover, it has been shown that the majority of autopsied AIDS patients have retinal microvasculopathy.83 These pieces of evidence suggest that, HIV infection may have its own role in predisposing the affected patients to develop cerebrovascular diseases. In children and adolescence, the incidence of cerebrovascular disease in HIV-positive patients is 1.3– 2.6%,84,85 and autopsy shows evidence of cerebrovas-
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cular disease in as high as 24% of patients.84 In this age group, stroke appears to be more directly related to HIV; cerebral arteriopathy with or without fusiform aneurysm formation is often observed in patients without concomitant opportunistic infection.84,85 The vasculopathy frequently involves intracranial arteries near the circle of Willis such as MCA or ACA. The arterial lesions may be transient and reversible.86,87 Autopsy findings show panarteritis involving vasa vasorum and multiple fusiform aneurysms occurring in the major cerebral vessels. Microscopically, thickened vascular wall was observed, due primarily to subintimal fibrosis.88 Thus, HIV infection is one of the causes of intracranial vascular diseases, although the direct role of HIV remains uncertain in adult patients. Parasitic infection Among parasites affecting the CNS, cysticercosis is the most important cause of vascular involvement. Cysticercosis is prevalent in Southern Asia, China, subSaharan Africa, and Latin America. Cysticercosis used to be endemic in the southern part of the Korean peninsula area. With improved hygiene and mass education prohibiting raw pork ingestion, the incidence has dramatically decreased. On the other hand, patients with neurocysticerosis are nowadays occasionally observed in developed countries, due probably to increasing international travel and the increasing incidence of HIV infection. Cerebral cysticercosis can roughly be divided into parenchymal and subarachoid (or cisternal) cysticercosis. The parenchymal form produces seizures, focal neurologic deficits, and occasional vasculitis of small vessels resulting in lacunar syndromes.89 However, major vascular complications are quite uncommon in this type. On the other hand, subarachoid cysticercosis produces arachnoiditis, hydrocephalus, and vasculitis of the large cerebral artery. It has been considered that occlusive arteritis of small perforating artery is more common than large artery involvement in patients with cysticercosis.90,91 Pathologically, the involved vessels in the base of the brain show advanced endarteritic changes with luminal narrowing, adventitial fibrosis, and chronic panarteritis. Thrombosis or smooth muscle vacuolization of the media suggestive of vasospasm can also be observed.92 In some patients, especially in those with cysticercosis involving the sylvian cisterns, an occlu-
sion of the main trunk of the intracranial artery is observed,93–95 which produces significant hemiparesis, aphasia, apraxia, and seizures. Hydrocephalus is commonly present, and the prognosis of these patients is usually poor. Barinagarrementeria and Cantu´ 96 studied 28 patients with subarachnoid cysticercosis using cerebral arteriography and brain MRI. Among them, 15 patients had angiographic evidence of cerebral arteritis (53%), in whom 12 had clinical stroke syndromes, and eight had evidence of cerebral infarction on MRI. The vessels most commonly involved were the MCA and the PCA. This result suggested that the prevalence of large artery involvement in cerebral cysticercosis may be higher than previously thought, and that subarachnoid cysticercosis should be considered one of the important causes of non-atherosclerotic intracranial vascular disease in endemic areas. The treatment of cysticercosis with vascular involvement is not well established. Albendazol or praziquantel should not be used, or should be cautiously used in conjunction with a high dose of corticosteroid because degenerated parasites may induce extensive inflammation and immunologic reactions, further augmenting vascular damage and ischemic symptoms. The use of anti-parasite agents in these patients may even lead to a catastrophic cerebral infarction.97 Spirochetal infection Syphilis Syphilis used to be one of the most common causes of strokes occurring in young adults. The incidence, however, has dramatically decreased with the introduction of penicillin, and we rarely see strokes related to syphilis nowadays. However, a recent increase in syphilitic infection has been observed possibly due to the increased incidence of HIV infection. Moreover, after the introduction of antibiotics, the relative importance of meningovascular syphilis seems to have become greater than other subtypes of neurosyphilis, such as general paresis or tabes dorsalis.98 Meningovascular syphilis develops 1–12 years (mostly 6–7 years) after the initial infection. CSF studies usually show increased cells, protein, and positive serologic tests. The infarcts may develop anywhere in the brain but most often occur in the subcortical area of the anterior circulation, such as the internal capsule and basal ganglia, which produce hemiparesis, speech disturbances, and hemisensory changes. Cognitive and 237
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emotional disturbances are seen when the lesions are multiple.99 Pathologically, widespread arteritis is noted, characterized by lymphocytes and plasma cell infiltration in the vasa vasorum, the adventitia, and, eventually, the media of medium-sized or large arteries. Occlusion of vasa vasorum destroys the smooth muscle and elastic tissue of the media, which are replaced by fibrous tissue, producing progressive narrowing and eventual occlusion of the vessel due to superimposed thrombosis.99 However, in many autopsied patients, atherosclerosis or embolic occlusion was observed as a cause of stroke without the presence of active arteritis, in whom chronic inflammatory environments may have accelerated the progression of atherosclerosis. Antibiotics may arrest the active inflammation but cannot reverse the existing vascular or brain damage. Leptospirosis Leptospirosis is a spirochetal infection characterized clinically by hepatitis, conjunctival suffusion, and photophobia. Aseptic meningitis, sometimes severe in degree, may develop as a second-phase illness. According to Chen,100 leptospiral meningitis is an important cause of cerebral arteritis in children and young adults in rural China. Among 12 pathologically verified cases of cerebrovascular leptospirosis, there were multiple occlusive vascular disorders in nine, intracranial hemorrhage in two, and intracranial hypertension in one patient. Cerebral panarteritis involving the main trunks of large arteries at the base of the brain was a usual pathologic finding. Narrowing of the intracranial portions of the ICA was common, and infarcts usually developed in areas supplied by the MCA, often accompanied by smaller infarcts at watershed areas. Leptospirosis seems to be one of the most important causes of moyamoya syndrome in China.101 Fungal infections Fungal infection is a rare cause of intracranial arterial disease. The affected patients are usually immunocompromised, for example those having transplantation surgery or those having HIV infection or uncontrollable diabetes mellitus. In patients with mucormycosis, thrombotic occlusion of the distal part of the ICA is occasionally encountered, because the agent frequently invades the orbital or cavernous sinus re-
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gions. In these cases, numerous hyphae are present within the thrombi and vessel wall, often invading the surrounding parenchyma as well. Although rare, pontine infarction due to arteritis involving the basilar artery was reported in a patient with mucormycosis.102 Hyphae invasion of a cerebral artery is also observed in patients with aspergillosis, resulting in thrombotic occlusion or hemorrhages.103–105 The hemorrhages may be related to the formation of mycotic aneurysms. Patients usually develop infarcts in the perforating artery territory,104,105 although large cortical infarction has also been reported.106
Radiation injury Cerebral arteriopathy may result from therapeutic irradiation of neck or intracranial malignancies such as lymphoma, thyroid cancer, or glioma. According to animal experiments, irradiation primarily affects the vascular endothelial cells. Pathologically, there are deposition of lipophages in the intima and structural changes in the elastic fibers. These adverse effects are exacerbated in the presence of hypercholesterolemia.107 Similarly, autopsy findings of human cases showed vacuolization and thickening of the intima, degeneration of the endothelial cells, and accumulation of fat-laden macrophages in the media.108 Proliferation and calcification of the intima are also observed.109 The vascular complication usually develops 6 months to 10 years after irradiation. Kang et al.110 recently reviewed 12 patients with radiation-induced arteriopathy who presented with stroke syndromes. Significant extracranial carotid stenosis was observed in seven patients, and five of them had neck malignancies. Intracranial vascular diseases were documented in seven (three had distal vertebral/basilar arteries disease, six had distal ICA and/or MCA disease, and two had both). Five of them had head malignancies. Thus, vascular lesions generally correlated with the irradiation sites. The mean interval from the time of irradiation to the development of stroke was 13.4 years (ranging from 4 to 30 years) for extracranial diseases and was 5.1 years (ranging from 2 to 9 years) for intracranial diseases. This observation is consistent with a previous notion that the interval between the irradiation and the onset of stroke correlates with the diameter of the involved artery.
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This result, together with previous reports,111–113 illustrates that irradiation should be considered one of the etiologies of intracranial arterial disease. Extensive arterial lesions may produce vasculopathy mimicking moyamoya disease.114,115 The mechanisms of stroke in patients with irradiation-induced intracranial arterial disease include in situ thromboocclusion with or without embolic generation and hemodynamic insufficiency.110 Lacune-like infarction due to occlusion of the orifice of a perforator is also encountered.116
Sarcoidosis Sarcoidosis is a disease of unknown etiology characterized by the presence of epithelioid cell tubercles in multiple organs. The organs frequently involved are lymph nodes, lungs, liver, spleen, skin, eyes, small bones of hands and feet, and salivary glands. There is a slight female preponderance and the peak incidence in both sexes is around the age of 25–30 years. Sarcoidosis affects the CNS in about 5% of patients, usually in the form of cranial neuropathies, basilar meningitis, intracranial masses, diabetes insipidus, encephalopathies, or seizures.117 Despite the frequent observation of vasculitis and cerebral infarcts at autopsy, clinical stroke events are rare.118,119 Characteristic postmortem findings of these patients include the presence of sarcoid granulomas in the leptomeninges and brain parenchyma, with invasion of the arterial wall by epithelioid cell granulomas that disrupt the media and the internal elastica causing vascular stenosis or occlusion. In many instances, small perforating and medium-sized arteries are primarily affected,117,120 resulting in small, usually asymptomatic, cerebral infarctions. The involvement of large intracranial arteries is rare in sarcoidosis, and cerebral angiographic findings are rarely positive even in those with symptomatic stroke. An occlusion of the A1 segment of the ACA has been reported that was considered to be related to a granulomatous mass adjacent to the distal ICA.121 Another study reported segmental narrowing and dilatation of large cerebral arteries;122 however, a clinical correlation was not made. At least two reports described patients who had moyamoya-like vasculopathy associated with sarcoidosis.119,123
Thromboangiitis obliterans Thromboangiitis obliterans (TAO) or Buerger’s disease is a vasoocclusive disease of unknown cause affecting mainly the peripheral vessels of the upper and lower extremities. Ischemic stroke or TIAs have been occasionally described to complicate TAO.124–130 The incidence of this cerebral TAO has been shown to range from 0.5% to 18%.128,130 Pathologically, Spatz131 first described the picture of white “worm-like” occluded vessels overlying the areas of cerebral infarcts, focal in distribution in some patients but symmetrical and bilateral in others. To explain this characteristic vascular pathologies, a socalled “stagnation hypothesis” has been proposed,128 which suggests the original occlusion of a major, proximal artery resulting in ischemic infarction in the territory of the artery. Then, blood flow through the involved vessels becomes arrested, intravascular thrombosis of the stagnant blood takes place, and finally the clot becomes organized and is replaced by fine connective tissue, which gives the vessel its characteristic white appearance. Angiography studies have described thrombotic occlusion of ICAs, proximal MCAs, ACA, or PCA.125 Exaggerated tapering of MCAs was also described.130 However, these findings were not clearly distinguishable from the usual atherosclerosis in patients who had a long-standing history of heavy smoking. Therefore, there remain controversies regarding whether there are specific pathologic or angiographic findings in patients with cerebral TAO.131 However, in some patients, the vascular occlusion associated with worm-like white strings was limited to the distal small arteries while the proximal vessels remained intact.128 This finding was distinguishable from usual atherosclerosis. Moreover, a few studies132 have reported interesting angiographic findings, which included multiple alternative areas of arterial occlusions in the distal segments of both MCAs and extensive pathological collateral vessels around the occluded segment, resembling the “tree root” or “corkscrew” vessels described in the peripheral arteries in patients with TAO133 (Fig. 19.5). Thus, although uncommon, at least some patients present with characteristic intracranial vascular diseases that resemble pathologic changes shown in the limb arteries of TAO patients.
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Fig 19.5 A 29-year-old man with known Buerger’s disease developed tingling sensations (not shown here) his left limbs. MRI showed an infarction in the left parietal area in. Lateral view of a right carotid angiogram shows multiple tandem arterial occlusion in the cortical segments of both middle cerebral arteries. Extensive fine collateral vessels are seen around the occluded segment (arrows). (From No YJ, Lee EM, Lee PH, Kim JS. Cerebral angiograpic findings in thromboangitis obliterans. Neuroradiology 2005; 47: 912–915, with permission).
CADASIL CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a hereditary disorder characterized clinically by recurrent migraine, stroke episodes, and dementia. Various mutations in the Notch 3 gene in chromosome 19 are responsible for this disease.134 Stroke and TIA are the most common symptoms of CADASIL, occurring in more than 80% of symptomatic patients. Stroke manifests usually with lacunar syndromes. As strokes recur, depression and subcortical dementia develop. The symptoms gradually or stepwisely aggravate, and the patients become significantly disabled before they die (mean age 65 years). Autopsy findings show that the involved vessels are cerebral and leptomeningeal arterioles. The media is thickened and smooth muscle cells are swollen and degenerated. The thickened vessels produce luminal narrowing and occlusion. On electron microscopy, dense, granular osmiophilic materials (GOMs) are charac240
Fig 19.6 A 52-year-old man without vascular risk factor had repeated episodes of transient ischemic attacks. MRI showed multiple white matter ischemic lesions (not shown here). He had a family history of stroke and gene analysis revealed Notch3 mutation (R110C). The initial MR angiogram showed no definite abnormalities (A), but a follow-up image 2 years later shows focal stenosis of right middle cerebral artery (B) (arrow). The stenosis persisted in the follow-up image 2 years later (C) (arrow). (From Choi EJ, Choi CG, Kim JS. Large cerebral artery involvement in CADASIL. Neurology 2005; 65: 1322–1324, with permission)
teristically observed.135 MRI is abnormal in almost all symptomatic patients, showing multifocal or diffuse periventricular and white matter high signals, subcortical lacunar infarcts, and microbleeds.136 Involvement of the temporal lobe and external capsules is characteristic.137
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Since the involved vessels are mainly small arterioles, angiographic findings are usually negative. However, a patient with multifocal segmental stenosis of cerebral arteries similar to primary angiitis of the CNS has been reported.138 The presence of atherosclerotic changes in the BA, ICA, MCA, ACA, and PCA has been described in Japanese patients with CADASIL who did not have any vascular risk factors.139 Coronary artery occlusion140 has also been described in CADASIL patients. Recently, Choi et al.141 evaluated the involvement of the large cerebral arteries using angiography in 13 CADASIL patients. They found five patients (38%) had stenosis: the MCA in three, vertebral artery in one, the ICA in one. The stenosis persisted on a follow-up angiogram in two patients (Fig. 19.6). There were no differences in vascular risk factors between patients with angiographic abnormalities and those without. One autopsy study reported the presence of GOM deposition with relatively preserved vascular smooth muscle cells in the aorta, carotid, and renal arteries.142 These pieces of evidence suggest that involvement of the large cerebral artery may not be so uncommon in CADASIL, which might represent accelerated atherosclerosis in the presence of vascular wall damage associated with GOM deposition.
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Moyamoya disease Susumu Miyamoto, Jun C. Takahashi and Jong S. Kim
Moyamoya disease (MMD) denotes a condition characterized by progressive occlusion of the major arteries of the anterior circulation, i.e., the distal internal carotid artery (ICA), proximal middle cerebral artery (MCA), or anterior cerebral artery (ACA). There is also a fine meshwork of basal collateral vessels (moyamoya vessels). In a strict sense, the vascular lesion should be present bilaterally (definite MMD).1 However, unilateral cases are often observed, which may be called “probable moyamoya disease.” After 1–2 years of follow-up, approximately 40–50% of the unilateral MMD become bilateral.2,3 When there are causative diseases or associated conditions, the terms such as “moyamoya syndrome” and “angiographic moyamoya” are often used.4 The posterior circulation is usually spared, but may be involved in the late stage, most often in the posterior cerebral artery (PCA). Although uncommon, MMD is an important cause of non-atherosclerotic intracranial arterial disease, especially in far-east Asian countries. In these regions, cases of isolated MCA stenosis in young patients are observed, which eventually evolve into MMD.5 MMD is also the most important cause of stroke or transient ischemic attack (TIA) in children in this area.
Epidemiology For unknown reasons, MMD is relatively common in people living in far-east Asian countries, such as Japan and Korea, compared with those in the western hemisphere. According to an epidemiological survey performed in Japan in 1995, the prevalence of MMD was approximately 3.16/100 000, with an estimated inci246
dence of 0.35 /100 000.6 A more recent survey carried out in 2004 showed that the number of patients had increased considerably, with an estimated incidence of 0.54/100 000.7 Moreover, the age of patients was slightly older in the recent survey. The proportions of young (younger than 10 years) and old patients (older than 50 years) were 15.3% and 19%, respectively, in the previous survey, whereas those of the recent survey were 11.9% and 25.5%, respectively. This finding may indicate an actual increase in the incidence of MMD in Japan. However, a more likely explanation would be an increase in newly diagnosed patients, owing to the recent advent of non-invasive diagnostic tools such as MR angiography. Another explanation is improved patient prognosis because of improved management. Approximately 10–12% of patients with MMD have a family history, and the risk of having MMD in family members is about 30–40 times higher than the general population.6,7 Familial cases have also been reported in other countries.8 The male–female ratio was approximately 1:1.8 in both surveys. The epidemiology of MMD has been less well characterized in other countries. According to a joint study comparing MMD patients in Korea and those in Japan,9 Korean patients appear to have a lower incidence (2%) of family history, a higher percentage (20% larger) of the adult population, and a higher incidence of stroke (infarction or hemorrhages) and a relatively lower incidence of TIAs or seizures. However, both groups had a female preponderance and two peaks of age at onset. Considering possible sampling bias or differences in inclusion criteria, it seems that there may be no fundamental differences between MMD in Korea and in Japan.
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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A hospital-based study showed that, unlike Japanese MMD patients, Taiwanese patients were mostly male and usually presented with hemorrhages.10 However, a subsequent study investigating a larger number of patients (n = 92) showed that female patients were more common than male patients. Cerebral infarction occurred in 83% of juvenile patients whereas hemorrhages were relatively common in adult patients (35%).11 Thus, MMD in China does not appear to be fundamentally different from that in Japan, either. It was suggested that, unlike in Japan, MMD in China is more often seen in men than in women, occurs at an older age, and presents with hemorrhages rather than ischemic symptoms, even in young patients.12 However, more than half of the study subjects had a secondary cause of moyamoya angiopathy (moyamoya syndrome), most importantly leptospiral infection. Therefore, the results do not reflect the true figure of MMD. In Washington state and California, the incidence of MMD was reported to be 0.086/100 000. Among the different ethnic groups, the incidence was the highest in Asians, similar to that of Japanese living in Japan, followed by black people, white people’ and Hispanics. A female preponderance was also noticed.13
Pathology and pathogenesis The cause of MMD remains unknown, and a diagnosis of MMD is established only when there are no obvious causes or other related conditions. Pathologic examination shows bilateral occlusion or narrowing of the terminal ICA and the proximal portion of the MCA or ACA. Microscopic examination shows thickening of the intima and media, proliferation or degeneration of smooth muscle cells, and tortuosity and fragmentation of the internal elastic lamina. Unlike in atherosclerosis, inflammatory changes and lipid deposition are not present.14–15 Based on these pathological changes, abnormal regulation of the proliferation and migration of vascular smooth muscle cells has been considered to be related to the pathogenesis of MMD. Evidence suggests a role of increased expression of basic fibroblast growth factors,16 inflammatory cells such as macrophages or T cells,17 or genetic/immunologic mediators18 in the pathogenesis of MMD. Genetic linkage analyses per-
formed in familial MMD patients have shown various chromosomal loci possibly linked to the disease phenotype, such as chromosome band 3p, chromosome 6, and chromosome band 17q.19 The genes involved in the regulation of matrix metalloproteinase (MMP)-2 and MMP-9 may be responsible for the pathogenesis of MMD. Indeed, it is the tissue inhibitor of the metalloproteinase (TIMP) gene rather than the MMP gene itself that is located in the disease loci revealed in familial MMD. Kang et al.20 recently investigated the promoter regions, exon–intron junctions, and the exons of the TIMP2 and TIMP4 genes by direct sequencing in 11 patients with familial MMD, 50 with non-familial MMD, and in 50 subjects without MMD. They found that there was a significantly higher frequency of the G/C heterozygous genotype at position –418 of the TIMP2 promoter in patients with familial MMD than in those with nonfamilial MMD or subjects without MMD. Thus, the authors hypothesized that an abnormal tissue repair mechanism due to dysregulation of the TIMP system after certain vascular injury might be related to the development of vascular intimal thickening in vulnerable vessels such as the terminal ICA. Further studies are required to elucidate more clearly the genetic disturbances and consequent pathogenic process related to familial MMD. Although these results have provided some insights into the pathogenesis of MMD, the majority of patients with MMD do not have a family history. Moreover, there was no difference in the genetic polymorphism between non-familial MMD patients and subjects without MMD. Therefore, the pathogenesis of non-familial MMD still remains elusive. Moyamoya disease-like vasculopathy associated with other disease conditions is called “moyamoya syndrome.” Numerous conditions that have been reported to be associated with moyamoya vasculopathy may be categorized as (1) genetic, hereditary disorders: neurofibromatosis,21,22 Down syndrome,23 Noonan syndrome,24 and trisomy 12p syndrome;25 (2) hematologic disorders: sickle cell disease,26,27 essential thrombocythemia,28 hereditary spherocytosis,29 protein C deficiency,30 and protein S deficiency;31 (3) connective tissue diseases: systemic lupus erythematosus,32 antiphospholipid antibody,33 livedo reticularis;34 (4) infectious or chronic inflammatory conditions: pneumococcal meningitis,35 tuberculous meningitis,36 HIV infection,37 leptospirosis,38 pulmonary sarcoidosis,39–40 and Behcet’s disease;41 247
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(5) metabolic diseases: diabetes mellitus, thyrotoxicosis42 and hyperhomocysteinemia;43 (6) vascular injury: radiation therapy;44 and (7) others: renovascular hypertension45 and oral contraceptive use especially in cigarette smokers.46 Whether these disease conditions are causally related to the moyamoya vasculopathy remains unclear. They may be mere bystanders or simply play a role as triggering factors for symptom development. However, it is also possible that these conditions play a role in the yet unknown disease process. In this sense, a recent report by Czartoski et al.35 deserves attention. They described a 20-year-old woman who developed cerebral infarction due to vasculitis caused by pneumococcal meningitis. Approximately 4 months later, she developed new infarcts when anti-b2-glycoprotein titers were elevated. Four months later, she developed another infarct, and the angiogram showed lenticulostriate artery collaterals reminiscent of moyamoya vessels. Autopsy confirmed severe narrowing of the vessels without evidence of inflammation or atherosclerosis, mimicking moyamoya pathology. This observation, therefore, seems to be consistent with a theory that the development of moyamoya vessels may be related to a long-standing immunologic process initially triggered by a vascular injury perhaps in genetically susceptible subjects.
Clinical features The clinical presentations of MMD include TIA, ischemic stroke, hemorrhagic stroke, seizures, headache, and cognitive impairment. The incidence of each symptom varies according to the age of the patients. An ischemic event is the most important clinical manifestation of MMD. Cerebral hypoperfusion due to progressive major vessel occlusion results in repeated hemodynamic TIAs or ischemic strokes in children or young adults. Thus, MMD is a classical example of a hemodynamic cause of stroke. We often encounter patients who develop repeated TIAs when they are hyperventilating: crying, eating hot noodles, or blowing a harmonica or flute. Perhaps, decreased arterial PaCO2 due to hyperventilation may induce vasodilation of normal vessels and subsequent hypoperfusion in vulnerable areas via the steal phenomenon. Stress, fatigue, infection, and dehydration may also precipitate ischemic symptoms. Less often, 248
patients have territorial infarction due to embolism or thromobotic occlusion in the distribution of the MCA, ACA, or PCA.47 Occasionally, the infarct topography in these patients includes the borderzone area beyond the classical vascular territory (Fig. 20.1). This is partly because of the concomitant presence of hemodynamic insufficiency and partly because of altered vascular territories secondary to long-standing major vessel occlusion along with diversely developed collateral channels. The most frequent ischemic symptom is hemiparesis, which is followed by speech disturbances and hemisensory abnormalities.48 Although uncommon, involuntary movements such as chorea or dystonia are observed,49 which are probably related to functional derangement of the basal ganglionic motor circuitry. Approximately 30% of patients present with intracranial hemorrhages secondary to the friable collateral vessels harboring microaneurysms or false aneurysms.48 The hemorrhages usually occur in the anterior circulation territory. Although any brain region can be affected, intraventricular hemorrhage appears to be more common than in hypertensive hemorrhages.50 Caudate hemorrhage with extension into the ventricle is frequent, while lobar (temporal or frontal) hemorrhages are occasionally encountered.10,11 Thus, MMD should be suspected when the patients are young, without vascular risk factors, or when the location of the hemorrhage is atypical. For unclear reasons, hemorrhagic strokes are less common in Caucasians than in Asians.50–52 Intracranial hemorrhage seems to be more common in Chinese than in Japanese patients, perhaps related to the higher average age of Chinese MMD patients.10 With significant brain hypoperfusion, cognitive impairment, intellectual decline, or mental retardation may develop,53–55 which are grave problems for children of school age. Seizures occur in approximately 5% of patients secondary to an ischemic lesion or hypoperfusion, usually starting in childhood. Headache either presents as a symptom of MMD or develops after bypass surgery. Although the prevalence of headache in MMD has been considered to be low,48 a recent study56 reported that 44 of 204 (21.6%) children with MMD suffered from headache. Nausea/vomiting was present in 12. In four, headache developed during hyperventilation, and in three, TIAs and headache occurred simultaneously. The cause of headache in MMD remains unclear. Perhaps, cerebral
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Fig 20.1 A 64-year-old woman developed visual field defect on the right side. Computed tomography shows an infarct in the left occipital area that extends to the borderzone area between the posterior cerebral artery and middle cerebral artery. Asymptomatic subcortical infarcts are also shown on
the left side (A). Angiogram shows bilateral occlusion of distal internal carotid arteries and numerous basal moyamoya vessels. Posterior circulation was also involved and left posterior cerebral artery appears to be occluded (B–D).
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hypoperfusion may lower the threshold for migraine development and increase the risk of spreading cortical depression.57,58 The headache occasionally improves after the revascularization process, suggesting that cerebral hypoperfusion is related to the pathogenesis of headache, at least in some of these patients. The experience of preoperative headache is a strong predictor for post-operative headache.56 There are two peaks of age with different clinical presentations: around 10 years and at 30–40 years. The peak appears to be delayed in women compared with men.7 In children, ischemic symptoms, especially TIAs, are predominant (70%).59 Intellectual decline and seizures are also more common in this age group. On the other hand, adult patients present with intracranial hemorrhages more often than pediatric patients. These different age peaks and different clinical presentations in each age group were observed in MMD patients living in Washington state and California13 but not in those from Texas.50
Diagnosis For definite diagnosis, conventional angiography is mandatory, which shows bilateral terminal ICA occlusion, basal moyamoya vessels, and the status of collaterals from external carotid arteries or the posterior circulation. Aneurysms are detected in about 10% of the cases. However, this relatively invasive technique is associated with procedure-related complications, and therefore pre-procedural care including sufficient hydration should be taken appropriately, especially in pediatric patients. Based on various angiographic findings, Suzuki and Takaku1 proposed six stages of angiographic evolution. However, a stepwise progression from stage 1 through stage 6 has been observed only in a limited number of patients60 and the practical value of the classification remains unsettled. MRI and CT scan may show symptomatic or asymptomatic ischemic or hemorrhagic lesions. Ischemic lesions are usually located in the borderzone area or centrum semiovale. Cerebral atrophy indicating chronic ischemia may also be observed. In addition, several features suggestive of MMD can be detected by MRI, which include the absence of signal voids of major arteries in the area of the circle of Willis and multiple, punctated signal voids in the 250
basal ganglia reflecting abnormally dilated perforating arteries. Gadolinium-enhanced MRI may show enhanced collateral vessels in the cortex. Nowadays, MR angiography and CT angiography can non-invasively detect the occlusion of cerebral vessels. Using these techniques, more cases have been diagnosed recently. However, these techniques have limitations in assessing collateral channels and in identifying basal moyamoya vessels.
Non-surgical Treatment Patients with MMD are advised to avoid precipitating conditions, such as excessive fatigue, hyperventilation, hunger, and dehydration. Although patients presenting with ischemic symptoms are usually managed with anitplatelet agents, the efficacy of these agents has not yet been examined in controlled trials. Moreover, the efficacy of antiplatelet agents in patients with severe hemodynamic failure remains questionable, and these drugs may even precipitate or potentiate bleeding complications in MMD. Currently, the choice of medication is left to the treating physicians, who should weigh the individual risks of ischemic and hemorrhagic complications. On the other hand, the benefits of revascularization surgery for treating MMD have been well established, at least in patients presenting with ischemic symptoms.61–63
Surgical treatment Children and adults with MMD who have cerebral infarction or frequent TIAs caused by definite hemodynamic impairment are candidates for revascularization surgery. Single-photon emission CT (SPECT) is widely used to measure regional cerebral blood flow (rCBF) and detect hemodynamic failure in these patients. Many authors have described the usefulness of SPECT studies obtained after intravenous administration of acetazolamide (Diamox) to measure the cerebrovascular reserve capacity.64 Since MMD usually involves both cerebral hemispheres, surgery is usually recommended for both sides. The majority of surgeons prefer a two-stage operation in which the first stage targets the symptomatic or hemodynamically more significantly compromised
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hemisphere, except in cases where simple indirect procedures are used to treat both hemispheres simultaneously.
Selection and application of surgical revascularization procedures Numerous surgical techniques have been developed to establish adequate collateral circulation in a brain with ischemic MMD. They can be roughly categorized as either indirect bypass procedures or direct anastomotic bypass procedures. Indirect bypass Indirect methods of revascularization are based principally on the idea that neovascularization can be induced from the extracranial arteries to the cortical arteries by placing the vascular-rich tissues on the pial brain surface. A variety of indirect revascularization procedures, such as encephalomyosynangiosis (EMS), encephalogaleosynangiosis (EGS), encephaloduroarteriosynangiosis (EDAS), and omentum transplantation, have been described.65–68 The EDAS procedure devised by Matsushima et al.67 is most often used. In this procedure, a scalp artery with a strip of galea is transplanted to a linear dural opening made during an osteoplastic craniotomy. There are many variations of indirect revascularization based on this technique.
Fig 20.2 Schematic drawing of standard superficial temporal artery-to-middle cerebral artery anastomosis. The parietal branch is anastomosed to the cortical branches of the middle cerebral artery. Indirect procedures can be
Recently, more complex and extensive indirect procedures have been reported that span a larger area of the cortex.69 Indirect revascularization is technically easy and can be performed even by a surgeon with limited experience in microsuturing cerebral vessels. The success of this strategy depends mainly on the natural neovascularization capability of the patient’s brain; in some cases, postoperative collateral formation is insufficient and the progression of cerebral ischemia cannot be halted.70,71 It is well known that neovascularization tends to be insufficient more often in adult patients than in pediatric patients. Direct bypass Direct bypass is a procedure for directly inducing collateral blood flow from extracranial arteries to intracranial cortical vessels using a microvascular anastomotic technique. Superficial temporal artery-tomiddle cerebral artery (STA–MCA) anastomosis has been widely used70,72 and has been shown to be effective in improving cerebral circulation in MMD. Direct bypass surgery provides an immediate improvement in rCBF, but this procedure requires sophisticated skills, especially in the treatment of pediatric MMD because the donor and recipient arteries are very small and the walls of the recipient arteries are extremely fragile. The standard procedures for direct bypass are shown in Fig. 20.2; typical findings of postoperative angiography and SPECT are shown in Figs 20.3
performed simultaneously by putting the temporal muscle flaps on the brain surface and stitching them to the dural edges.
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A
B
Fig 20.3 Angiograms obtained after standard superficial temporal artery-to-middle cerebral artery anastomosis. (A) A postoperative external carotid angiogram of a pediatric patient. Well-developed collateral blood flow from the bypass graft (arrowhead) and arteries of the temporal
muscle flaps (encephalomyosynangiosis) is demonstrated. (B) A postoperative external carotid angiogram of an adult patient. Direct bypass flow (white arrowhead) is more dominant than in pediatric cases, and the flow of the indirect bypass cannot be detected.
and 20.4, respectively. Direct bypass can be combined with various indirect procedures, and we have adopted “STA-MCA anastomosis plus EMS” in the treatment of pediatric MMD. Several reports have described other combined procedures.73 Moreover, direct bypass can be performed in cases refractory to indirect non-anastomotic revascularization procedures such as EDAS (Fig. 20.5).
between 35 and 45 mmHg, and systemic hypotension should be avoided. Repeated CT studies are recommended during the postoperative acute period to detect unfavorable subdural or epidural hematomas because most patients with the ischemic type of MMD are prescribed preoperative antiplatelet drugs such as aspirin. If any evidence of compression of the brain is detected, the hematomas should be removed immediately. Transient neurological deficits are frequently observed after a direct bypass without any evidence of infarction apparent on MRI. Although they may mimic TIAs, these phenomena have not been clarified in terms of their pathophysiology. Recently, some authors have described these attacks as being caused by local hyperperfusion,78 but we have noted an extreme diversity in the hemodynamic condition of the treated brain.
Perioperative management In both direct and indirect procedures, maximum care should be taken to maintain CBF in order to avoid perioperative ischemic complications. Throughout the perioperative period, an adequate intravenous drip should be administered to prevent dehydration. The anesthetic risks in patients with MMD are known to be high because of the hemodynamic instability of the brain. It has been reported that some non-surgical intraoperative factors such as hypercapnia, hypocapnia, and hypotension can increase the risk of postoperative ischemic complications.74–77 Intraoperative PaCO2 levels should be strictly controlled to maintain 252
Bypass surgery for hemorrhagic moyamoya disease Management of the hemorrhagic type of MMD, which accounts for roughly half the cases of adult MMD, is a serious issue because the rate of rebleeding
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Rest
Acetazolamide i.v.
Fig 20.4 SPECT images at resting state and after an acetazolamide challenge in a pediatric patient. Top, preoperative SPECT images show decreased cerebral blood flow and severely impaired cerebrovascular reserve capacity in bilateral frontal lobes (arrowheads). Bottom, SPECT images obtained six months after bilateral superficial temporal artery-to-middle cerebral artery anastomosis with encephalomyosynangiosis. Hemodynamic failure is dramatically improved.
Post EDAS
attacks is extremely high. A survey by Nishimoto et al.79 revealed that 33% of 175 patients with hemorrhagic MMD sought medical attention for rebleeding attacks.79 Moreover, Kobayashi et al.80 reported the annual rebleeding rate to be 7.09%. Although these hemorrhagic events can be life-threatening and often produce permanent neurological deficits, there have been no therapeutic methods established to prevent rebleeding attacks. At present, the only potentially effective strategy is revascularization surgery. It has been supposed that microaneurysms formed in the abnormally dilated moyamoya vessels are the main source of bleeding, even though they may not be detected by cerebral angiography.81 Moreover, these microaneurysms are believed to be induced by hemodynamic stresses affecting the moyamoya vessels, which work to compensate for the hemodynamic failure caused by the occlusion of the main arterial trunks.82 Therefore, the rate of hemorrhagic events can possibly be decreased by reducing this hemodynamic stress and consequently, the abnormal moyamoya vessels. It is well known that, in ischemic MMD, reductions in moyamoya vessels can often be detected by angiography after bypass surgery (Fig. 20.6). The hypothesis that bypass surgery prevents bleeding has thus emerged. In fact, some authors have reported the effectiveness of direct anastomotic bypass in hemorrhagic MMD.81,82
STA-MCA bypass
Fig 20.5 Superficial temporal artery-to-middle cerebral artery (STA–MCA) bypass after failure of encephaloduroarteriosynangiosis (EDAS) in a pediatric patient. (A) An external carotid angiogram obtained after EDAS was performed at another hospital. No collateral
channels are present from the parietal branches of the STA that was used in EDAS. (B) An external carotid angiogram obtained after follow-up STA–MCA anastomosis. Collateral blood flow via the parietal branch of the STA (white arrowhead) is well developed.
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A
C
B
D
E
Fig 20.6 Reduction of moyamoya vessels after Superficial temporal artery-to-middle cerebral artery (STA–MCA) bypass in adult patients. (A and B) Left internal carotid angiograms obtained before surgery. Moyamoya vessels are remarkably well developed. (C) A left internal carotid angiogram obtained after STA–MCA anastomosis.
Collateral blood flow via the direct bypass covers approximately two-thirds of the outer surface of the left hemisphere. (D and E) Left internal carotid angiograms obtained after surgery. The reduced size of the moyamoya vessels is evident.
Additionally, these reports have emphasized that direct bypass was more favorable than the indirect procedure. However, surgical treatment of adult hemorrhagic MMD remains controversial because no randomized trials have yet been reported. To resolve these issues, the Japan Adult Moyamoya (JAM) Trial began in 2001 and is now underway.83 This randomized controlled trial seeks to determine whether direct bypass surgery affects the prognosis of the patients and reduces the incidence of recurrent bleeding attacks. Although the results of this trial are yet to be reported, it is hoped that the JAM trial will establish guidelines in the treatment of hemorrhagic MMD.
Prognosis
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Since majority of strokes are related to hemodynamic insufficiency, ischemic strokes caused by MMD are rarely catastrophic. Mortality in the acute stage has been reported to be 2.4% in the ischemic type and to be 16.4% in the hemorrhagic type of stroke.84 Although long-term followup studies have rarely been performed in patients with MMD, approximately 75–80% of patients follow a benign course without a significant compromise in their daily activities.60 However, maladaptation to social or school life is sometimes problematic.85
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Patients with an early age of onset of symptoms (3 or 4 years) appear to have a worse prognosis; they tend to have progressive mental deterioration86 and frequent infarction.57 Although the treatment strategy in this age group has not been well established, early surgery has been recommended for this reason.57 The clinical course of patients with late onset of symptoms appears to be relatively benign. However, Kuroda et al.87 recently followed adult patients (age >20 years) with MMD for a mean duration of 73.6 months, and found that disease progression occurred in 15 of 63 patients (23.8%) or 15 of 86 (17.4%) non-operated hemispheres. Vascular progression occurred in both anterior and posterior circulations. Eight of the 15 patients developed clinical symptoms related to either ischemic or hemorrhagic strokes. Female gender was a factor related to the progression. In another study,88 40 asymptomatic MMD patients were followed for a mean duration of 43.7 months. During the study period, seven developed ischemic or hemorrhagic strokes with the annual risk for stroke being 3.2%. Disease progression was closely related to symptom occurrence in this population as well. These results suggest that the outcome of MMD in adult patients may not be as benign as has been considered previously and that patients with MMD should be carefully followed even if they are asymptomatic. Strangely, however, despite the advanced angiographic findings in elderly patients with MMD, the number of symptomatic patients dramatically decreases in the elderly population for an unknown reason.7
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moyamoya disease: a preoperative positron emission tomography study. J Neurosurg 1994; 81: 843–850. Hogan AM, Kirkham FJ, Isaacs EB, Wade AM, VarghaKhadem F. Intellectual decline in children with moyamoya and sickle cell anaemia. Dev Med Child Neurol 2005; 47: 824–829. Imaizumi C, Imaizumi T, Osawa M, et al. Serial intelligence test scores in pediatric moyamoya disease. Neuropediatrics 1999; 30: 294–299. Seol HJ, Wang KC, Kim SK, et al. Headache in pediatric moyamoya disease: review of 204 consecutive cases. J Neurosurg 2005; 103: 439–442. Olesen J, Friberg L, Olsen TS et al. Ischaemia-induced (symptomatic) migraine attacks may be more frequent than migraine-induced ischaemic insults. Brain 1993; 116: 187–202. Park-Matsumoto YC, Tazawa T, Shimizu. Migraine with aura-like headache associated with moyamoya disease. Acta Neurol Scand 1999; 100: 119–121. Kim SK, Seoul HJ, Cho BK, et al. Moyamoya disease among young patients: its aggressive clinical course and the role of active surgical treatment. Neurosurgery 2004; 54: 840–844. Yonekawa Y, Khan N. Moyamoya disease. In: , Barnett HJM, Bogousslavsky J, Meldrum H (eds) Ischemic stroke: advances in neurology, vol 92. Philadelphia,PA: Lippincott Williams & Wilkins, 2003: pp. 113–118. Houkin K, Kuroda S, Nakayama N: Cerebral revascularization for moyamoya disease in children. Neurosurg Clin N Am 2001; 12: 575–584. Irikura K, Miyasaka Y, Kurata A, Tanaka R, Yamada M, Kan S, et al: The effect of encephalo-myo-synangiosis on abnormal collateral vessels in childhood moyamoya disease. Neurol Res 2000; 22: 341–346. Ishikawa T, Houkin K, Kamiyama H, Abe H: Effects of surgical revascularization on outcome of patients with pediatric moyamoya disease. Stroke 1997; 28: 1170– 1173. Nakagawara J, Takeda R, Suematsu K, Nakamura J: Quantification of regional cerebral blood flow and vascular reserve in childhood moyamoya disease using [123I] IMP-ARG method. Clin Neurol Neurosurg 1997; 99 (Suppl 2): S96–S99. Karasawa J, Kikuchi H, Furuse S, Sakaki T, Yoshida Y, Ohnishi H, Taki W: A surgical treatment of “Moyamoya” disease – “encephalomyo-synangiosis.” Neurol Med Chir (Tokyo) 1977; 17: 29–37. Takeuchi S, Abe H, Ozawa T, Tanaka R: Surgical treatment for moyamoya disease. Surgical effect of encephalogaleo-synangiosis on moyamoya disease. Surg Cereb Stroke 2000; 28: 98–103. Matsushima Y, Fukai N, Tanaka K, Tsuruoka S, Inaba Y, Aoyagi M, et al: A new surgical treatment of moyamoya
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disease in children: a preliminary report. Surg Neurol 1981; 15: 313–320. Karasawa J, Kikuchi H, Kawamura J, Sakaki T: Intracranial transplantation of the omentum for cerebrovascular moyamoya disease: A two-year follow-up study. Surg Neurol 1980; 14: 444–449,. Park JH, Yang SY, Chung YN, et al. Modified encephaloduroarteriosynangiosis with bifrontal encephalogaleoperiosteal synangiosis for the treatment of pediatric moyamoya disease. J Neurosurg 2007; 106 (Suppl 3): 237– 242. Miyamoto S, Kikuchi H, Karasawa J, et al. Pitfalls in the surgical treatment of moyamoya disease. Operative techniques for refractory cases. J Neurosurg 1988; 68: 537–543. Nakagawa Y, Abe H, Kamiyama H, et al. Revascularization surgery for 50 patients with moyamoya disease. In: Suzuki J (ed) Advances in surgery for cerebral stroke. Tokyo: Springer, 1988: 141–149. Karasawa J, Kikuchi H, Furuse S, Kawamura J, Sakaki T. Treatment of moyamoya disease with STA-MCA anastomosis. J Neurosurg 49: 1987; 679–688. Houkin K, Kamiyama H, Takahashi A, et al. Combined revascularization surgery for childhood moyamoya disease: STA-MCA and encephalo-duroarterio-myo-synangiosis. Child’s Nerv Syst 1997; 13: 24–29. Iwama T, Hashimoto N, Yonekawa Y. The relevance of hemodynamic factors to perioperative ischemic complications in childhood moyamoya disease. Neurosurgery 1996; 38: 1120–1126. Nomura S, Kashiwagi S, Uetsuka S, et al. Perioperative management protocols for children with moyamoya disease. Childs Nerv Syst 2001; 17: 270–274. Sakamoto T, Kawaguchi M, Kurehara K, et al. Risk factors for neurologic deterioration after revascularization surgery in patients with moyamoya disease. Anesth Analg 1997; 85: 1060–1065. Sato K, Shirane R, Yoshimoto T: Perioperative factors related to the development of ischemic complications in patients with moyamoya disease. Childs Nerv Syst 1997; 13: 68–72. Fujimura M, Kaneta T, Mugikura S, et al. Temporary neurologic deterioration due to cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in patients with adult-onset moyamoya disease. Surg Neurol 2007; 67 (3): 273–282. Nishimoto A, Ueda K, Honma Y. Follow-up study on outcome of the occlusion of the circle of Willis. In: Gotoh S (ed.) 1982 Proceedings of the Research Committee on Spontaneous Occlusion of the Circle of Willis [in Japanese]. Tokyo, Japan: Ministry of Health and Welfare: 1983; pp. 66–74.
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80 Kobayashi E, Saeki N, Oishi H, et al. Long-term natural history of hemorrhagic moyamoya disease in 42 patients. J Neurosurg 2000; 93: 976–980. 81 Houkin K, Kamiyama H, Abe H, et al. Surgical therapy for adult moyamoya disease. Can surgical revascularization prevent the recurrence of intracranial hemorrhage? Stroke 1996; 27: 1342–1346. 82 Kawaguchi S, Okuno S, Sakaki T: Effect of direct arterial bypass on the prevention of future stroke in patients with the hemorrhagic variety of moyamoya disease. J Neurosurg 2000; 93: 397–401. 83 The Japan Adult Moyamoya (JAM) Trial Group: Study Design for a Prospective Randomized Trial of Extracranial-intracranial (EC-IC) Bypass Surgery for Adults with Moyamoya Disease with Hemorrhagic Onset. Neurol Med Chir (Tokyo) 2004; 44: 218–219.
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84 Yonekawa Y, Taub E. Moyamoya disease: status 1998. Neurologist 1999; 5: 13–23. 85 Imaizumi T, Hayashi K, Saito K, et al. Long-term outcomes of pediatric moyamoya disease monitored to adulthood. Pediatr Neurol 1998; 18: 321–325. 86 Moritake K, Handa H, Yonekawa Y, et al. Follow up study on the relationship between age at onset of illness and outcome in patients with moyamoya disease. No Shinkei Geka 1986; 14: 957–963. 87 Kuroda S, Ishikawa T, Houkin K, et al. Incidence and clinical features of disease progression in adult moyamoya disease. Stroke 2005; 36: 2148–2153. 88 Kuroda S, Hashimoto N, Yoshimoto T, Iwasaki Y. Radiological findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 2007; 38: 1430–1435.
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Note: Italicized page numbers refer to figures and tables. abulia, 93, 101 acetazolamide, 197, 250 activated clotting time (ACT), 186 acute ischemic stroke, 177–179 adhesion molecules, 49, 120 adiponectin, 49–50 Adult Treatment Panel III (ATP-III), 45 African American Antiplatelet Stroke Prevention Study (AAASPS), 168 African Americans, risk for atherosclerosis, 24, 50 age, 47 Aggrenox (drug), 166 AIDS, 221 albendazol, 237 albumin, 207 albuminuria, 34t, 37 Alzheimer’s disease, 102–105 circle of Willis arteries in, 104 hypoperfusion of brain in, 103 pathological studies, 103–104 stenosis index of intracranial arteries, 103 transcranial Doppler studies, 105 American College of Rheumatology (ACR), 218 amnesia, 75, 93 amphetamine, 221–222 amyloid cascade, 105 amyloid-beta, 102 anger proneness, 108 angiogenesis, 120–121, 208 angioplasty, 181–191 contraindications, 184–185 endovascular therapy, 184 history of, 177–178 indication for, 182–184 outcome of, 187–189 patient selection, 182 preoperative assessment and medical treatment, 186 procedural success, 184–186 animal models, 23–24
anterior carotid artery (ACA), 6, 10f, 101, 116 anterior cerebral artery (ACA), 9–11 cortical branches of, 10–11 proximal segment of, 10 territory infarction, 64 transcranial Doppler examination of, 150 anterior cerebral artery atherosclerosis, 74–77 ACA territory infarction, 75 artery-to-artery embolism, 76–77 general features of, 74–75 in situ thrombotic occlusion, 76 local branch occlusion, 75–76 territory infarction, 74–75 anterior choroidal artery (AChA), 8 anterior circulation disorders, 69–79. See also posterior circulation disorders ACA territory infarction, 64, 74–77 due to ACA atherosclerosis, 74–77 general features, 74–75 intracranial internal carotid artery disease, 77–79 MCA territory infarction, 63–64, 69–72 due to MCA atherosclerosis, 69–70 general features, 69 lesion patterns and clinical syndrome, 70–72 subcortical infarction, 72–74 anterior circulation, proximal segments of, 4 anterior inferior cerebellar artery, 13, 89 anterograde memory, 93 anterolateral infarction, 93 anteromedial infarction, 94 anticardiolipin antibodies, 219 anticoagulants, 167–168, 219
anticoagulation therapy, 173–179 for acute ischemic stroke, 177–179 for secondary stroke prevention, 173–174 WASID trial, 174–176 antiphospholipid antibodies, 183 antiplatelet drugs, 163–165 versus anticoagulants, 167–168 aspirin, 165 cilostazol, 165–166 clopidogrel, 165 combined use of, 166–167 dipyridamole, 165–166 ticlopidine, 165 antiplatelet therapy, 163–170 antiplatelets versus anticoagulants, 167–168 combined use of agents in, 166–167 for intracranial atherosclerosis, 167, 168–170 mechanisms of drugs in, 163–165 for stroke prevention, 165–166 antithrombotic drugs, mechanisms of, 164f antithrombotic therapy, 120 antitrypsin deficiency, 230 anti-tumor necrosis factor, 207 apolipoprotein E, 104 Apollo stents, 186–187 apparent diffusion coefficient (ADC), 140 arachnoiditis, 237 arrhythmia, 106, 221 arterial anatomy, 3 arterial dissections, intracranial, 229–234 clinical manifestations, 230–231 dissection in anterior circulation, 230–231 dissection in posterior circulation, 231 epidemiology of, 229 etiology of, 230
Intracranial Atherosclerosis Edited by Jong S Kim, Louis R Caplan and KS Lawrence Wong © 2008 Blackwell Publishing Ltd. ISBN: 978-1-405-17822-8
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arterial dissections, intracranial (cont.) versus extracranial dissections, 229–230 outcome of, 234 pathology of, 230 treatment, 231–234 arterial flow velocity, 148 arterial lumen, 3, 5, 104, 120 arterial wall, 4–6 artery-to-artery embolism, 58–59, 76–77, 101 aseptic meningitis, 238 Asia-Honolulu Aging Study, 105 Asian populations post-stroke emotional incontinence in, 107–108 risk for atherosclerosis, 24, 33–38 aspergillosis, 238 aspirin, 114, 163, 165–170, 173–176 aspirin resistance, 165 ASSIST trial, 190t Asymptomatic Carotid Emboli Study (ACES), 156 asymptomatic ICAS, prevalence of, 37 asymptomatic occlusive disease, 40 ataxia, 88, 93–95 ataxic hemiparesis, 69, 89, 220 atheroembolism, animal model of, 24 atherogenesis, 113 atheromatous branch occlusion, 59 atherosclerosis, 19–28 animal models, 23–24 distribution of, 25–26 general features of, 19–20 human autopsy studies, 24 natural course of, 22–23 overview of, 19 pathogenesis of, 27–28 pathological characteristics of, 21–22 plaques, 19 progression of, 20f risk factors, 24–25, 45–51 Atherosclerosis Risk in Communities (ARIC), 41 autopsy studies, 24, 33–38 axial lateropulsion, 94 Babinski signs, 86 bacterial infections, 234–235. See also central nervous system (CNS) infection meningitis, 234–235
260
tuberculosis, 235 bacterial meningitis, 234–235 balloon-expandable stents, 182 Barthel index, 168, 177 basilar artery, 12–13 atherosclerosis, 65 occlusion, 89–90, 91f risk factor for occlusive lesions, 50 transcranial Doppler examination of, 151–152 Behcet’s disease, 247 Benedikt syndrome, 93 Bernoulli’s principle, 62 bilateral pontine infarction, 87–89 Biodiv Ysio coronary stent, 188f black blood magnetic resonance angiography (BBMRA), 132 black people, risk for atherosclerosis, 25 blood flow rate, 148 blood pressure, 207–208 and arterial wall, 4 and hyperfusion, 188 and metabolic syndrome, 119 as risk factor, 25, 46 blood–brain barrier, 5 border-zone infarcts, 139–140 bottom-frequency signals (BFSs), 155 Braak neurofibrillary stages, 104 brain infarction, mechanisms of, 58t brain lesions, localization of, 83 branch occlusive disease, 59–61 Buerger’s disease, 239 bulbar muscles, weakness of, 88 bypass surgery, 194–196 and cognitive function, 101 direct, 251–252 high-flow, 194–196 history of, 196–197 indications for, 198–199 indirect, 251 low-flow, 194–196 for moyamoya disease, 251–252 for posterior circulation ischemia, 199–200 risk of stroke in, 197–198 trial, 196–197 CADASIL, 240–241 calcium channel blockers, 224 Call–Fleming syndrome, 222 Call’s syndrome, 222
Canadian–American Ticlopidine Study (CATS), 165 CAPRIE trial, 165 cardioembolic stroke, 58–59 Cardiovascular Health Study (CHS), 41, 100 CARESS trial, 166 Carotid Occlusion Surgery Study (COSS), 199 carotid stenosis, prevalence of, 36 carotid T, 6 catheter angiography, 127–128 Caucasians, risk for atherosclerosis, 24–25 caudate infarction, 101 Center for Epidemiology Studies Depression (CES-D), 107 central nervous system (CNS) infection, 234–239 bacterial meningitis, 234–235 cysticercosis, 237 fungal infections, 238 Herpes zoster infection, 236 human immunodeficiency virus, 236–237 isolated angiitis, 217–218 leptospirosis, 237–238 sarcoidosis, 239 syphilis, 237–238 tuberculosis, 235 cerebellar infarction, 86 cerebral angiography, population-based studies, 37 cerebral atherosclerosis, and depression, 106 cerebral blood flow (CBF), 207–212 blood pressure and volume management, 207–208 diastolic counterpulsation, 208–209 sphenopalatine ganglion stimulation, 209–212 cerebral blood volume (CBV), 197, 207–208 cerebral cysticercosis, 236 cerebral metabolic rate of oxygen (CMRO2 ), 198 cerebral perfusion pressure (CPP), 197 cerebral vasculitis, 219 cerebrovascular atherosclerosis, racial distribution of, 41–42 cerebrovascular reserve capacity (CVRC), 197, 199
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Cervical Artery Dissection in Ischemic Stroke Patients (CADISO) study, 233 chalk (methamphetamine), 221 CHARISMA trial, 167 children, atherosclerosis in, 25 China, intracranial atherosclerosis in, 33–38 Chinese stroke patients, population-based studies, 38 Choice PT microwire, 188–189f cholesterol, 25 accumulation of, 25 and Alzheimer’s disease, 102 embolism, 58–59 high-density lipoprotein, 34t, 103, 207 high-fat, 23 low-density lipoprotein, 22, 41, 206, 219 cigarette smoking, 25, 48 cilostazol, 165–166, 168–170 Cilostazol Stroke Prevention Study (CSPS), 166 circle of Willis, 4, 7, 26, 104–105, 236 classic SCA syndrome, 94 Claude syndrome, 93 clopidogrel, 165, 169 CLOTBUST trial, 156 clots, imaging of, 135–137 cocaine, 221 cognitive dysfunction, in extracranial atherosclerosis, 100 collagen, 5, 19 Collier’s sign, 93 color velocity imaging quantification (CVIQ), 209 community-based populations, 36 computed tomographic (CT) angiography, 128–131 accuracy of, 129–131 disadvantages of, 131 history of, 128–129 image post-processing techniques, 129 continuous wave mode, 148 contralateral hemiparesis, 93 coronary artery bypass graft (CABG), 47 coronary artery bypass graft surgery (CABG), 37 coronary diseases, 45–46, 114–116 corticobulbar fibers, 85
corticosteroids, 219–220, 237 crack cocaine, 221 C-reactive protein (CRP), 74, 120, 207 CREDO trial, 166 crystal (methamphetamine), 221 CURE trial, 166 cyclic guanosine monophosphate (GMP), 165 cyclooxygenase-1 (COX-1), 163, 165 cystic medial necrosis, 230 cysticercosis, 237 cytochrome P450 3A4 (CYP3A4), 165 cytokines, 219
top of the basilar syndrome, 93 Dominican Republic, intracranial atherosclerosis in, 33 Doppler, Christian, 147 Doppler effects, 147–148 Doppler shift, 148 dorsolateral infarction, 93 Down syndrome, 247 drug abuse, 221–222 dysarthria, 61f, 84–85, 92f, 93, 94, 137f dysarthria – clumsy hand syndrome, 89 dysphagia, 84–85, 88
Davidoff–Schechter artery, 14 decompressive craniectomy, 200–201 dementia, 104 depression, 105–107 cerebellar atherosclerosis, 106 and intracranial atherosclerosis, 106–107 post-stroke, 105–106 DESTINY trial, 201 diabetes mellitus, 48, 119, 248 Diamox (drug), 250 diastolic counterpulsation, 208–209 diffuse encephalopathy, 217 diffusion-weighted imaging (DWI), 138–140. See also magnetic resonance imaging (MRI) advantages of, 138 assessing recurrent strokes, 140–141 assessing stroke mechanisms, 138–140 in assessment of MCA infarction, 71, 73 limitations of, 140 for stroke mechanisms, 57, 59, 63 digital subtraction angiography, 127–128, 186, 218 dipyridamole, 165–166, 174 direct bypass, 251 distal intracranial territory infarcts, 95–97 distal posterior circulation intracranial territory, 93–95. See also posterior circulation disorders posterior cerebral artery territory infarction, 94–95 pure midbrain infarction, 93–94 superior cerebellar artery territory infarction, 94
early recurrent ischemic lesions (ERILs), 140–141 Ehlers–Danlos syndrome, 230 elastin fibers, 5, 19 embolic MCA occlusion (eMCAO), 143 embolism, 58–59 embryology, 4 emotional disturbances, 107–108 anger proneness, 107–108 panic disorders, 108 post-stroke emotional incontinence, 107–108 emotional incontinence, 107–108 encephaloduroarteriosynangiosis (EDAS), 251, 253f encephalogaleosynangiosis (EGS), 251 encephalomyosynangiosis (EMS), 251, 252f encephalopathy, 217 endogenous fibrinolysis, 120 endothelial cells, 5 endothelial dysfunction, 207 endothelin-1 (ET-1), 208–209 epidemiology, 33–42 Asian region studies, 33–38 European studies, 38–39 North Americas and related regions, 39–40 racial distribution of atherosclerosis, 40–41 ESPRIT trial, 166, 173–174 Europe, symptomatic ICAS in, 38–39 European Stroke Prevention Study 2 (ESPS-2), 166 European Wingspan pilot study, 182 European–Asian Wingspan trial, 190t external carotid artery (ECA), 7
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external counterpulsation (ECP), 208–209 clinical applications, 208 contraindications, 208 and ischemic stroke, 208–211 mechanisms of, 208 extracranial atherosclerosis in Asian populations, 36–37 cognitive dysfunction in, 100 early recurrent ischemic lesions in, 141 predictors for, 36–37 risk factors, 46 extracranial dissections, 229–230 Extracranial/Intracranial Bypass Study, 41, 46, 114, 196 extracranial/intracranial bypass surgery, 194–196 history of, 196–197 trial, 196–197 fatty streaks, 19–20, 22, 24 fibrinolysis, 120 fibromuscular dysplasia, 230 flow rate, 148 flow resistance, 148 flow velocity, 148 fluid-attenuated inversion recovery (FLAIR), 57, 136, 223 focused-frequency signals (FFSs), 155 folate, 207 Fraxiparine in Ischemic Stroke (FISS) study, 168, 177–178 fungal infections, 238 GATED-SPECT, 115f Gateway balloon, 182, 187 gender, 47–48, 102, 104–105, 120 Gerstmann syndrome, 95 GESICA study, 38, 116 glass (methamphetamine), 221 glossopharyngeal nerve, 12 glycoprotein IIb-IIIa, 163 gradient-echo susceptibility vessel sign (GRE SVS), 136–138 granular osmiophilic materials (GOMs), 240–241 granulomas, 218 Guillain–Mollaret triangle, 88 Haemophilus influenza, 235 Hagen–Poiseuille law, 148 hallucinations, 93
262
HAMLET trial, 201 Hawaii, intracranial atherosclerosis in, 37 HeADDFIRST study, 201 hemianopia, 69, 95, 96f hemimedullary infarction, 86 hemiparesis, 88, 143f, 236 hemiplegia, 95, 143f HeMMI trial, 201 hemodynamic compromise, 118 hemodynamic strokes, 61 hemoglobin, 41, 48, 136 hemorrhagic moyamoya disease (MMD), 252–254 hemosiderin, 136 heparin, 186 Heparin Aspirin Ischemic Stroke Trial (HAEST), 177 hepatitis B surface antigenemia, 219 herald hemiparesis, 88 herniation, 86 heroin, 222 Herpes zoster, 236 hiccups, 85 high-density lipoprotein (HDL) cholesterol, 34t, 103, 207 high-fat cholesterol (HFC), 23 high-flow bypass surgery, 194–196 high-frequency turbulence, 149 high-resolution magnetic resonance imaging (HR-MRI), 135–136 high-risk patients, 37 Hispanics, risk for atherosclerosis, 50 homocysteine, 114, 120, 206–207 Hong Kong Chinese people post-stroke emotional incontinence in, 107 risk for atherosclerosis, 25 stroke patients, 38 Honolulu Heart Program, 26 Hounsfield, Godfrey, 128–131 human autopsy studies, 24 human immunodeficiency virus (HIV), 236–237 hydrocephalus, 235, 237 hypercholesterolemia, 45, 48, 238 hyperglycemia, 119, 181, 219 hyperhomocysteinemia, 230, 248 hyperintense vessel sign, 136 hyperlipidemia, 25, 36, 41, 46, 48, 72t, 174 hyperperfusion, 100, 188, 191, 193, 252
hypersomnolence, 93 hypertension, 48 and moyamoya disease, 248 racial differences in, 25 and systemic lupus erythematosus, 219 hypoadiponectinemia, 49 hypoperfusion, 61–63, 101–102 hypoplasia, 7, 10–12, 153 ice (methamphetamine), 221 immunologic disorders, 217–221. See also central nervous system (CNS) infection isolated central nervous angiitis, 217–218 polyarteritis nodosa, 219–220 systemic lupus erythematosus, 218–219 Takayasu’s arteritis, 220–221 in situ thrombotic occlusion, 58, 76 indirect bypass, 251 Indo-Asians, risk for atherosclerosis, 50 infants, atherosclerosis in, 25 infarction pathogenesis of, 138–140 recurrence of, 140–141 infectious diseases, of central nervous system, 234–238 bacterial infections, 234–235 meningitis, 234–235 tuberculosis, 235 fungal infections, 238 parasitic infections, 237 spirochetal infections leptospirosis, 238 syphilis, 237–238 viral infections, 236–237 Herpes zoster infection, 236 human immunodeficiency virus, 236–237 infectious endocarditis, 222 inflammation, 120 and drug abuse, 221 lymphoplasmacytic, 220 metabolic syndrome, 50 modulation of, 207 transmural, 217 vascular, 105 Insulin Resistance Atherosclerosis Study, 41
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Insulin Resistance Intervention After Stroke (IRIS) trial, 49 intercellular adhesion molecule-1 (ICAM-1), 120 internal border-zone infarction (IBI), 197 internal carotid artery (ICA), 6–8 autopsy studies, 24 diseases, 77–79 occlusion, 194, 198f origin of, 25 risk factor for occlusive lesions, 48–49 siphon, 151 stenosis in, 78f, 79f, 231f International Stroke Trial (IST), 177 intimamedial thickness (IMT), 106 intracerebral hemorrhage (ICH), 183, 186–187, 217 intracranial arterial disease, 217–220 in isolated central nervous angiitis, 217–218 in polyarteritis nodosa, 220 in systemic lupus erythematosus, 218–219 intracranial arteries, 3–15 anatomical features of, 3 anterior cerebral artery, 9–11 anterior choroidal artery, 8 anterior inferior cerebellar artery, 13 arterial wall, 4–6 basilar artery, 12–13 embryology, 4 internal carotid artery, 6–8 middle cerebral artery, 8–9 posterior cerebral artery, 13–15 posterior inferior cerebellar artery, 11–12 superior cerebellar artery, 13 vertebral artery, 11 intracranial atherosclerosis (ICAS), 33–42 and Alzheimer’s disease, 102–105 antiplatelet therapy for, 163–170 classification of, 184–185 cognitive dysfunction in, 100–102 depression and emotional disturbances in, 105–108 distribution of, 25–26 early recurrent ischemic lesions in, 141 epidemiology, 33–42 local factors, 116–118
natural course of, 113–114 prevalence of, 36–37 prognostic factors, 116 progression of, 117f, 118 racial differences in, 39 risk factors, 45–51 coronary diseases, 46–47, 114–116 metabolic syndrome, 49–51 in vascular territories, 48–49 risk of clinical recurrence, 114 stroke mechanisms, 57–63 artery-to-artery embolism, 58–59 branch occlusive disease, 59–61 hypoperfusion, 61–63 in situ thrombotic occlusion, 58 therapeutic implications, 121 intracranial dissections, 229–234 clinical manifestations, 230–231 dissection in anterior circulation, 230–231 dissection in posterior circulation, 231 epidemiology of, 229 etiology of, 230 versus extracranial dissections, 229–230 outcome of, 234 pathology of, 230 treatment, 231–234 intracranial internal carotid artery disease, 77–79 intracranial revascularization, 194–196 hemodynamic impairment in, 197–198 high-flow bypass surgery, 194–196 history of, 196–197 indications for, 198–199 low-flow bypass surgery, 194–196 for moyamoya disease, 251–252 for posterior circulation ischemia, 199–200 risk of stroke in, 197–198 trial, 196–197 intracranial stenosis, 116–119 and artery-to-artery embolism, 59 in Asian patients, 36–38 in European patients, 38–39 extent of, 118 hemodynamic compromise in, 118 location of symptomatic stenosis, 118 microembolic signals, 118–119
plaque composition, 119 progression of, 118 severity of, 116–118 symptomatic versus asymptomatic, 118 types of lesions, 185 intraplaque neovasculature, 26f ipsilateral eye, 84 ipsilateral tongue paralysis, 86 ischemic heart disease (IHD), 46–49 ischemic stroke, 26–27 animal models, 24 and arterial dissections, 229 in drug abuse, 221–222 and external counterpulsation, 208–211 gender factor in, 120 and HIV infection, 236 microembolic signals, 119 and moyamoya disease, 254 pathogenesis of, 26–27 isolated central nervous angiitis, 217–218 description of, 217 intracranial arterial disease in, 217–218 stroke in, 217 Japan Adult Moyamoya (JAM) trial, 254 Japanese EC/IC Trial (JET), 199 Japanese people, risk for atherosclerosis, 24–26 Japanese Wechsler Adult Intelligence Scale, 101 Joint Study of Extracranial Arterial Occlusion, 77 Kaposi’s sarcoma, 236 Koreans intracranial atherosclerosis in, 33–38 post-stroke emotional incontinence in, 107 lacunar syndrome, 73–74, 89, 138–139, 220, 237, 240 lateral medullary infarction, 83–85 lenticulostriate vessels, 9, 26 leptomeninges, 218, 239 leptospiral meningitis, 238 leptospirosis, 238 leukoaraiosis, 220 leukocytes, 19
263
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Libman–Sacks endocarditis, 218 lingual gyrus, 95 lipohyalinosis, 39, 59, 60, 72, 90 lipoprotein, 114, 120 lipoprotein-associated phospholipase (Lp-PLA2), 207 livedo reticularis, 220 local branch occlusion, 75–77 location morphology access (LMA), 181–182, 185 locked-in syndrome, 88, 90f low-density lipoprotein (LDL) cholesterol, 41, 206, 219 low-flow bypass surgery, 194–196 low-frequency turbulence, 149 low-molecular-weight heparin (LMWH), 168 luminal stenosis, 26f M1 segment, 8–9, 20, 26 macrophages, 19, 22, 65, 247 macular sparing, 95 magnetic resonance angiography (MRA), 131–132 3D time-of-flight sequence, 131–132 black blood, 132 population-based studies, 37–38 predictive values, 132 magnetic resonance imaging (MRI), 135–144 assessing pathogenesis of infarction, 138–140 assessing perfusion status, 141–144 assessing recurrence of infarction, 140–141 of clots, 136–138 of plaques, 135–136 Marfan syndrome, 230 massive infarction, 200–201 MATCH study, 167 matrix metalloproteinase-2 (MMP-2), 247 matrix metalloproteinase-9 (MMP-9), 120, 247 maximum intensity projection (MIP), 129 maximum internal carotid plaque thickness (MICPT), 41 mean flow velocity (MFV), 105 medial longitudinal fasciculus (MLF), 88 medial medullary infarction, 85–86 MEDLINE database, 208–209
264
meningitis, 234–235 meningovascular syphilis, 237–238 metabolic syndrome, 49–51 definition, 45 and ethnic differences, 50–51 and intracranial atherosclerosis, 49–50, 119–120 as risk factor, 49 treatment of, 207 metallic stents, 132 methamphetamine, 221–222 methemoglobin, 136 Michael Reese Hospital Stroke Registry, 40 microembolic signals, 153–156 characteristics of, 154–155 clinical significance of, 156 detection of, 118–119, 153–156 intra-intervention monitoring of, 156 midbrain infarction, 93–94 middle cerebral artery atherosclerosis, 69–74 lesion patterns and clinical syndrome, 70–72 in MCA territory infarction, 69–70 and subcortical infarction, 72–74 middle cerebral artery (MCA), 8–9 atherosclerosis of, 20 characteristics of, 5–6 decompressive craniectomy for, 200–201 diagnostic criteria, 152 dissections, 230–231, 232f infarction, 69–72 intrinsic atherosclerosis, 69–70 lesion patterns, 70–72 massive, 200–201 subcortical, 72–74 occlusion, 39, 143 proximal segment of, 8–9 risk factor for occlusive lesions, 48 schematic of, 8f stenosis, 116, 188–189f stroke mechanisms, 138–140 territory infarction, 63–64 transcranial Doppler examination of, 150 transverse paraffin sections of, 26–27f middle intracranial posterior circulation territory, 87–89 anterior inferior cerebellar artery infarction, 89
bilateral pontine infarction, 87–89 unilateral pontine infarction, 89 middle intracranial territory ischemia, 89–92 mini-mental state examination (MMSE), 100, 105 modified Rankin score (mRS), 201, 209, 233 monocyte chemoattractant protein-1 (MCP-1), 120 monocytes, 19, 22, 165, 220 moyamoya disease (MMD), 246–255 bypass surgery for, 252–254 clinical features, 248–250 description of, 246 diagnosis, 250 epidemiology of, 246–247 pathology and pathogenesis of, 247–248 prognosis, 254–255 surgical indication of, 250–254 for hemorrhagic type, 252–254 perioperative management, 252 revascularization procedures, 251–252 treatment of, 250 moyamoya syndrome, 102, 238, 247 multifocal encephalopathy, 217 multifocal stenoses, 189–191 multifrequency signals (MFSs), 155 multiplanar reformation (MPR), 129 murmurs, 149, 152–153 musical murmurs, 149, 152–153 myocardial infarction, 114, 135, 165–168, 173–175, 221 myocarditis, 221 nadroparin, 177–178 National Alzheimer’s Coordination Center, 104 National Institute of Health Stroke Score (NIHSS), 71, 140, 184, 209, 233 necrotizing angiitis, 222 neurofibrillary tangle (NFT), 103 Neurolink stent systems, 187 New England Stroke Registry, 71 niacin, 207 nicardipine, 224 nimodipine, 186, 224 nitric oxide, 5, 163, 164f, 223 non-Hispanic whites, risk for atherosclerosis, 50
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INDEX
non-subarachnoid hemorrhage (SAH), 229 non-verbal memory, 93 Noonan syndrome, 247 North America early autopsy studies, 39 racial differences in ICAS, 39–41 North American Symptomatic Carotid Endarterectomy Trial (NASCET), 197 North Americans, risk for atherosclerosis, 24 Northern Manhattan Stroke Study (NoMASS), 41, 47 nystagmus, 84, 86, 88, 95 obstructive sleep apnea, 50–51 occipital artery, 194–196 ocular bobbing, 86, 88 ocular torsion, 84, 93 oculomotor nerve, 13 omentum transplantation, 251 Ondine’s curse, 85 one-and-a-half syndrome, 89, 93 ophthalmic artery, 7, 78, 151 oral contraceptives, 248 Oxfordshire Community Stroke Project, 38 oxidative stress, 49–50, 113, 209 oxygen extraction fraction (OEF), 197–198 Palmaz–Schatz stent, 177–178 panic disorders, 108 parasitic infections, 237 pathogenesis, 27–28 pathological laughing and crying, 107 percent stenosis, 128 perfusion, assessing status of, 141–144 perfusion-weighted imaging (PWI), 141–144 periarteritis nodosa, 219 Persantin Retard (drug), 166 phenylpropanolamine (PPA), 222 phosphodiesterase, 163–165 pial infarcts, 139 plaques, 19–20 components of, 19, 119 imaging of, 135–136 increase of, 22 vulnerability of, 27–28 plasminogen activator inhibitor-1 (PAI-1), 120
pneumococcal meningitis, 247 polyarteritis nodosa (PAN), 219–220. See also immunologic disorders description of, 219 intracranial arterial disease in, 220 stroke in, 219–220 polycystic ovarian syndrome, 50 pontine infarction, 87–89 bilateral, 87–89 MRI imaging of, 92f unilateral, 89 pontine ischemia, 87–88 pontine lacune, 220 pontine paramedian reticular formation (PPRF), 88 population-based studies, 36 positron emission tomography (PET), 102, 141, 197 posterior cerebral artery (PCA), 13–15. See also intracranial arteries atherosclerosis, 65–66 dissections, 231 stenosis, 116 territory infarction, 94–95 transcranial Doppler examination of, 151 posterior circulation disorders, 83–97. See also anterior circulation disorders distal intracranial territory infarcts, 95–97 distal posterior circulation intracranial territory, 93–95 localization of brain lesions, 83 middle intracranial posterior circulation territory, 87–89 middle intracranial territory ischemia, 89–92 proximal intracranial posterior circulation territory, 83–86 proximal intracranial territory infarction, 86–87 revascularization surgery for, 199–200 stroke mechanisms, 64–66 basilar artery atherosclerosis, 65 posterior cerebral artery atherosclerosis, 65–66 vertebral artery atherosclerosis, 64–65 posterior inferior cerebellar artery (PICA), 11–12, 86, 231
post-stroke anger proneness (PSAP), 108 post-stroke depression, 105–106 post-stroke emotional incontinence (PSEI), 107–108 praziquantel, 237 Primary Prevention Project study, 167 PROFESS trial, 166 Progression of the Symptomatic Intracranial Arterial Stenosis study, 116 prostacyclin, 163–165 protein C deficiency, 247 protein S deficiency, 236, 247 prothrombotic state, 120 proximal intracranial posterior circulation territory, 83–86. See also posterior circulation disorders cerebellar infarction, 86 hemimedullary infarction, 86 lateral medullary infarction, 83–85 medial medullary infarction, 85–86 stroke mechanisms, 86–87 vascular lesions in, 86–87 Puerto Rico, intracranial atherosclerosis in, 33 pulsatility index (PI), 105 pulse wave mode, 148 pure midbrain infarction, 93–94 racial differences, 39–40 radiation injury, 238–239 recipient arteries, 194–196 recreational drugs, 221–222 amphetamine, 221–222 cocaine, 221 heroin, 222 methamphetamine, 221–222 recurrent strokes, 74, 101, 140, 220 regional cerebral blood flow (rCBF), 142, 250 regional cerebral blood volume (rCBV), 142 regional mean transit time (rMTT), 141 regional oxygen extraction fraction (rOEF), 101 regional time-to-peak (rTTP), 141 response to injury hypothesis, 22 restless leg syndrome, 208 retrograde memory, 93
265
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INDEX
reversible cerebral vasoconstriction syndrome (RCVS), 222–224 Reynolds number, 149 risk factors, 45–51 age, 47 cigarette smoking, 48 clinical studies, 47t coronary diseases as, 45–46 diabetes mellitus, 48 extra-versus intracranial atherosclerosis, 46 gender, 47–48 hyperlipidemia, 48 hypertension, 48 metabolic syndrome, 49–51 in vascular territories, 48–49 basilar artery, 49 internal carotid artery, 48–49 middle cerebral artery, 48 Ross, Russell, 22 sarcoidosis, 239 secondary stroke, prevention of, 173–174 selective serotonin re-uptake inhibitors (SSRI), 108 self-expandable stenting, 190t serine-530, 163 sex differences, 39 Shwartzman phenomenon, 219 sickle cell disease, 247 simvastatin, 206 single photon emission computed tomography (SPECT), 78f, 114, 115f, 141 siphon internal carotid, 151 sleep apnea, 50–51 smoking, 25, 48, 239 smooth muscle cells, 5, 15, 19, 22, 187, 240, 247 SONIA trial, 132 speed (methamphetamine), 221 Spencer’s curve, 148, 152 sphenopalatine ganglion (SPG), 209–212 spherocytosis, 247 spinal chord ischemia, 219 spirochetal infections, 237–238 leptospirosis, 238 syphilis, 237–238 SSYLVIA study, 182, 190t stagnation hypothesis, 239 STA–MCA anastomosis, 251–252
266
stem cell therapy, 207 stenosis autopsy studies, 26 measurement of, 128 multifocal, 189–191 tandem, 189–191 treatment for, 189–191 stenting, 181–191 contraindications, 184–185 endovascular therapy, 184 history of, 181–182 indication for, 182 in magnetic resonance angiography, 132 outcome of, 187–189 patient selection, 182 practical issues of, 186–187 preoperative assessment and treatment, 186 procedural success, 184–186 strategic infarct dementia, 100–101 street methamphetamine, 221–222 Streptococcus pneumonia, 235 stroke and isolated central nervous angiitis, 217 and polyarteritis nodosa, 219–220 recurrent, 74, 101, 140, 220 and systemic lupus erythematosus, 218 stroke mechanisms, 57–66 diffusion-weighted imaging studies of, 138–140 in distal intracranial territory infarcts, 95–97 in intracranial atherosclerosis, 57–63 artery-to-artery embolism, 58–59 branch occlusive disease, 59–61 hypoperfusion, 61–63 in situ thrombotic occlusion, 58 in middle intracranial territory ischemia, 89–92 neuroimaging investigations of, 57 in proximal intracranial territory infarction, 86–87 in vascular territories, 63–66 anterior cerebral artery, 64 basilar artery, 65 middle cerebral artery, 63–64 posterior cerebral artery, 65–66 vertebral artery, 64–65 stroke patients, 33–38 autopsy studies, 24
early recurrent ischemic lesions in, 140–141 external counterpulsation for, 209–210 MCA territory infarction in, 70 symptomatic ICAS in, 37–39 subarachnoid hemorrhage (SAH), 217, 221, 223, 229 subclavian steal, 152 subcortical infarction, 72–74 subthreshold depressive disorder, 107 sudden death, 114, 175 superficial temporal artery (STA), 194 superficial temporal artery-to-middle cerebral artery (STA–MCA) anastomosis, 251–252 superior cerebellar artery (SCA), 13, 94 surgical therapy, 194–201 decompressive craniectomy, 200–201 hemodynamic impairment in, 197–198 indications for, 198–199 intracranial revascularization, 194–196 for posterior circulation ischemia, 198–199 suture MCA occlusion (sMCAO), 143 symptomatic ICAS, 38–39 risk of clinical recurrence, 114 in stroke patients, 37 vascular disease risk in, 114–116 symptomatic occlusive disease, 40 syphilis, 237–238 systemic lupus erythematosus, 218–219. See also immunologic disorders description of, 218 intracranial arterial disease in, 218–219 and moyamoya disease, 247 stroke in, 218 T cells, 207, 247 Taiwan, intracranial atherosclerosis in, 37 Takayasu’s arteritis, 220–221 tandem stenoses, 189–191 tandem stenting, 188–189 territory infarction, 74–75 Thailand intracranial atherosclerosis in, 33 ischemic stroke patients in, 38
BLBK041-Kim
August 18, 2008
11:41
INDEX
thalamus, arterial supply to, 14f thienopyridine drugs, 163, 168 thrombin, 163, 164f thromboangiitis obliterans (TAO), 239 thrombocythemia, 247 thrombosis, 27–28, 58, 65, 120 thrombotic occlusion, 58 thromboxane A2 , 163, 165, 220 thunderclap headache, 222 thyrotoxicosis, 248 ticlopidine, 165, 168 Ticlopidine–Aspirin Stroke Study (TASS), 165 time-of-flight (TOF) sequence, 132 tina (methamphetamine), 221 Tinzaparin in Acute Ischemic Stroke Trial (TAIST), 177 tissue inhibitor of the metalloproteinase (TIMP), 247 TOAST stroke classification, 156 tongue paresis, 86 top of the basilar syndrome, 93 Transcend 14 EX microwire, 186 transcranial color-coded duplex sonography, 148 transcranial Doppler ultrasound (TCD), 147–157 accuracy of, 133 in Alzheimer’s disease studies, 105 applications in intracranial atherosclerosis, 153–157 microembolic signal detection, 153–156 diagnostic criteria, 152–153 intracranial large artery stenosis, 152 middle cerebral artery, 152 examination of intracranial arteries, 149–152 anterior cerebral artery, 150 basilar artery, 151–152 criteria, 149t middle cerebral artery, 150 ophthalmic artery, 151 posterior cerebral artery, 151 siphon internal carotid, 151 vertebral artery, 151 hemodynamic principles, 148–149 flow resistance, 148 flow velocity, 148 turbulent flow, 149
overview of, 147 physical principles, 147–148 continuous wave mode, 148 Doppler effects, 147–148 pulse wave mode, 148 transcranial color-coded duplex sonography, 148 transcranial power motion mode, 148 ultrasound, 147 population-based studies, 36–38 in studies of stroke mechanisms, 57 transcranial power motion mode, 148 transient ischemic attacks (TIAs), 33, 48 and cognitive dysfunction, 101 racial differences in, 38 and risks of cerebral angiography, 127 stenting, 183f tremor, 75, 86, 93 Trial of Cilostazol in Symptomatic Intracranial Stenosis (TOSS), 168–170 Trial of ORG 10172 in Acute Stroke Treatment (TOAST), 177 triglycerides, 119, 207, 219 trisomy 12p syndrome, 247 trochlear nerve, 13 tuberculosis, 235 tuberculous meningitis, 247 tuberous sclerosis, 230 tuna media, 220 turbulent flow, 149 ultrasound, 147 unilateral pontine infarction, 89 vagus nerve, 12 varicella virus, 236 vascular dementia, 104, 108 vascular depression hypothesis, 106 vascular diseases, 114–116 vascular imaging, 127–133. See also magnetic resonance imaging (MRI) catheter angiography, 127–128 CT angiography, 128–131 magnetic resonance angiography, 131–132 transcranial Doppler ultrasound, 133
vascular lesions in distal intracranial territory infarcts, 95–97 in middle intracranial territory ischemia, 89–92 in proximal intracranial territory infarction, 86–87 vasculitis, 219, 235–237 vasoconstriction, 222–224 verapamil, 224 verbal memory, 93 vertebral artery, 11 hypoplasia in, 11 stenosis, 87 stroke mechanisms, 64–65 transcranial Doppler examination of, 151 vertigo, 84, 86, 94 vessel perforation, 188 vessel wall, modulation of, 206–207 vestibular system, abnormalities in, 84 viral infections, 236–237. See also central nervous system (CNS) infection Herpes zoster infection, 236 human immunodeficiency virus, 236–237 vitamin B6, 207 vitamin B12, 207 vulnerable intracranial stenosis, 116–119 extent of, 118 hemodynamic compromise in, 118 location of symptomatic stenosis, 118 microembolic signals, 118–119 plaque composition, 119 progression of, 118 severity of, 116–118 vulnerable intracranial stenosis patients, 119–121 endogenous angiogenic response, 120–121 failure of antithrombotic therapy in, 120 gender, 120 genetic factors, 121 inflammation, 120 metabolic syndrome, 119–120 prothrombotic state, 120 vascular risk factors, 119 vulnerable plaques, 22
267
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INDEX
warfarin, 114, 167–168, 173–176 Warfarin Aspirin Recurrent Stroke Study (WARSS), 168 Warfarin–Aspirin Symptomatic Intracranial Disease (WASID)
268
trial, 41, 49, 114, 120, 128, 168, 174–176, 184, 190t, 197 Watanabe heritable hyperlipidemic (WHHL) rabbits, 23 Weber syndrome, 93
white blood cell, 120 white people, risk for atherosclerosis, 25 Wingspan stent, 182, 187, 189f young adults, atherosclerosis in, 25
